CN110002961B - 一种去外消旋化合成手性醇的方法 - Google Patents
一种去外消旋化合成手性醇的方法 Download PDFInfo
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- CN110002961B CN110002961B CN201910258055.5A CN201910258055A CN110002961B CN 110002961 B CN110002961 B CN 110002961B CN 201910258055 A CN201910258055 A CN 201910258055A CN 110002961 B CN110002961 B CN 110002961B
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- ethyl acetate
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 title abstract description 8
- 238000003786 synthesis reaction Methods 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 106
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 99
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 75
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000003054 catalyst Substances 0.000 claims abstract description 33
- VATRWWPJWVCZTA-UHFFFAOYSA-N 3-oxo-n-[2-(trifluoromethyl)phenyl]butanamide Chemical compound CC(=O)CC(=O)NC1=CC=CC=C1C(F)(F)F VATRWWPJWVCZTA-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000004280 Sodium formate Substances 0.000 claims abstract description 28
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims abstract description 28
- 235000019254 sodium formate Nutrition 0.000 claims abstract description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 150
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 50
- 238000000926 separation method Methods 0.000 claims description 37
- 239000012071 phase Substances 0.000 claims description 28
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 27
- 239000001301 oxygen Substances 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 238000004440 column chromatography Methods 0.000 claims description 25
- 239000012074 organic phase Substances 0.000 claims description 25
- 239000003208 petroleum Substances 0.000 claims description 25
- 238000005406 washing Methods 0.000 claims description 25
- 238000011914 asymmetric synthesis Methods 0.000 claims description 13
- WAPNOHKVXSQRPX-ZETCQYMHSA-N (S)-1-phenylethanol Chemical compound C[C@H](O)C1=CC=CC=C1 WAPNOHKVXSQRPX-ZETCQYMHSA-N 0.000 claims description 6
- WAPNOHKVXSQRPX-UHFFFAOYSA-N 1-phenylethanol Chemical compound CC(O)C1=CC=CC=C1 WAPNOHKVXSQRPX-UHFFFAOYSA-N 0.000 claims description 6
- 238000004817 gas chromatography Methods 0.000 claims description 6
- DZLZSFZSPIUINR-LURJTMIESA-N (1s)-1-(2-bromophenyl)ethanol Chemical compound C[C@H](O)C1=CC=CC=C1Br DZLZSFZSPIUINR-LURJTMIESA-N 0.000 claims description 4
- SXFYVXSOEBCFLV-LURJTMIESA-N (1s)-1-(2-fluorophenyl)ethanol Chemical compound C[C@H](O)C1=CC=CC=C1F SXFYVXSOEBCFLV-LURJTMIESA-N 0.000 claims description 4
- ZUBPFBWAXNCEOG-ZETCQYMHSA-N (1s)-1-(3-methoxyphenyl)ethanol Chemical compound COC1=CC=CC([C@H](C)O)=C1 ZUBPFBWAXNCEOG-ZETCQYMHSA-N 0.000 claims description 4
- IUUULXXWNYKJSL-ZETCQYMHSA-N (1s)-1-(4-methoxyphenyl)ethanol Chemical compound COC1=CC=C([C@H](C)O)C=C1 IUUULXXWNYKJSL-ZETCQYMHSA-N 0.000 claims description 4
- AXRKCRWZRKETCK-VIFPVBQESA-N (1s)-1-naphthalen-2-ylethanol Chemical compound C1=CC=CC2=CC([C@@H](O)C)=CC=C21 AXRKCRWZRKETCK-VIFPVBQESA-N 0.000 claims description 4
- WBIYLDMSLIXZJK-LURJTMIESA-N (1s)-1-(2-aminophenyl)ethanol Chemical compound C[C@H](O)C1=CC=CC=C1N WBIYLDMSLIXZJK-LURJTMIESA-N 0.000 claims description 3
- WBIYLDMSLIXZJK-UHFFFAOYSA-N 1-(2-aminophenyl)ethanol Chemical compound CC(O)C1=CC=CC=C1N WBIYLDMSLIXZJK-UHFFFAOYSA-N 0.000 claims description 2
- DZLZSFZSPIUINR-UHFFFAOYSA-N 1-(2-bromophenyl)ethanol Chemical compound CC(O)C1=CC=CC=C1Br DZLZSFZSPIUINR-UHFFFAOYSA-N 0.000 claims description 2
- SXFYVXSOEBCFLV-UHFFFAOYSA-N 1-(2-fluorophenyl)ethanol Chemical compound CC(O)C1=CC=CC=C1F SXFYVXSOEBCFLV-UHFFFAOYSA-N 0.000 claims description 2
- ZUBPFBWAXNCEOG-UHFFFAOYSA-N 1-(3-methoxyphenyl)ethanol Chemical compound COC1=CC=CC(C(C)O)=C1 ZUBPFBWAXNCEOG-UHFFFAOYSA-N 0.000 claims description 2
- AXRKCRWZRKETCK-UHFFFAOYSA-N 1-naphthalen-2-ylethanol Chemical compound C1=CC=CC2=CC(C(O)C)=CC=C21 AXRKCRWZRKETCK-UHFFFAOYSA-N 0.000 claims description 2
- IUUULXXWNYKJSL-UHFFFAOYSA-N 4-methoxy-alpha-methylbenzyl alcohol Chemical compound COC1=CC=C(C(C)O)C=C1 IUUULXXWNYKJSL-UHFFFAOYSA-N 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims 7
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims 1
- 229910001873 dinitrogen Inorganic materials 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 claims 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 abstract description 7
- 239000000543 intermediate Substances 0.000 abstract description 6
- 229910052751 metal Inorganic materials 0.000 abstract description 5
- 239000002184 metal Substances 0.000 abstract description 5
- 150000002576 ketones Chemical class 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- 238000006356 dehydrogenation reaction Methods 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 230000006340 racemization Effects 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 2
- 239000012327 Ruthenium complex Substances 0.000 abstract description 2
- 150000004985 diamines Chemical class 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000012847 fine chemical Substances 0.000 abstract 1
- 239000011259 mixed solution Substances 0.000 abstract 1
- 239000000758 substrate Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 15
- 238000006467 substitution reaction Methods 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 229920002160 Celluloid Polymers 0.000 description 13
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 13
- 239000008346 aqueous phase Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- -1 diaryl ethylenediamine Chemical compound 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 description 3
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 3
- JAAJQSRLGAYGKZ-JTQLQIEISA-N (1s)-1,2,3,4-tetrahydronaphthalen-1-ol Chemical compound C1=CC=C2[C@@H](O)CCCC2=C1 JAAJQSRLGAYGKZ-JTQLQIEISA-N 0.000 description 2
- YESOPGLEIJQAEF-LURJTMIESA-N (1s)-1-(3-fluorophenyl)ethanol Chemical compound C[C@H](O)C1=CC=CC(F)=C1 YESOPGLEIJQAEF-LURJTMIESA-N 0.000 description 2
- CRJFHXYELTYDSG-LURJTMIESA-N (1s)-1-(4-nitrophenyl)ethanol Chemical compound C[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 CRJFHXYELTYDSG-LURJTMIESA-N 0.000 description 2
- SVCRDVHXRDRHCP-LBPRGKRZSA-N (1s)-1-phenylhexan-1-ol Chemical compound CCCCC[C@H](O)C1=CC=CC=C1 SVCRDVHXRDRHCP-LBPRGKRZSA-N 0.000 description 2
- PPHIIIRFJKDTLG-LURJTMIESA-N (1s)-1-pyridin-2-ylethanol Chemical compound C[C@H](O)C1=CC=CC=N1 PPHIIIRFJKDTLG-LURJTMIESA-N 0.000 description 2
- JGDRELLAZGINQM-ZDUSSCGKSA-N (s)-(2-chlorophenyl)-phenylmethanol Chemical compound C1([C@H](O)C=2C(=CC=CC=2)Cl)=CC=CC=C1 JGDRELLAZGINQM-ZDUSSCGKSA-N 0.000 description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-trimethylbenzene Chemical compound CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical compound CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 229910052741 iridium Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- RLPGNSAFCQVLDC-UHFFFAOYSA-N (2-chlorophenyl)-cyclopentylmethanol Chemical compound C=1C=CC=C(Cl)C=1C(O)C1CCCC1 RLPGNSAFCQVLDC-UHFFFAOYSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- JAAJQSRLGAYGKZ-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-1-ol Chemical compound C1=CC=C2C(O)CCCC2=C1 JAAJQSRLGAYGKZ-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
- CRJFHXYELTYDSG-UHFFFAOYSA-N 1-(4-nitrophenyl)ethanol Chemical compound CC(O)C1=CC=C([N+]([O-])=O)C=C1 CRJFHXYELTYDSG-UHFFFAOYSA-N 0.000 description 1
- PPHIIIRFJKDTLG-UHFFFAOYSA-N 1-pyridin-2-ylethanol Chemical compound CC(O)C1=CC=CC=N1 PPHIIIRFJKDTLG-UHFFFAOYSA-N 0.000 description 1
- JGDRELLAZGINQM-UHFFFAOYSA-N 2-Chlorobenzhydrol Chemical compound C=1C=CC=C(Cl)C=1C(O)C1=CC=CC=C1 JGDRELLAZGINQM-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 238000007294 asymmetric addition reaction Methods 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229930007927 cymene Natural products 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- YUWFEBAXEOLKSG-UHFFFAOYSA-N hexamethylbenzene Chemical compound CC1=C(C)C(C)=C(C)C(C)=C1C YUWFEBAXEOLKSG-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- BEZDDPMMPIDMGJ-UHFFFAOYSA-N pentamethylbenzene Chemical compound CC1=CC(C)=C(C)C(C)=C1C BEZDDPMMPIDMGJ-UHFFFAOYSA-N 0.000 description 1
- WQIQNKQYEUMPBM-UHFFFAOYSA-N pentamethylcyclopentadiene Chemical compound CC1C(C)=C(C)C(C)=C1C WQIQNKQYEUMPBM-UHFFFAOYSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- WPIKUEAGHULWBL-UHFFFAOYSA-N phosphane ruthenium Chemical compound P.P.[Ru].[Ru] WPIKUEAGHULWBL-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
- C07C205/19—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/68—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/18—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/18—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part
- C07C33/20—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part monocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/18—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part
- C07C33/20—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part monocyclic
- C07C33/22—Benzylalcohol; phenethyl alcohol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/40—Halogenated unsaturated alcohols
- C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/40—Halogenated unsaturated alcohols
- C07C33/50—Halogenated unsaturated alcohols containing six-membered aromatic rings and other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
- C07C35/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings
- C07C35/36—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings the condensed ring system being a (4.4.0) system, e.g. naphols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明涉及一种去外消旋化合成手性醇（式I）的方法。本发明所涉及的制备方法为一锅法不对称串联反应，包括步骤1）：外消旋醇（式II）为原料，二丙二醇二甲醚为溶剂，120℃反应12小时，经脱氢反应生成中间体酮（式Ⅲ）；步骤2）：直接向反应体系中加入2.5mol%的手性二胺金属钌络合物作催化剂，5当量的甲酸钠做氢源，甲醇和水的混合溶液为溶剂，在氮气保护下50℃反应12小时，经不对称转移氢化得到手性醇（式I）。该方法具有反应条件简单、温和，步骤经济性、原子经济性等绿色合成优点，而且底物适应范围广，对映选择性高，在合成手性醇类医药中间体以及和精细化工原料方面具有广阔的应用前景。
Description
技术领域
本发明属于绿色合成技术领域，具体涉及一种去外消旋化合成手性醇的方法。
背景技术
手性醇是一种重要的医药中间体和化工原料，通常由酮的不对称还原或者酮与有机金属试剂不对称加成反应来制备，但是有些酮和有机金属试剂合成复杂，不易得到。从简单易得的消旋体醇为起始原料，通过一锅串联反应直接制备手性醇具有原子经济性和步骤经济性等绿色合成的优点。目前报道的去外消旋化合成手性醇的方法有限。比如，通过金属钌络合物催化苯乙醇脱氢为苯乙酮，中间体在手性双膦双胺钌络合物催化下经不对称氢化反应得到手性醇。该方法使用了双金属催化，氢化反应对设备要求高，手性双膦配体价格昂贵且对水和空气敏感 (ChemCommun.,2005,44:5578-9；ChemCommun.,2007,25:2608-9.Chem Asian J.,2007,2:393-396)。
发明内容
一种去消旋化合成手性醇的方法，其特征在于以廉价易得的外消旋醇为原料，采用“两步一锅法”，不需分离纯化中间体，直接合成手性醇；步骤1)：外消旋醇(式II)在溶剂二丙二醇二甲醚中经氧气氧化脱氢得中间体Ⅲ；步骤2)：中间体Ⅲ经不对称转移氢化制备手性醇I。
化合物II，Ar选自:
R是C1-C3烷基、C1-C3烷基氧基、三氟甲基、环已基、环戊基、氟、氯、溴、羟基、硝基、氰基中的任意一种；
上面给出的化合物II的定义中，所用术语不论单独使用还是用在复合词中，代表如下取代基：
卤素：指氟、氯、溴、碘；
烷基：指直链或支链烷基；
卤代烷基：指直链或支链烷基，在这些烷基上的氢原子部分或全部被卤原子取代；
所述步骤1)：氧化脱氢反应的溶剂为四氢呋喃、乙腈、二丙二醇二甲醚、聚乙二醇等，进一步优选为：二丙二醇二甲醚。
所述步骤1)：氧化脱氢反应的温度为120℃，反应时间为16小时；
所述步骤2)：不对称转移氢化反应所用催化剂为(R,R)或(S,S)-N-单磺酰二芳基乙二胺与过渡金属钌、铑、铱的络合物；其结构通式如式V所示，
所述结构通式V中，M为Ru、Rh、Ir；
Ar为苯基或对甲氧基、甲基取代的苯基、萘基；
R为-CH3、-CF3、-C6H5、4-CH3C6H4、4-CF3C6H4、4-(t-Bu)-C6H4-、
3,4-(CH3)2-C6H3-、2,4,6-(CH3)3-C6H2-、2,6-Cl2-C6H3-、2,4,6-(i-Pr)3-C6H2-、C6F5-、或萘基；
L为苯、1,4-二甲基苯、1-甲基-4-异丙基苯、1,3,5-三甲基苯、1,2,3,4,5-
五甲基苯、1,2,3,4,5,6-六甲基苯或五甲基环戊二烯；
X为Cl-、[OTf]-、[PF6]-、[BF4]-、[SbF6]-或手性磷酸阴离子；
所述步骤2)：不对称转移氢化反应所用催化剂，进一步优选结构如下：
所述步骤2)：不对称转移氢化反应所用氢源为甲酸钠、甲酸钾、甲酸/三乙胺的混合物，优选为5当量的甲酸钠；
所述步骤2)：不对称转移氢化反应的温度为25-80℃，进一步优选为50℃。
采用本发明的技术方案具有以下有益效果：脱氢步骤采用氧气为氧化剂，不需要添加金属催化剂；还原步骤采用手性二胺金属络合物催化的不对称转移氢化制备手性醇。手性二胺配体作为一类十分重要的手性配体，较手性膦配体而言，在空气和水存在下更稳定，廉价易得、国内市场有售，而且反应条件温和，不需要高温高压。相比而言，本发明方法更适合工业化应用。
具体实施方式
下面结合具体实施例，对本发明作进一步说明，但本发明并不限于以下实施例。
本发明中所用手性催化剂通用备方法，以催化剂A合成为例： 0.005mmol(S,S)-N-(4-三氟甲基)苯磺酰二苯基乙二胺和 0.0025mmol[Ru(cymene)]2Cl2溶解在0.5毫升二氯甲烷中，加入0.005mmol三乙胺，室温下反应30分钟，水洗，水相用1毫升二氯甲烷萃取3次，合并后浓缩至干得催化剂A，直接用于催化反应。
实施例1：(S)-1-苯基乙醇的不对称合成
将0.5mmol的1-苯乙醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时，用气相色谱检测至反应完全，向反应体系中加入甲酸钠2.5mmol，再加入0.0025mmol催化剂A，加入甲醇：水(3:1)4mL，氮气置换 3次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝10:1)，得到(S)-1-乙醇(54.9mg)，产率为90％，ee值为85％。HPLC分离条件：手性柱大赛璐OD-H柱，流动相：正己烷/异丙醇＝97:3(体积比)，流速：1.0ml/min，波长：254nm，温度，25℃，t1＝11.43 min，t2＝14.82min；1H NMR(400MHz,CDCl3):δ＝7.44-7.38(m,4H),7.34-7.30(m,1H),4.94(q,J＝6.4Hz,1H),2.03(s,1H),1.54(d,J＝6.4Hz,3H),13C NMR(100 MHz,CDCl3):δ＝145.8,128.5,127.5,125.4,70.4,25.2.
实施例2：(S)-1-苯基乙醇的不对称合成
将0.5mmol的1-苯乙醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时，用气相色谱检测至反应完全，向反应体系中加入甲酸钠2.5mmol，再加入0.0025mmol催化剂B，加入甲醇：水(3:1)4mL，氮气置换 3次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝10:1)，得到(S)-1-乙醇(57.3mg)，产率为93％，ee值为95％。
实施例3：(S)-1-苯基乙醇的不对称合成
将0.5mmol的1-苯乙醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时，用气相色谱检测至反应完全，向反应体系中加入甲酸钠2.5mmol，再加入0.0025mmol催化剂C，加入甲醇：水(3:1)4mL，氮气置换 3次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝10:1)，得到(S)-1-乙醇(55.5mg), 产率为91％，ee值为87％。
实施例4：(S)-1-苯基乙醇的不对称合成
将0.5mmol的1-苯乙醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时，用气相色谱检测至反应完全，向反应体系中加入甲酸钠2.5mmol，再加入0.0025mmol催化剂D，加入甲醇：水(3:1)4mL，氮气置换 3次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝10:1)，得到(S)-1-乙醇(21.9mg)，产率为36％，ee值为75％。
实施例5：(S)-1-苯基乙醇的不对称合成
将0.5mmol的1-苯乙醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时，用气相色谱检测至反应完全，向反应体系中加入甲酸钠2.5mmol，再加入0.0025mmol催化剂E，加入甲醇：水(3:1)4mL，氮气置换 3次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝10:1)，得到(S)-1-乙醇(28.7mg)，产率为47％，ee值为71％。
实施例6：(S)-1-(2-氟苯基)乙醇的不对称合成
将0.5mmol的1-(2-氟苯基)乙醇加入到试管中，加入二丙二醇二甲醚1.5 mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠 2.5mmol，再加入0.0025mmol催化剂B，加入甲醇：水(3:1)4mL，氮气置换3 次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝10:1)，得到(S)-1-(2-氟苯基)乙醇 (61.6mg)，产率为88％，ee值为86％。HPLC分离条件：手性柱大赛璐OD-H 柱，流动相：正己烷/异丙醇＝98:2(体积比)，流速：1.0ml/min，波长：254nm，温度，25℃，t1＝11.82min，t2＝12.72min；1H NMR(400MHz,CDCl3):δ＝7.54-7.49 (m,1H),7.31-7.25(m,1H),7.20-7.16(m,1H),7.08-7.03(m,1H),5.22(q,J＝9.2Hz, 1H),2.48(s,1H),1.54(d,J＝6.4Hz,3H).13C NMR(100MHz,CDCl3):δ＝159.7 (d,1JC-F＝243.6Hz),132.7(d,JC-F＝13.2Hz),128.8(d,3JC-F＝8.2Hz),126.6(d, 4JC-F＝4.5Hz),124.3(d,4JC-F＝3.5Hz),115.3,(d,2JC-F＝21.8Hz),64.4(d,4JC-F＝ 3.1Hz),24.0.
实施例7：(S)-1-(2-溴苯基)乙醇的不对称合成
将0.5mmol的1-(2-溴苯基)乙醇加入到试管中，加入二丙二醇二甲醚1.5 mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠 2.5mmol，再加入0.0025mmol催化剂B，加入甲醇：水(3:1)4mL，氮气置换3 次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝10:1)，得到(S)-1-(2-溴苯基)乙醇 (67.3mg)，产率为91％，ee值为88％。HPLC分离条件：手性柱大赛璐OD-H 柱，流动相：正己烷/异丙醇＝97:3(体积比)，流速：1.0ml/min，波长：215nm，温度，25℃，t1＝20.63min，t2＝23.05min；1H NMR(400MHz,CDCl3):δ＝7.61-7.52 (m,2H),7.38-7.34(m,1H),7.17-7.12(m,1H),5.24(q,J＝6.4Hz,1H),2.85(s,1H), 1.48(d,J＝6.4Hz,3H)；13C NMR(100MHz,CDCl3):δ＝144.7,132.6,128.8,127.9, 126.7,121.7,69.1,23.6.
实施例8：(S)-1-(2-氨基苯基)乙醇
将0.5mmol的1-(2-氨基苯基)乙醇加入到试管中，加入二丙二醇二甲醚1.5 mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠 2.5mmol，再加入0.0025mmol催化剂B，加入甲醇：水(3:1)4mL，氮气置换3 次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝10:1)，得到(S)-1-(2-氨基苯基) 乙醇(61.2mg)，产率为90％，ee值为94％。HPLC分离条件：手性柱大赛璐AD-H 柱，流动相：正己烷/异丙醇＝90:10(体积比)，流速：1.0ml/min，波长：254nm，温度，25℃，t1＝10.07min，t2＝11.64min；1HNMR(400MHz,CDCl3):δ＝7.16-7.12 (m,2H),6.83-7.63(m,2H),7.50-7.48(m,2H),4.97(q,J＝6.6Hz,1H),4.22(s,1H), 2.21(s,1H),1.62(d,J＝6.6Hz,3H)；13C NMR(100MHz,CDCl3):δ＝145.1,128.6, 128.4,126.6,118.2,116.7,69.6,21.5.
实施例9：(S)-1-(3-氟苯基)乙醇
将0.5mmol的1-(3-氟苯基)乙醇加入到试管中，加入二丙二醇二甲醚1.5 mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠2.5 mmol，再加入0.0025mmol催化剂B，加入甲醇：水(3:1)4mL，氮气置换3次， 50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝10:1)，得到(S)-1-(3-氟苯基)乙醇 (60.9mg)，产率为87％，ee值为77％。HPLC分离条件：手性柱大赛璐AD-H柱，流动相：正己烷/异丙醇＝95:5(体积比)，流速：1.0ml/min，波长：254nm，温度，25℃，t1＝13.57min，t2＝17.88min；1H NMR(400MHz,CDCl3):δ＝7.37-7.31 (m,1H),7.17-7.11(m,2H),7.02-6.97(m,1H),4.92(q,J＝6.4Hz,1H),2.14(s,1H), 1.52(d,J＝6.4Hz,3H)；13C NMR(100MHz,CDCl3):δ＝163.0(d,1JC-F＝244.2Hz), 148.52(d,3JC-F＝6.5Hz),130.0(d,3JC-F＝8.0Hz),121.0(d,4JC-F＝2.7Hz),114.2(d, 2JC-F＝21.0Hz),112.3,(d,2JC-F＝21.6Hz),69.8(d,4JC-F＝1.8Hz),25.2.
实施例10：(S)-1-(3-甲氧基苯基)乙醇
将0.5mmol的1-(3-甲氧基苯基)乙醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠 2.5mmol，再加入0.0025mmol催化剂B，加入甲醇：水(3:1)4mL，氮气置换3 次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝10:1)，得到(S)-1-(3-甲氧基苯基) 乙醇(71.4mg)，产率为94％，ee值为91％。HPLC分离条件：手性柱大赛璐OD-H 柱，流动相：正己烷/异丙醇＝95:5(体积比)，流速：1.0ml/min，波长：210nm，温度，25℃，t1＝13.94min，t2＝17.90min；1H NMR(400MHz,CDCl3):δ＝7.33-7.24(m,1H),6.99-6.92(m,2H),6.88-6.79(m,1H),4.84(t,J＝6.4Hz,1H),3.82(d,J＝3.6Hz,3H),1.49(dd,J1＝6.8Hz,J2＝3.2Hz)；13C NMR(100MHz,CDCl3):δ＝ 159.7,147.8,129.5,117.8,112.8,110.9,70.1,55.2,25.2.
实施例11：(S)-1-(4-硝基苯基)乙醇
将0.5mmol的1-(4-硝基苯基)乙醇加入到试管中，加入二丙二醇二甲醚1.5 mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠2.5 mmol，再加入0.0025mmol催化剂B，加入甲醇：水(3:1)4mL，氮气置换3次， 50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝10:1)，得到(S)-1-(4-硝基苯基)乙醇 (76.6mg)，产率为87％，ee值为81％。HPLC分离条件：手性柱大赛璐OJ-H柱，流动相：正己烷/异丙醇＝95:5(体积比)，流速：1.0ml/min，波长：254nm，温度，25℃，t1＝36.74min，t2＝41.44min；1H NMR(400MHz,CDCl3):δ＝8.23-8.20(m,2H),7.59-7.55(m,2H),5.04(q,J＝6.8Hz,1H),2.37(s,1H),1.54(d,J＝6.4Hz, 3H).13CNMR(100MHz,CDCl3):δ＝153.2,147.1,126.2,123.8,69.5,25.5.
实施例12：(S)-1-(4-甲氧基苯基)乙醇
将0.5mmol的1-(4-甲氧基苯基)乙醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠 2.5mmol，再加入0.0025mmol催化剂B，加入甲醇：水(3:1)4mL，氮气置换3 次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝10:1)，得到(S)-1-(4-甲氧基苯基) 乙醇(69.2mg)，产率为91％，ee值为93％。HPLC分离条件：手性柱大赛璐OD-H 柱，流动相：正己烷/异丙醇＝95:5(体积比)，流速：1.0ml/min，波长：220nm，温度，25℃，t1＝13.15min，t2＝14.03min；1H NMR(400MHz,CDCl3):δ＝7.34-7.31(m,2H),6.93-6.90(m,2H),4.88(q,J＝6.4Hz,1H),3.84(s,3H),2.23(s,1H),1.50 (d,J＝6.4Hz,3H)；13C NMR(100MHz,CDCl3):δ＝158.9,138.1,126.7,113.8, 69.9,55.3,25.1.
实施例13：(S)-1-(萘-2-基)乙醇
将0.5mmol的1-(萘-2-基)乙醇加入到试管中，加入二丙二醇二甲醚1.5 mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠2.5 mmol，再加入0.0025mmol催化剂B，加入甲醇：水(3:1)4mL，氮气置换3次， 50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝10:1)，得到(S)-1-(萘-2-基)乙醇 (76.5mg)，产率为89％，ee值为90％。HPLC分离条件：手性柱大赛璐AD-H柱，流动相：正己烷/异丙醇＝90:10(体积比)，流速：1.0ml/min，波长：215nm，温度，25℃，t1＝30.37min，t2＝43.52min；1H NMR(400MHz,CDCl3):δ＝7.89-7.45 (m,4H),7.56-7.50(m,3H),5.14-5.08(m,1H),2.09(s,1H),1.63(d,J＝6.4Hz,3H)；13C NMR(100MHz,CDCl3):δ＝143.2,133.3,133.0,128.4,128.0,127.7,126.2, 125.8,123.9,123.8,70.6,25.2.
实施例14：(S)-1-(吡啶-2-基)乙醇
将0.5mmol的1-(吡啶-2-基)乙醇加入到试管中，加入二丙二醇二甲醚1.5 mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠2.5 mmol，再加入0.0025mmol催化剂B，加入甲醇：水(3:1)4mL，氮气置换3次， 50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝2:1)，得到(S)-1-(吡啶-2-基)乙醇 (48.2mg)，产率为79％，ee值为85％。HPLC分离条件：手性柱大赛璐OD-H柱，流动相：正己烷/异丙醇＝49:1(体积比)，流速：0.5ml/min，波长：254nm，温度，25℃，t1＝14.63min，t2＝15.58min；1H NMR(400MHz,CDCl3):δ＝8.53(d,J ＝4.8Hz,1H),7.72-7.67(m,2H),7.32(d,J＝8.0Hz,1H),7.21-7.18(m,1H),4.91(q, J＝6.4Hz,1H),4.61(brs,1H),1.51(d,J＝6.8Hz,3H)；13C NMR(100MHz, CDCl3):δ＝163.3,148.1,136.9,122.2,119.8,69.0,24.2.
实施例15：(S)-1-苯基己烷-1-醇
将0.5mmol的1-1-苯基己烷-1-醇加入到试管中，加入二丙二醇二甲醚1.5 mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠2.5 mmol，再加入0.0025mmol催化剂B，加入甲醇：水(3:1)4mL，氮气置换3次， 50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝2:1)，得到(S)-1-苯基己烷-1-醇(75.7mg)，产率为85％，ee值为83％。HPLC分离条件：手性柱大赛璐OD-H柱，流动相：正己烷/异丙醇＝99:1(体积比)，流速：1.0ml/min，波长：220nm，温度，25℃， t1＝20.67min，t2＝25.71min；1H NMR(400MHz,CDCl3):δ＝7.40-7.37(m,4H), 7.34-7.30(m,1H),4.69(dd,J1＝7.6Hz,J2＝6.0Hz,1H),2.11(s,1H),1.89-1.70(m, 2H),1.50-1.44(m,1H),1.36-1.29(m,5H),0.95-0.91(m,3H)；13C NMR(100MHz, CDCl3):δ＝145.0,128.5,127.5,125.9,100.0,74.7,39.1,31.8,25.6,22.6,14.1.
实施例16：(S)-(2-氯苯基)(苯基)甲醇
将0.5mmol的1-(2-氯苯基)(苯基)甲醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠2.5mmol，再加入0.0025mmol催化剂B，加入甲醇：水(3:1)4mL，氮气置换3次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝2:1)，得到(S)-1-(2-氯苯基) (苯基)甲醇(97.01mg)，产率为89％，ee值为95％。HPLC分离条件：手性柱大赛璐OD-H柱，流动相：正己烷/异丙醇＝95:5(体积比)，流速：1.0ml/min，波长：254nm，温度，25℃，t1＝13.87min，t2＝17.21min；1H NMR(400MHz,CDCl3): δ＝7.67(dd,J1＝7.6Hz,J2＝1.2Hz,1H),7.46-7.44(m,2H),7.41-7.37(m,3H), 7.29-7.25(m,1H),6.28(s,1H),3.51(s,1H)；13C NMR(100MHz,CDCl3):δ＝142.2, 140.9,132.5,129.6,128.8,128.5,128.1,127.8,127.2,127.0,72.7.
实施例17：(S)-(2-氯苯基)(环戊基)甲醇
将0.5mmol的1-(2-氯苯基)(环戊基)甲醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠2.5mmol，再加入0.0025mmol催化剂B，加入甲醇：水(3:1)4mL，氮气置换3次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝2:1)，得到(S)-1-(2-氯苯基)(环戊基)甲醇(67.2mg)，产率为64％，ee值为65％。HPLC分离条件：手性柱大赛璐OD-H柱，流动相：正己烷/异丙醇＝95:5(体积比)，流速：1.0ml/min，波长：254nm，温度，25℃，t1＝19.88min，t2＝21.54min；1H NMR(400MHz, CDCl3):δ＝7.57(dd,J1＝7.6Hz,J2＝1.6Hz,1H),7.38-7.29(m,2H),7.25-7.21(m, 1H),5.02(d,J＝7.6Hz,1H),2.40-2.30(m,1H),1.82-1.50(m,8H),1.39-1.29(m, 1H)；13C NMR(100MHz,CDCl3):δ＝141.8,132.4,129.4,128.4,128.1,128.1,127.0, 73.9,46.5,29.0,28.7,25.6.
实施例18：(S)-1,2,3,4-四氢萘-1-醇
将0.5mmol的1,2,3,4-四氢萘-1-醇加入到试管中，加入二丙二醇二甲醚1.5 mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠2.5 mmol，再加入0.0025mmol催化剂B，加入甲醇：水(3:1)4mL，氮气置换3次， 50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离(石油醚：乙酸乙酯＝2:1)，得到(S)-1,2,3,4-四氢萘-1-醇(66.6mg)，产率为90％，ee值为91％。HPLC分离条件：手性柱大赛璐OD-H柱，流动相：正己烷/异丙醇＝98:2(体积比)，流速：1.0ml/min，波长：254nm，温度，25℃，t1＝7.37min，t2＝7.68min；1H NMR(400MHz,CDCl3):δ＝7.49-7.47(m, 1H),7.26-7.23(m,2H),7.17-7.14(m,1H),4.82(d,J＝4.8Hz,1H),3.5(s,1H), 2.92-2.74(m,2H),2.09-1.94(m,3H),1.85-1.78(m,1H)；13C NMR(100MHz, CDCl3):δ＝138.8,137.2,129.1,128.7,127.6,126.2,68.2,32.3,29.3,18.8. 。
Claims (7)
1.一种(S)-1-苯基乙醇的不对称合成方法，其特征在于，包括如下步骤，
将0.5mmol的1-苯乙醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时，用气相色谱检测至反应完全，向反应体系中加入甲酸钠2.5mmol，再加入0.0025mmol催化剂，加入4mL的甲醇：水的混合液，其中甲醇：水的比例为3:1，氮气置换3次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离，石油醚：乙酸乙酯＝10:1，得到(S)-1-乙醇，所述的催化剂的结构为
中的任意一种。
2.一种(S)-1-(2-氟苯基)乙醇的不对称合成方法，其特征在于，包括如下步骤，将0.5mmol的1-(2-氟苯基)乙醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠2.5mmol，再加入0.0025mmol催化剂
加入4mL的甲醇：水的混合液，其中甲醇：水的比例为3:1，氮气置换3次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离，石油醚：乙酸乙酯＝10:1，得到(S)-1-(2-氟苯基)乙醇。
3.一种(S)-1-(2-溴苯基)乙醇的不对称合成方法，其特征在于，包括如下步骤，将0.5mmol的1-(2-溴苯基)乙醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠2.5mmol，再加入0.0025mmol催化剂
加入4mL的甲醇：水的混合液，其中甲醇：水的比例为3:1，氮气置换3次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离，石油醚：乙酸乙酯＝10:1，得到(S)-1-(2-溴苯基)乙醇。
4.一种(S)-1-(2-氨基苯基)乙醇的不对称合成方法，其特征在于，包括如下步骤，将0.5mmol的1-(2-氨基苯基)乙醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠2.5mmol，再加入0.0025mmol催化剂
加入4mL的甲醇：水的混合液，其中甲醇：水的比例为3:1，氮气置换3次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离，石油醚：乙酸乙酯＝10:1，得到(S)-1-(2-氨基苯基)乙醇。
5.一种(S)-1-(3-甲氧基苯基)乙醇的不对称合成方法，其特征在于，包括如下步骤，将0.5mmol的1-(3-甲氧基苯基)乙醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠2.5mmol，再加入0.0025mmol催化剂
加入4mL的甲醇：水的混合液，其中甲醇：水的比例为3:1，氮气置换3次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离，石油醚：乙酸乙酯＝10:1，得到(S)-1-(3-甲氧基苯基)乙醇。
6.一种(S)-1-(4-甲氧基苯基)乙醇的不对称合成方法，其特征在于，包括如下步骤，将0.5mmol的1-(4-甲氧基苯基)乙醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠2.5mmol，再加入0.0025mmol催化剂
加入4mL的甲醇：水的混合液，其中甲醇：水的比例为3:1，氮气置换3次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离，石油醚：乙酸乙酯＝10:1，得到(S)-1-(4-甲氧基苯基)乙醇。
7.一种(S)-1-(萘-2-基)乙醇的不对称合成方法，其特征在于，包括如下步骤，将0.5mmol的1-(萘-2-基)乙醇加入到试管中，加入二丙二醇二甲醚1.5mmol充入氧气球，120℃反应12小时至反应完全，向反应体系中加入甲酸钠2.5mmol，再加入0.0025mmol催化剂
加入4mL的甲醇：水的混合液，其中甲醇：水的比例为3:1，氮气置换3次，50℃反应12h，反应结束后用水洗，水相用乙酸乙酯萃取3次，合并有机相浓缩至干，柱层析分离，石油醚：乙酸乙酯＝10:1，得到(S)-1-(萘-2-基)乙醇。
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