CN112409253A - 一种催化动力学拆分合成手性α-叔胺的方法 - Google Patents
一种催化动力学拆分合成手性α-叔胺的方法 Download PDFInfo
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- CN112409253A CN112409253A CN202011361366.3A CN202011361366A CN112409253A CN 112409253 A CN112409253 A CN 112409253A CN 202011361366 A CN202011361366 A CN 202011361366A CN 112409253 A CN112409253 A CN 112409253A
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- alkyl
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- 238000000034 method Methods 0.000 title claims abstract description 39
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 22
- 230000003197 catalytic effect Effects 0.000 title abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 126
- 239000003054 catalyst Substances 0.000 claims abstract description 53
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 238000007345 electrophilic aromatic substitution reaction Methods 0.000 claims abstract description 29
- 125000005604 azodicarboxylate group Chemical group 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims description 51
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- -1 2,4, 6-trimethylphenyl Chemical group 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 24
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 21
- 238000005906 dihydroxylation reaction Methods 0.000 claims description 20
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 18
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 13
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 150000007530 organic bases Chemical group 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004650 C1-C8 alkynyl group Chemical group 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical group C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 claims description 2
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003377 acid catalyst Substances 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- 150000004679 hydroxides Chemical class 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 150000003457 sulfones Chemical class 0.000 claims description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims 1
- 150000004703 alkoxides Chemical class 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 26
- 238000001308 synthesis method Methods 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 6
- 230000003321 amplification Effects 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 5
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 184
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 106
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 84
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 82
- 238000004896 high resolution mass spectrometry Methods 0.000 description 55
- 238000005160 1H NMR spectroscopy Methods 0.000 description 53
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 238000004128 high performance liquid chromatography Methods 0.000 description 46
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000007787 solid Substances 0.000 description 37
- 230000035484 reaction time Effects 0.000 description 26
- 238000011084 recovery Methods 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 16
- 238000002390 rotary evaporation Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 12
- FLEHQRTTWKDNGI-XTJILODYSA-N (1s,3r)-5-[(2e)-2-[(7ar)-1-[(2s)-5-(cyclopropylamino)pentan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-2-methylidenecyclohexane-1,3-diol Chemical compound C([C@H](C)C1[C@]2(CCCC(/C2CC1)=C\C=C1C[C@@H](O)C(=C)[C@@H](O)C1)C)CCNC1CC1 FLEHQRTTWKDNGI-XTJILODYSA-N 0.000 description 11
- 102100030613 Carboxypeptidase A1 Human genes 0.000 description 11
- 101000772551 Homo sapiens Carboxypeptidase A1 Proteins 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 102100030614 Carboxypeptidase A2 Human genes 0.000 description 9
- 108091006675 Monovalent cation:proton antiporter-2 Proteins 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 239000003480 eluent Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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
- IRJKSAIGIYODAN-ISLYRVAYSA-N benzyl (ne)-n-phenylmethoxycarbonyliminocarbamate Chemical compound C=1C=CC=CC=1COC(=O)/N=N/C(=O)OCC1=CC=CC=C1 IRJKSAIGIYODAN-ISLYRVAYSA-N 0.000 description 4
- UEYMRBONTZTXQP-UHFFFAOYSA-N benzyl n-(phenylmethoxycarbonylamino)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NNC(=O)OCC1=CC=CC=C1 UEYMRBONTZTXQP-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000005044 dihydroquinolinyl group Chemical class N1(CC=CC2=CC=CC=C12)* 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000007429 general method Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 150000004658 ketimines Chemical class 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 2
- 102100030621 Carboxypeptidase A4 Human genes 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 108091006676 Monovalent cation:proton antiporter-3 Proteins 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
- 229940045803 cuprous chloride Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical group N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- RVCQIGZPOPBKHB-UHFFFAOYSA-N 2,3-dimethyl-2-phenyl-1H-quinoline Chemical compound CC1(NC2=CC=CC=C2C=C1C)C1=CC=CC=C1 RVCQIGZPOPBKHB-UHFFFAOYSA-N 0.000 description 1
- JFIHDQBNPQNPHW-UHFFFAOYSA-N 2-(3-methoxyphenyl)-2-methyl-1H-quinoline Chemical compound COC=1C=C(C=CC1)C1(NC2=CC=CC=C2C=C1)C JFIHDQBNPQNPHW-UHFFFAOYSA-N 0.000 description 1
- QJUOVGFPYHSHOQ-UHFFFAOYSA-N 2-(3-methoxyphenyl)-2-methyl-3,4-dihydro-1H-quinoline Chemical compound CC1(NC2=CC=CC=C2CC1)C1=CC(=CC=C1)OC QJUOVGFPYHSHOQ-UHFFFAOYSA-N 0.000 description 1
- ISTAVHKNASRLBT-UHFFFAOYSA-N 2-(4-chlorophenyl)-2-methyl-3,4-dihydro-1H-quinoline Chemical compound CC1(NC2=CC=CC=C2CC1)C1=CC=C(C=C1)Cl ISTAVHKNASRLBT-UHFFFAOYSA-N 0.000 description 1
- OMCHAYNIPGXHBY-UHFFFAOYSA-N 2-(4-fluorophenyl)-2-methyl-3,4-dihydro-1H-quinoline Chemical compound CC1(NC2=CC=CC=C2CC1)C1=CC=C(C=C1)F OMCHAYNIPGXHBY-UHFFFAOYSA-N 0.000 description 1
- CBVYKOIFFOXQRF-UHFFFAOYSA-N 2-(4-methoxyphenyl)-2-methyl-1H-quinoline Chemical compound COC1=CC=C(C=C1)C1(NC2=CC=CC=C2C=C1)C CBVYKOIFFOXQRF-UHFFFAOYSA-N 0.000 description 1
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- AKAHMVTUFXZQMZ-UHFFFAOYSA-N 2-benzyl-2-phenyl-3,4-dihydro-1H-quinoline Chemical compound C(C1=CC=CC=C1)C1(NC2=CC=CC=C2CC1)C1=CC=CC=C1 AKAHMVTUFXZQMZ-UHFFFAOYSA-N 0.000 description 1
- QKJAZPHKNWSXDF-UHFFFAOYSA-N 2-bromoquinoline Chemical compound C1=CC=CC2=NC(Br)=CC=C21 QKJAZPHKNWSXDF-UHFFFAOYSA-N 0.000 description 1
- FCJUFVWUUWZOGE-UHFFFAOYSA-N 2-ethyl-2-phenyl-3,4-dihydro-1H-quinoline Chemical compound C(C)C1(NC2=CC=CC=C2CC1)C1=CC=CC=C1 FCJUFVWUUWZOGE-UHFFFAOYSA-N 0.000 description 1
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- LEXNGUOWHWSXEZ-UHFFFAOYSA-N 2-methyl-2-(3-methylphenyl)-3,4-dihydro-1H-quinoline Chemical compound CC1(NC2=CC=CC=C2CC1)C1=CC(=CC=C1)C LEXNGUOWHWSXEZ-UHFFFAOYSA-N 0.000 description 1
- WXZKLAQXFWEFFK-UHFFFAOYSA-N 2-methyl-2-(4-methylphenyl)-3,4-dihydro-1H-quinoline Chemical compound CC1(NC2=CC=CC=C2CC1)C1=CC=C(C=C1)C WXZKLAQXFWEFFK-UHFFFAOYSA-N 0.000 description 1
- CKSYUXSZWVPGQC-UHFFFAOYSA-N 2-methyl-2-naphthalen-2-yl-1H-quinoline Chemical compound CC1(NC2=CC=CC=C2C=C1)C1=CC2=CC=CC=C2C=C1 CKSYUXSZWVPGQC-UHFFFAOYSA-N 0.000 description 1
- LEHSYLLKPBZUFE-UHFFFAOYSA-N 2-methyl-2-phenyl-1h-quinoline Chemical compound N1C2=CC=CC=C2C=CC1(C)C1=CC=CC=C1 LEHSYLLKPBZUFE-UHFFFAOYSA-N 0.000 description 1
- OUPNGLJWJPOXKE-UHFFFAOYSA-N 2-methyl-2-phenyl-3,4-dihydro-1H-quinoline Chemical compound CC1(NC2=CC=CC=C2CC1)C1=CC=CC=C1 OUPNGLJWJPOXKE-UHFFFAOYSA-N 0.000 description 1
- YIMQBYQQURXICY-UHFFFAOYSA-N 2-methyl-2-thiophen-3-yl-1H-quinoline Chemical compound CC1(NC2=CC=CC=C2C=C1)C1=CSC=C1 YIMQBYQQURXICY-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
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- RMAPFVXPNODUPG-UHFFFAOYSA-N 4-methoxy-2-methyl-2-phenyl-1H-quinoline Chemical compound COC1=CC(NC2=CC=CC=C12)(C1=CC=CC=C1)C RMAPFVXPNODUPG-UHFFFAOYSA-N 0.000 description 1
- YQQRKUQVFWYEPV-UHFFFAOYSA-N 5,6-dihydrophenanthridine Chemical compound C1=CC=C2CNC3=CC=CC=C3C2=C1 YQQRKUQVFWYEPV-UHFFFAOYSA-N 0.000 description 1
- VBSXGFXEEXRMLA-UHFFFAOYSA-N 6-methyl-6-phenyl-5h-phenanthridine Chemical compound N1C2=CC=CC=C2C2=CC=CC=C2C1(C)C1=CC=CC=C1 VBSXGFXEEXRMLA-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- JSZPAFKNKLZWSH-UHFFFAOYSA-N 9-methoxy-6-methyl-6-phenyl-5H-phenanthridine Chemical compound C=1C(OC)=CC=C2C=1C1=CC=CC=C1NC2(C)C1=CC=CC=C1 JSZPAFKNKLZWSH-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229920002160 Celluloid Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 241000400611 Eucalyptus deanei Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
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- 238000004566 IR spectroscopy Methods 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
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- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- 238000009835 boiling Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 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
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- 238000006481 deamination reaction Methods 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
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- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
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- 239000011737 fluorine Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
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- 150000002500 ions Chemical class 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
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
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- 150000002832 nitroso derivatives Chemical class 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- 229960005017 olanzapine Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000004095 oxindolyl group Chemical class N1(C(CC2=CC=CC=C12)=O)* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical compound C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical class NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 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
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 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
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- GSHFHRJLPDQLAB-UHFFFAOYSA-N tert-butyl 2,3-dimethyl-3-phenyl-7-[phenylmethoxycarbonyl(phenylmethoxycarbonylamino)amino]-2,4-dihydroquinoxaline-1-carboxylate Chemical compound C(C1=CC=CC=C1)OC(=O)N(NC(=O)OCC1=CC=CC=C1)C=1C=C2N(C(C(NC2=CC1)(C1=CC=CC=C1)C)C)C(=O)OC(C)(C)C GSHFHRJLPDQLAB-UHFFFAOYSA-N 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
- 150000003530 tetrahydroquinolines Chemical class 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D267/20—[b, f]-condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
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Abstract
本发明涉及有机化学领域，特别是涉及一种催化动力学拆分合成手性α‑叔胺的方法。本发明提供一种手性α‑叔胺的拆分合成方法，包括：将消旋的式A化合物在催化剂存在的条件下与偶氮二甲酸酯进行不对称亲电芳香取代反应，以提供(R)或(S)构型的式A化合物和与式A化合物相反构型的式C化合物。本发明所提供的手性α‑叔胺的拆分合成方法，具有动力学拆分效果好、反应的底物适用性广、原料易得、催化活性高、反应便于放大，反应操作简单等优点，具有良好的产业化前景。
Description
技术领域
本发明涉及有机化学领域，特别是涉及一种催化动力学拆分合成手性α-叔胺的方法。
背景技术
手性α-叔胺结构广泛存在于具有生理活性的天然产物和药物分子中，是一类重要的有机化合物。然而相较于手性α-仲胺不对称催化合成的快速发展，高效不对称催化合成手性α-叔胺的方法发展仍较为缓慢，其可能的原因是处于氨基α-位的三个基团中由于缺少小立体位阻的氢导致立体区分比较困难，同时该位点较大的立体位阻作用也限制对其的高效合成。目前合成手性α-叔胺的直接方法是碳亲核试剂对酮亚胺的不对称加成反应，但目前该方法受限于需要使用一些较为特殊的酮亚胺底物，例如在α-位连有吸电子基团的活化酮亚胺或者/以及环内endo-型酮亚胺(Chem.Commun.2018,54,10394)。通过碳亲核试剂和偶氮化合物或亚硝基化合物的不对称亲电胺化反应也可应用于α-叔胺的不对称合成，但该方法受限于：1)碳亲核试剂需是一些活泼的底物，例如醛、酮、氧化吲哚、1,3-二羰基化合物等；2)为得到手性α-叔胺，以上反应的产物往往需要经过一步或者多步的官能团转换(Synthesis 2014,46,2983)。
动力学拆分是合成手性化合物的一种实用方法，然而由于胺基较强的亲核性，相比于醇的动力学拆分，胺类化合物的动力学拆分更为困难(Angew.Chem.Int.Ed.2011,50,6012)，特别是对于α-叔胺类底物的动力学拆分，至今仍未有通用的策略被报道。
综上所述，目前发展的不对称合成手性α-叔胺的反应类型较少，底物适用性也存在一些限制。因此，发展一种新颖、高效的不对称催化动力学拆分合成手性α-叔胺的通用方法具有很大的合成意义。
发明内容
鉴于以上所述现有技术的缺点，本发明的目的在于提供一种手性α-叔胺的拆分合成方法，用于解决现有技术中的问题。
为实现上述目的及其他相关目的，本发明提供一种手性α-叔胺的拆分合成方法，包括：
将消旋的式A化合物在催化剂存在的条件下与偶氮二甲酸酯进行不对称亲电芳香取代反应，以提供(R)或(S)构型的式A化合物和与式A化合物相反构型的式C化合物，反应方程式如下：
其中，R1、R2各自独立地选自H，C1-C8烷基，C1-C8烯基，C1-C8炔基，取代基选自卤素、C1-C6烷基、C1-C6烷氧基的取代或未取代的芳基，芳基烷基，杂芳基，-OC(O)R’，R’选自H、C1-C6烷基；
X选自NR”，O，S，C(O)OR”’，C(O)R”’，或不存在，R”选自H，C1-C6烷基，R”’选自C1-C6烷基；
Y选自C，或不存在；
R3、R6各自独立地选自H，C1-C6烷基，C1-C6烷氧基，或与它们所连接的原子一起形成稠合的取代基选自C1-C6烷氧基的取代或未取代的芳基；
R4选自H、C1-C8烷基、芳基、卤素、C1-C6烷氧基；
R5选自C1-C8烷基、芳基、芳基烷基；
所述催化剂选自手性磷酸催化剂。
具体实施方式
为了使本发明的发明目的、技术方案和有益技术效果更加清晰，以下结合实施例对本发明进行进一步详细说明，熟悉此技术的人士可由本说明书所揭露的内容容易地了解本申请发明的其他优点及功效。
本发明发明人经过大量实践研究，意外发现一种通过催化动力学拆分合成手性α-叔胺的方法，所述方法具有反应选择性系数高、底物适用性广、催化效率高、操作简单、成本低廉、环境友好、易于放大等优点，在此基础上完成了本发明。
本发明提供一种手性α-叔胺的拆分合成方法，包括：
将消旋的式A化合物在催化剂存在的条件下与偶氮二甲酸酯进行不对称亲电芳香取代反应，以提供(R)或(S)构型的式A化合物和与式A化合物相反构型的式C化合物：
其中，R1、R2各自独立地选自H，C1-C8烷基，C1-C8烯基，C1-C8炔基，取代基选自卤素、C1-C6烷基、C1-C6烷氧基的取代或未取代的芳基，芳基烷基，杂芳基，-OC(O)R’，R’选自C1-C6烷基；
X选自NR”，O，S，C(O)OR”’，C(O)R”’，或不存在，R”选自H，C1-C6烷基，R”’选自C1-C6烷基；
Y选自C，或不存在；
R3、R6各自独立地选自H，C1-C6烷基，C1-C6烷氧基，或与它们所连接的原子一起形成稠合的取代基选自C1-C6烷氧基的取代或未取代的芳基；
R4选自H、C1-C8烷基、芳基、卤素、C1-C6烷氧基；
R5选自C1-C8烷基、芳基、芳基烷基；
所述催化剂选自手性磷酸催化剂。
本申请中，“烷基”通常指饱和的脂肪族基团，可以是有直链或支链的。例如，C1-C8烷基通常指1个、2个、3个、4个、5个、6个、7个、8个碳原子的烷基基团。具体的烷基基团可以是例如甲基、乙基、丙基、正丙基、异丙基、丁基、正丁基、异丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基等。
本申请中，“烯基”通常指包含在任意位置具有1个以上双键的直链或支链状烃基，可以是有直链或支链的。例如，C1-C8烯基通常指1个、2个、3个、4个、5个、6个、7个、8个碳原子的烯基基团。具体的烯基基团可以是例如乙烯基、烯丙基、丙烯基、异丙烯基、丁烯基、异丁烯基、异戊二烯基(prenyl)、丁二烯基、戊烯基(pentenyl)、异戊烯基、戊二烯基、己烯基、异己烯基、己二烯基、庚烯基、辛烯基等。
本申请中，“炔基”通常指包含在任意位置具有1个以上三键的直链或支链状烃基，可以是有直链或支链的。例如，C1-C8炔基通常指1个、2个、3个、4个、5个、6个、7个、8个碳原子的炔基基团。具体的炔基基团可以是例如乙炔基、丙炔基、丁炔基、戊炔基、己炔基、庚炔基、辛炔基等。
本申请中，“卤素”通常指氟、氯、溴或碘。
本申请中，“烷氧基”表示上述“烷基”键合于氧原子而成的基团。例如，C1-C6烷氧基通常指1个、2个、3个、4个、5个、6个碳原子的烷氧基基团。具体的烷氧基基团可以是例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、异丁氧基、仲丁氧基、戊氧基、异戊氧基、己氧基等。
本申请中，“芳基”通常指具有至少一个芳香环的环体系(例如，单环或双环以上)、且没有杂原子的基团。具体的芳基基团可以是例如苯基、萘基、蒽基、菲基等。本发明中的芳基是可选的至少单取代的5或6元环体系，取代基可以选自卤素、C1-C6烷基、C1-C6烷氧基等，当为多取代时，至少部分的取代基可以与它们相连的原子一起形成稠合于该芳基基团的环体系，例如，杂环烷基(例如，二氧戊环)等。
本申请中，“芳基烷基”通常包含直链或支链的烷基(如上所定义)，该烷基键合于芳基上。具体的芳基烷基基团可以是例如苄基等。
本发明中，“杂芳基”通常指具有至少一个芳族环并且可以任选地含有一个或多个选自N、O的杂原子的杂环体系。具体的杂芳基基团可以是例如呋喃、苯并呋喃、吡咯、吡啶、嘧啶、哒嗪、吡嗪、喹啉、异喹啉、酞嗪、三唑、吡唑、异恶唑、吲哚、苯并三唑、苯并二氧戊环、苯并二恶烷、苯并咪唑、咔唑和喹唑啉等。本发明中的杂芳基是可选的至少单取代的5或6元环体系。
在本发明一具体实施例中，R1选自取代基选自卤素、C1-C6烷基、C1-C6烷氧基的取代或未取代的芳基，杂芳基。
在本发明一具体实施例中，R2选自C1-C8烷基、C1-C8烯基、芳基，芳基烷基。
在本发明一具体实施例中，X选自NR”，O，S，或不存在，R”选自H，C1-C6烷基。
在本发明一具体实施例中，Y选自C，或不存在。
在本发明一具体实施例中，R3、R6各自独立地选自H，C1-C6烷基，C1-C6烷氧基，或与它们所连接的原子一起形成稠合的取代基选自C1-C6烷氧基的取代或未取代的芳基。
在本发明一具体实施例中，R4选自H。
在本发明一具体实施例中，R5选自芳基烷基。
在本发明一更具体的实施例中，所述式A化合物选自化学结构式如下之一所示的化合物：
上述不对称亲电芳香取代反应中，手性磷酸催化剂通常为
酸催化剂，这一类手性磷酸催化剂通常可以具有SPINOL骨架、BINOL骨架、或H8-BINOL骨架等。具体来说，所述手性磷酸催化剂可以选自但不限于化学结构式如下之一所示的化合物，或这些催化剂的对映体：
其中，Rcat1和Rcat2可以为相同的基团，也可以为不同的基团，Rcat1和Rcat2各自独立地选自苯基、2,4,6-三甲基苯基、2,4,6-三环己基苯基、2,4,6-三异丙基苯基、1-萘基、2-萘基、取代或未取代的、单取代或多取代的9-蒽基、取代或未取代的、单取代或多取代的9-菲基，其中，取代基选自C1-C8烷基、C4-C14芳基、C1-C6烷氧基、氨基、卤原子、氰基、-C(O)ORc’，-C(O)Rc’，-OC(O)Rc”、-NC(O)Rc”，其中，Rc’选自C1-C6烷基，Rc”选自H，C1-C6烷基。
上述不对称亲电芳香取代反应中，手性磷酸催化剂的使用量通常可以是催化量的，例如，式A化合物与手性磷酸催化剂的摩尔比可以为1：0.001～0.5、1：0.001～0.01、1：0.01～0.1、1：0.1～0.3、或1：0.3～0.5，在本发明一具体实施例中，式A化合物与手性磷酸催化剂的摩尔比可以为1：0.1～0.02。
上述不对称亲电芳香取代反应中，反应体系中式A化合物的用量相对于偶氮二甲酸酯通常是可以被调整的，从而可以保证反应的转化率、并能够使反应充分正向，例如，式A化合物与偶氮二甲酸酯的摩尔比可以为1：0.5～1.1、1：0.5～0.55、1：0.55～0.6、1：0.6～0.65、1：0.65～0.7、1：0.7～0.75、1：0.75～0.8、1：0.8～0.85、1：0.85～0.9、1：0.9～0.95、1：0.95～1、1：1～1.05、或1：1.05～1.1，在本发明一具体实施例中，式A化合物与偶氮二甲酸酯的摩尔比为1：0.55～0.65。
上述不对称亲电芳香取代反应中，反应通常可以在溶剂存在的条件下进行，不对称亲电芳香取代反应中所使用的溶剂通常可以是非质子溶剂、且通常是反应体系的良溶剂。例如，不对称亲电芳香取代反应中所使用的溶剂具体可以是卤代烷烃类溶剂、芳香类溶剂等，在本发明一具体实施例中，不对称亲电芳香取代反应中所使用的溶剂可以是氯仿、二氯甲烷、甲苯、苯等中的一种或多种的组合。再例如，不对称亲电芳香取代反应中溶剂的使用量可以参照于式A化合物在体系中的浓度，例如，式A化合物在反应体系汇总的浓度可以为0.3～0.005mmol/mL、0.3～0.2mmol/mL、0.2～0.1mmol/mL、0.1～0.05mmol/mL、0.05～0.03mmol/mL、0.03～0.02mmol/mL、0.02～0.0125mmol/mL、或0.0125～0.005mmol/mL，在本发明一具体实施例中，式A化合物在反应体系汇总的浓度可以为0.1～0.0125mmol/mL。
上述不对称亲电芳香取代反应中，反应通常需要在无水条件下进行，其原因主要是由于反应体系中涉及催化剂与式A化合物间形成氢键从而活化A化合物并控制反应的立体选择性。
上述不对称亲电芳香取代反应中，反应通常需要在低温下进行，例如，不对称亲电芳香取代反应的反应温度可以为-80℃～50℃、-80℃～-70℃、-70℃～-60℃、-60℃～-50℃、-50℃～-40℃、-40℃～-30℃、-30℃～-20℃、-20℃～-10℃、-10℃～0℃、0℃～10℃、10℃～20℃、20℃～30℃、30℃～40℃、或40℃～50℃，在本发明一具体实施例中，不对称亲电芳香取代反应的反应温度可以为-40℃～-20℃。本领域技术人员可根据反应进程调整反应时间，例如，可以通过TLC、色谱法等方法判断不对称亲电芳香取代反应的反应进程，再例如，不对称亲电芳香取代反应的反应时间可以为4～240h、4～8h、8～12h、12～24h、12～24h、24～48h、48～72h、72～120h、120～180h、180～240h，在本发明一具体实施例中，不对称亲电芳香取代反应的反应时间可以为12h～120h。
上述不对称亲电芳香取代反应中，本领域技术人员可以选择合适的方法对不对称亲电芳香取代反应的产物进行后处理，例如，不对称亲电芳香取代反应的后处理可以包括：淬灭、脱除溶剂，纯化以提供(R)或(S)构型的式A化合物和与式A化合物相反构型的式C化合物。合适的淬灭方法对于本领域技术人员来说应该是已知的，例如，可以在反应体系中加入适量的碱(例如，三乙胺等)。不对称亲电芳香取代反应中合适的纯化方法对于本领域技术人员来说应该是已知的，例如，可以是柱层析等方法。
本发明所提供的手性α-叔胺的拆分合成方法中，还可以包括：通过式C化合物提供与其相同构型的式A化合物，反应方程式如下所示：
本领域技术人员可选择合适的方法，通过式C化合物提供与其相同构型的式A化合物，例如，所采用的方法具体可以为：将式C化合物在碱存在的条件下进行脱肼基反应，以提供与其相同构型的式A化合物。
上述脱肼基反应中，反应通常在碱存在的条件下进行。合适的碱的种类和使用量对于本领域技术人员来说应该可以是被调整的。例如，脱肼基反应中所使用的碱可以选自有机碱和/或无机碱。再例如，具体的无机碱可以是例如碱金属、碱土金属的氢氧化物和碳酸盐等中的一种或多种的组合，更具体可以为氢化化钾、氢氧化钠、氢氧化锂、碳酸钾、碳酸钠、碳酸锂、碳酸铯等中的一种或多种的组合。再例如，具体的有机碱可以是例如季铵碱、碱金属的醇盐等中的一种或多种的组合，更具体可以为氢氧化四甲基铵、叔丁醇钾、叔丁醇钠、叔丁醇锂、DBU(1,8-二氮杂二环十一碳-7-烯)中的一种或多种的组合。再例如，有机碱优选为季铵碱。
上述脱肼基反应中，反应通常可以在溶剂存在的条件下进行。合适的适用于脱肼基反应的溶剂的种类和使用量对于本领域技术人员来说应该是已知的。例如，脱肼基反应中所使用的溶剂体系可以是单一溶剂，也可以是两种或两种以上溶剂的混合。再例如，脱肼基反应中所使用的溶剂可以是水、醇类溶剂、醚类溶剂、酰胺类溶剂、砜类溶剂、芳香烃类溶剂等中的一种或多种的组合，更具体可以是水、甲醇、乙醇、异丙醇、叔丁醇、正丁醇、异丁醇、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、二甲亚砜、甲苯等中的一种或多种的混合。再例如，脱肼基反应中溶剂的使用量为使底物初始浓度在0.01mol/L～5mol/L、0.01mol/L～0.1mol/L、0.1mol/L～0.5mol/L、0.5mol/L～1mol/L、1mol/L～2mol/L、2mol/L～3mol/L、或3mol/L～5mol/L。
上述脱肼基反应中，反应通常需要在室温或加热条件下进行，例如，脱肼基反应的反应温度可以为室温至溶剂沸点的温度条件，更具体可以为20～100℃、20～30℃、30～40℃、40～50℃、50～60℃、60～70℃、70～80℃、80～90℃、或90～100℃，在本发明一具体实施例中，脱肼基反应的反应温度可以为60～80℃。本领域技术人员可根据反应进程调整反应时间，例如，可以通过TLC、色谱法等方法判断脱肼基反应的反应进程，再例如，脱肼基反应的反应时间可以为4～144h、4～8h、8～12h、12～24h、12～24h、24～48h、48～72h、72～144h，在本发明一具体实施例中，脱肼基反应的反应时间可以为12h～72h。
上述脱肼基反应中，本领域技术人员可以选择合适的方法对脱肼基反应的产物进行后处理，例如，脱肼基反应的后处理可以包括：萃取、脱除溶剂，纯化以提供与化合物C相同构型的式A化合物。脱肼基反应中合适的纯化方法对于本领域技术人员来说应该是已知的，例如，可以是柱层析等方法。
本发明所提供的手性α-叔胺的拆分合成方法，具有以下有益效果：
1、动力学拆分效果好，反应对消旋的底物进行动力学拆分后能以高收率和高对映选择性得到手性产物和手性原料，反应选择性系数(s-factor)可以得到高达259；
2、反应的底物适用性广，对α,α-二取代二氢喹啉、四氢喹啉、5,6-二氢菲啶、1,1-二取代炔丙胺等底物都有优良的拆分效果，手性碳上的基团R1、R2的选择性非常多；
3、原料易得，底物制备通过常规原料进行几步就可以得到高纯度、高光学活性的产物；
4、催化活性高，催化剂用量最低可以降低到0.5mol％以下，并保持很优异的反应效果；
5、反应便于放大，反应操作简单，可以放大到至少克级规模，同时仅用0.5mol％手性磷酸催化剂，有利于工业放大生产。
下面通过实施例对本申请的发明予以进一步说明，但并不因此而限制本申请的范围。
除非另外说明，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)使用黄海HSGF254硅胶板。
硅胶柱层析使用黄海HHGJ-300硅胶(300-400目)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。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，br表示宽峰。在13C NMR中，δ表示化学位移。
通过Agilent 1260手性HPLC仪器和大赛璐IA、IB、IC、ID和IG手性色谱柱测定对映体过量值。
高分辨质谱(HRMS)使用Agilent 6230TOF LC/MS质谱设备，离子源采用ESI。
红外光谱使用ThermoFisher Scientific Nicolet iS7光谱仪设备，单位是cm-1。
实施例1
底物的合成方法：
四氢喹啉底物的第一种合成方法：
在氮气氛围下，向2-溴喹啉(15.0毫摩尔)、芳基硼酸(22.5毫摩尔，1.5当量)和Pd(Ph3P)4(866毫克，0.75毫摩尔，5mol％)的甲苯(105毫升)和甲醇(18毫升)的混合物中加入碳酸钾水溶液(2.5M，18毫升，3.0当量)。在80摄氏度反应2小时后冷却到室温，用乙酸乙酯萃取三次。有机相用无水硫酸钠干燥，旋蒸除去溶剂，石油醚/二氯甲烷柱层析得到2-芳基喹啉S1。
室温下，向2-芳基喹啉S1(7.5毫摩尔)的冰醋酸(50毫升)溶液中一次加入NaBH3CN(15.0毫摩尔，2.0当量)。反应过夜后，旋蒸除去大部分冰醋酸，加入二氯甲烷(50毫升)再加足量饱和碳酸氢钠溶液，快速搅拌30分钟，然后用二氯甲烷萃取3次，合并有机相，无水硫酸钠干燥，旋蒸溶剂，用石油醚/二氯甲烷柱层析得到四氢二芳基喹啉S2。
2-芳基四氢喹啉(7.0毫摩尔)S2溶于30毫升干四氢呋喃中，在-78℃下，滴加正丁基锂(1.6M，11.2毫摩尔，1.6当量)。在同样温度下搅拌1小时后，Boc酸酐(14.0毫摩尔，2.0当量)溶于30毫升的干四氢呋喃的溶液往其中滴加，加完后温度逐渐升到室温，并继续搅拌1小时。反应用饱和碳酸氢钠溶液淬灭，并用乙酸乙酯萃取三次。有机相用无水硫酸钠干燥后，旋蒸溶剂，再把残留物溶于40毫升二氯甲烷，加N,N-二甲基乙二胺(617毫克，0.76毫升，7.0毫摩尔，1.0当量)，搅拌30分钟，然后用饱和食盐水洗3次，有机相用无水硫酸钠干燥，旋蒸溶剂，残留物柱层析(石油醚/乙酸乙酯作为洗脱剂)分出产物S3。
向含-78℃的S3(7.0毫摩尔)的干四氢呋喃20毫升中滴加丁基锂(5.7毫升，1.6M，9.1毫摩尔，1.3当量)。在同样温度下搅拌15分钟后，往其中滴加卤代烃RX(28.0毫摩尔，4.0当量)后，体系逐渐升温到室温，再搅拌1小时。向反应中加入1毫升甲醇淬灭反应，然后加100毫升乙酸乙酯稀释，再用饱和食盐水洗3次。有机相用无水硫酸钠干燥后，旋蒸溶剂，得到的残留物用柱层析分离(石油醚/乙酸乙酯为洗脱剂)得到产物S4。
S4(7.0毫摩尔)溶于二氯甲烷100毫升里，再向其中滴加三氟乙酸(5.3毫升，70毫摩尔，10.0当量)。在室温搅拌6小时后，加入足量饱和碳酸氢钠溶液中和，再用饱和食盐水洗3次。有机相用无水硫酸钠干燥，旋蒸溶剂后柱层析(石油醚/二氯甲烷洗脱剂)得到产物1。
二氢喹啉底物的第一种合成方法：
S1(1.0毫摩尔)溶于干四氢呋喃5毫升，冰水浴冷却下向其中滴加甲基锂(2.5M，1.2毫升，3.0毫摩尔，3.0当量)。在室温下搅拌6小时后，加冰水浴冷却，用饱和氯化铵水溶液淬灭，然后再加入30毫升乙酸乙酯，用饱和食盐水洗两次。有机相用无水硫酸钠干燥，旋蒸溶剂后，柱层析(石油醚/二氯甲烷洗脱剂)得到二氢喹啉产物。
四氢喹啉底物的第二种合成方法：
二氢喹啉底物(0.85毫摩尔)溶于乙酸乙酯4毫升里，加入钯碳催化剂(钯10％，55％水，30毫克，1.5mol％)，在一个大气压的氢气氛围下搅拌室温搅拌3小时。用硅藻土过滤后，柱层析(石油醚/二氯甲烷)得到四氢喹啉产物。
二氢喹啉底物的第二种合成方法：
底物S5经过乙酰化得到S6。在室温和氮气氛围下，S6(2.0克，11.9毫摩尔)溶于70毫升四氢呋喃中，再加入氯化亚铜(236毫克，2.38毫摩尔，0.2当量)、苯胺(1.3毫升，14.3毫摩尔，1.2当量)和三乙胺(2.48毫升，1.8克，17.9毫摩尔，1.5当量)。在63℃搅拌12小时后，冷却到室温，加乙酸乙酯100毫升稀释，用饱和食盐水洗三次，有机相用无水硫酸钠干燥后，旋蒸溶剂，柱层析(石油醚/乙酸乙酯洗脱剂)得到产物S7(1.29克，54％)。
室温氮气氛围下，S7(800毫克，3.97毫摩尔)溶于干四氢呋喃25毫升里，再加入氯化亚铜(512毫克，5.17毫摩尔，1.3当量)。57℃下搅拌12小时后，冷却到室温，用硅藻土过滤，并用80毫升乙酸乙酯洗。旋蒸溶剂后柱层析(石油醚/二氯甲烷洗脱剂)得到产物(136毫克，17％)
炔基-α-叔胺合成方法：
首先，芳基酮和芳基胺在
分子筛的存在下，在甲苯里回流得到N-芳基亚胺S8。氮气氛围下，炔S9(25毫摩尔)溶于干四氢呋喃15毫升。在冰水浴冷却下，向其中滴加正丁基锂(1.6M，15.0毫升，24.0毫摩尔)，在相同温度下继续搅拌30分钟。继续保持冰水浴冷却，并且向反应体系中按顺序加入20.0毫升六甲基磷酰三胺和N-芳基亚胺S8(20.0毫摩尔)。然后反应体系升到室温，并继续搅拌2小时。反应液倒入40毫升饱和氯化铵溶液，用正己烷/乙酸乙酯(5/1)的混合溶剂萃取三次，合并有机相，无水硫酸钠干燥，旋蒸溶剂。
对于R1是TMS(三甲基硅基)的产物，旋蒸除去溶剂后，无需纯化，直接如50毫升甲醇，并加入碳酸钾(6.6克，48毫摩尔)，搅拌直到薄层色谱检测TMS基团完全除去，加入50毫升饱和食盐水，再用乙酸乙酯萃取3次，有机相无水硫酸钠干燥，旋蒸除去溶剂，柱层析的到端炔产物；对于R1非TMS的产物，直接柱层析得到产物。
实施例2
消旋四氢喹啉的动力学拆分
本实施例中使用的手性磷酸催化剂结构如下：
四氢喹啉类底物的动力学拆分的通用方法：
氮气氛围下，消旋底物(0.2毫摩尔)、磷酸催化剂(0.02毫摩尔，10mol％)和
分子筛(100毫克)加入8毫升玻璃瓶内，加入2毫升干燥的氯仿。把带但气球的玻璃瓶放入一定温度的冷浴里搅拌3分钟。再向其中滴加溶解偶氮二甲酸二苄酯(36毫克，0.12毫摩尔，0.6当量)的2毫升干燥氯仿。通过手性高效液相色谱检测发现原料已经转化了大约50％的时候，向反应体系里加入20微升三乙胺淬灭反应。然后经过硅藻土过滤后，二氯甲烷洗硅藻土，旋蒸溶剂，再经柱色谱分离(石油醚/乙酸乙酯40/1到4/1)回收手性原料和胺化的产物。
2-甲基-2-苯基-1,2,3,4-四氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA1，反应温度-40℃，反应时间12小时。
(R)-1a:无色油状液体,20.5mg,回收率46％。1H NMR(400MHz,CDCl3)δ7.58–7.46(m,2H),7.41(td,J＝8.3,7.8,2.1Hz,2H),7.32(t,J＝7.3Hz,1H),7.16(t,J＝7.8Hz,1H),7.03(d,J＝7.4Hz,1H),6.73(dd,J＝9.0,7.0Hz,2H),4.21(s,1H),2.72(dt,J＝16.6,5.0Hz,1H),2.45(ddd,J＝16.3,11.1,5.0Hz,1H),2.33(dt,J＝12.9,4.8Hz,1H),2.03(tdd,J＝13.1,5.0,2.0Hz,1H),1.69(s,3H)。13C NMR(101MHz,CDCl3)δ148.3,143.9,129.3,128.4,127.0,126.4,125.5,120.4,116.7,113.5,55.5,35.4,30.7,24.4。高分辨质谱：(ESI)实测值[M+H]+224.1432,C16H18N+理论值224.1434。[α]D 20＝+218(c 1.0,CHCl3)。HPLC分析，Chiralpak IA柱,正己烷/异丙醇＝97/3,流速1.0mL/min；tR＝5.4min(major),5.9min(minor),95％ee。IR(cm-1):f＝3398,2961,2925,1607,1481,1312,1260,744,699。
3a:淡黄色泡沫状固体,51.4mg,产率49％。1H NMR(400MHz,CDCl3)δ7.43–7.01(m,16H),7.02–6.66(m,2H),6.43(d,J＝8.5Hz,1H),5.07(s,2H),5.03(s,2H),4.14(brs,1H),2.53–2.27(m,1H),2.27–2.00(m,2H),1.76(td,J＝12.0,4.9Hz,1H),1.46(s,3H)。13C NMR(126MHz,CDCl3)δ156.2,148.0,143.3,136.1,135.7,130.8,128.6,128.6,128.5,128.5,128.4,128.2,128.0,127.7(br),126.5,125.5,124.4(br),120.4,113.3,68.2,67.8,55.7,35.1,30.7,24.4。高分辨质谱(ESI)，实测值[M+H]+522.2380,C32H32N3O4 +理论值522.2387。[α]D 20＝-61.8(c 1.0,CHCl3)。HPLC分析，Chiralpak IC柱,正己烷/异丙醇＝70/30,流速1.0mL/min；tR＝17.1min(minor),18.3min(major),91％ee。IR(cm-1):f＝3377,3290,3031,2960,1705,1504,1392,1342,1216,1058,739,696。
2-甲基-2-(4-甲基苯基)-1,2,3,4-四氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA1，反应温度-40℃，反应时间21小时。
(R)-1b:无色油状液体,23.0mg,回收率49％。1H NMR(500MHz,CDCl3)δ7.40–7.29(m,2H),7.21–7.14(m,2H),7.10(t,J＝7.7Hz,1H),6.98(d,J＝7.4Hz,1H),6.72–6.60(m,2H),4.16(brs,1H),2.67(dt,J＝16.5,4.9Hz,1H),2.47–2.40(m,1H),2.39(s,3H),2.26(dt,J＝13.1,5.0Hz,1H),1.97(ddd,J＝13.1,11.0,4.9Hz,1H),1.63(s,3H)。13C NMR(126MHz,CDCl3)δ145.4,144.0,135.9,129.3,129.1,127.0,125.5,120.5,116.7,113.6,55.3,35.5,30.7,24.5,21.0。高分辨质谱：(ESI)实测值[M+H]+238.1587,C17H20N+理论值238.1590。[α]D 20＝+176(c 1.0,CHCl3)。HPLC分析，Chiralpak IA柱,正己烷/异丙醇＝90/10。流速1.0mL/min；tR＝4.4min(major),4.8min(minor),89％ee。IR(cm-1):f＝3408,2920,2853,1608,1455,1375,1312,1260,815,743。
3b:淡黄色泡沫状固体,52.5mg,产率49％。1H NMR(400MHz,CDCl3)δ7.53–7.20(m,12H),7.19–6.82(m,5H),6.55(d,J＝8.6Hz,1H),5.20(s,2H),5.16(s,2H),4.25(s,1H),2.58(d,J＝16.8Hz,1H),2.40–2.25(m,4H),2.18(dt,J＝13.0,4.8Hz,1H),1.88(td,J＝11.9,4.8Hz,1H),1.57(s,3H)。13C NMR(101MHz,CDCl3)δ156.2,145.1,143.3,136.1,136.0,135.7,130.7,129.1,128.6,128.5,128.3,128.2,128.0,125.4,120.4,113.2,67.8,55.4,35.1,30.6,24.4,20.9。高分辨质谱(ESI)实测值，[M+H]+536.2540,C33H34N3O4 +理论值，536.2544。[α]D 20＝-50.0(c 1.0,CHCl3)。HPLC分析Chiralpak IB柱,正己烷/异丙醇＝50/50,流速1.0mL/min；tR＝12.3min(major),14.0min(minor),92％ee。IR(cm-1):f＝3358,3289,2921,2852,1747,1670,1506,1456,1408,1350,1215,757,696。
2-甲基-2-(4-氯苯基)-1,2,3,4-四氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA1，反应温度-50℃，反应时间24小时。
(R)-1c:白色固体,24.2mg,回收率47％。1H NMR(500MHz,CDCl3)δ7.27–7.21(m,2H),7.19–7.14(m,2H),6.96(td,J＝7.7,1.6Hz,1H),6.83(dd,J＝7.6,1.5Hz,1H),6.59–6.48(m,2H),3.95(brs,1H),2.52(dt,J＝16.4,4.6Hz,1H),2.22(ddd,J＝16.5,11.4,5.1Hz,1H),2.09(dt,J＝13.0,4.7Hz,1H),1.82(ddd,J＝13.0,11.4,4.9Hz,1H),1.48(s,3H)。13C NMR(126MHz,CDCl3)δ146.9,143.6,132.2,129.4,128.5,127.2,127.1,120.4,117.0,113.7,55.4,35.4,30.7,24.4。高分辨质谱：(ESI)实测值[M+H]+258.1043,C16H17ClN+理论值258.1044。[α]D 20＝+167(c 1.0,CHCl3)。HPLC分析，Chiralpak IB柱,正己烷/异丙＝95/5,流速1.0mL/min；tR＝7.8min(minor),8.8min(major),91％ee。IR(cm-1):f＝3372,2949,2922,1606,1480,1370,1259,1093,1009,822,746。
3c:淡黄色泡沫状固体,54.8mg,产率49％。1H NMR(500MHz,CDCl3)δ7.45–6.68(m,17H),6.42(d,J＝8.6Hz,1H),5.07(s,2H),5.03(s,2H),4.11(brs,1H),2.50–2.29(m,1H),2.20–2.07(m,1H),2.03(dt,J＝13.0,4.6Hz,1H),1.73(td,J＝12.3,4.8Hz,1H),1.43(s,3H)。13C NMR(126MHz,CDCl3)δ156.2,146.6,142.9,136.1,135.7,132.3,131.0,128.6,128.5,128.5,128.4,128.2,128.1,127.6(br),127.1,125.3(br),120.3,113.4,68.2,67.8,55.5,35.0,30.6,24.2。高分辨质谱(ESI)实测值，[M+H]+556.2000,C32H31ClN3O4 +理论值，556.1998。[α]D 20＝-60.3(c 1.0,CHCl3)。HPLC分析，Chiralpak IB柱,正己烷/异丙醇＝50/50,流速1.0mL/min；tR＝13.2min(major),15.0min(minor),85％ee。IR(cm-1):f＝3374,3289,2959,2927,1705,1504,1394,1217,1058,826,744,695。
2-甲基-2-(4-甲氧基苯基)-1,2,3,4-四氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA1，反应温度-40℃，反应时间17小时。
(R)-1d:白色固体,22.9mg,回收率45％。1H NMR(500MHz,CDCl3)δ7.38–7.29(m,2H),7.05(t,J＝7.6Hz,1H),6.94(d,J＝7.5Hz,1H),6.89–6.81(m,2H),6.67–6.58(m,2H),4.11(s,1H),3.80(s,3H),2.63(dt,J＝16.4,5.0Hz,1H),2.37(ddd,J＝16.3,10.9,5.2Hz,1H),2.18(dt,J＝12.9,5.0Hz,1H),1.91(td,1H),1.58(s,3H)。13C NMR(126MHz,CDCl3)δ158.2,144.0,140.5,129.3,127.0,126.7,120.5,116.7,113.7,113.6,55.3,55.1,35.6,30.7,24.5。高分辨质谱：(ESI)实测值[M+H]+254.1536,C17H20NO+理论值254.1539。[α]D 20＝+212(c 1.0,CHCl3)。HPLC分析：(Chiralpak IA柱),90:10正己烷/异丙醇,流速1.0mL/min；tR＝5.6min(major),6.5min(minor),99.5％ee。IR(cm-1):f＝3398,2956,2927,1607,1510,1481,1311,1245,1179,1033,829,744。
3d:淡黄色泡沫状固体,58.2mg,产率53％。1H NMR(500MHz,CDCl3)δ7.38–7.06(m,13H),6.99(brs,1H),6.87(brs,1H),6.71(d,J＝8.2Hz,2H),6.40(d,J＝8.7Hz,1H),5.06(s,2H),5.02(s,2H),4.10(s,1H),3.64(s,3H),2.51–2.29(m,1H),2.19(t,J＝13.8Hz,1H),2.07–1.95(m,1H),1.72(td,J＝12.0,4.7Hz,1H),1.42(s,3H)。13C NMR(126MHz,CDCl3)δ158.1,156.2,143.3,140.2,136.1,135.7,130.7,128.6,128.6,128.5,128.3,128.2,128.0,127.6(br),126.6,125.2(br),120.3,113.7,113.2,68.1,67.7,55.3,55.2,35.2,30.6,24.4。高分辨质谱：(ESI)实测值[M+H]+552.2490,C33H34N3O5 +理论值552.2493。[α]D 20＝-44.4(c 1.0,CHCl3)。HPLC分析：(Chiralpak IA柱),50:50正己烷/异丙醇,流速1.0mL/min；tR＝10.6min(minor),12.3min(major),88％ee。IR(cm-1):f＝3375,3284,2962,1701,1504,1391,1245,1028,738,696。
2-甲基-2-(4-氟苯基)-1,2,3,4-四氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，偶氮二甲酸二苄酯用1.0当量，催化剂用CPA1，反应温度-50℃，反应时间36小时。
(R)-1e:无色油状液体,23.0mg,回收率48％。1H NMR(500MHz,CDCl3)δ7.42–7.29(m,2H),7.04(td,J＝7.7,1.5Hz,1H),7.01–6.94(m,2H),6.92(d,J＝7.6Hz,1H),6.67–6.55(m,2H),4.09(brs,1H),2.62(dt,J＝16.4,4.7Hz,1H),2.32(ddd,J＝16.2,11.1,5.0Hz,1H),2.17(dt,J＝13.0,4.9Hz,1H),1.90(td,1H),1.57(s,3H)。13C NMR(126MHz,CDCl3)δ161.5(d,J＝245.7Hz),144.1,143.7,129.3,127.2(d,J＝7.6Hz),127.1,120.4,116.9,115.1(d,J＝21.4Hz),113.6,55.3,35.6,30.8,24.4。19F NMR(471MHz,CDCl3)δ-117.1。高分辨质谱：(ESI)实测值[M+H]+242.1336,C16H17FN+理论值242.1340。[α]D 20＝+202(c 1.0,CHCl3)。HPLC分析：(Chiralpak IA柱),90:10正己烷/异丙醇,流速1.0mL/min；tR＝4.8min(major),5.5min(minor),87％ee。IR(cm-1):f＝3371,2946,2925,1600,1504,1480,1311,1260,1227,1160,1131,829,748。
3e:淡黄色泡沫状固体,54.2mg,产率50％。1H NMR(500MHz,CDCl3)δ7.34–7.04(m,13H),6.97(brs,1H),6.90–6.65(m,3H),6.40(d,J＝8.6Hz,1H),5.05(s,2H),5.00(s,2H),4.13(brs,1H),2.51–2.27(m,1H),2.20–2.05(m,1H),2.01(dt,J＝13.0,4.7Hz,1H),1.71(td,J＝12.1,4.8Hz,1H),1.42(s,3H)。13C NMR(126MHz,CDCl3)δ161.5(d,J＝245.7Hz),156.2,143.7,143.7,142.9,136.0,135.6,130.9,128.5,128.4,128.3,128.2,128.0,127.6(br),127.1(d,J＝7.6Hz),125.3(br),120.2,115.1(d,J＝21.4Hz),113.3,68.1,67.7,55.3,35.1,30.6,24.2。19F NMR(471MHz,CDCl3)δ-117.3。高分辨质谱：(ESI)实测值[M+H]+540.2288,C32H31FN3O4 +理论值540.2293。[α]D 20＝-65.0(c 1.0,CHCl3)。HPLC分析：(Chiralpak IA柱),50:50正己烷/异丙醇,流速1.0mL/min；tR＝8.6min(minor),9.9min(major),83％ee。IR(cm-1):f＝3376,3288,2963,2927,1705,1504,1394,1220,1160,1057,738,695。
2-甲基-2-(3-甲基苯基)-1,2,3,4-四氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA1，反应温度-50℃，反应时间36小时。
(R)-1f:无色油状液体,20.6mg,回收率44％。1H NMR(500MHz,CDCl3)δ7.22(t,J＝6.4Hz,3H),7.05(d,J＝7.1Hz,2H),6.94(d,J＝7.4Hz,1H),6.63(t,J＝7.5Hz,2H),4.11(s,1H),2.64(dt,J＝16.4,4.9Hz,1H),2.44–2.31(m,4H),2.23(dt,J＝12.7,5.0Hz,1H),1.92(ddd,J＝12.7,10.9,4.8Hz,1H),1.59(s,3H)。13C NMR(126MHz,CDCl3)δ148.5,144.0,138.0,129.3,128.3,127.3,127.0,126.2,122.7,120.5,116.7,113.6,55.5,35.5,30.7,24.5,21.8。高分辨质谱：(ESI)实测值[M+H]+238.1587,C17H20N+理论值238.1590。[α]D 20＝+210(c 1.0,CHCl3)。HPLC分析：(Chiralpak IB柱),97:3正己烷/异丙醇,流速1.0mL/min；tR＝7.3min(minor),8.1min(major),97％ee。IR(cm-1):f＝3401,2958,2923,1606,1480,1312,1261,1131,785,744,705。
3f:淡黄色泡沫状固体,54.2mg,产率51％。1H NMR(500MHz,CDCl3)δ7.41–7.27(m,10H),7.24–7.14(m,4H),7.14–6.82(m,3H),6.55(d,J＝8.6Hz,1H),5.20(s,2H),5.16(s,2H),4.23(s,1H),2.65–2.46(m,1H),2.40–2.26(m,4H),2.20(dt,J＝13.1,4.9Hz,1H),1.87(td,J＝11.9,4.6Hz,1H),1.57(s,3H)。13C NMR(126MHz,CDCl3)δ156.2,148.1,143.3,138.0,136.1,135.7,130.7,128.7,128.6,128.5,128.4,128.3,128.1,127.3,126.1,122.6,120.4,113.3,68.2,67.8,55.6,35.1,30.6,24.4,21.8。高分辨质谱：(ESI)实测值[M+H]+536.2540,C33H34N3O4 +理论值536.2544。[α]D 20＝-56.1(c 1.0,CHCl3)。HPLC分析：(Chiralpak IA柱),70:30正己烷/异丙醇,流速1.0mL/min；tR＝14.2min(minor),15.1min(major),85％ee。IR(cm-1):f＝3375,3290,2960,2925,1706,1504,1392,1217,1058,738,695。
2-甲基-2-(3-甲氧基苯基)-1,2,3,4-四氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA1，反应温度-40℃，反应时间15小时。
(R)-1g:白色固体,23.3mg,回收率46％。1H NMR(500MHz,CDCl3)δ7.23(td,J＝7.9,1.8Hz,1H),7.06–6.94(m,3H),6.91(d,J＝7.9Hz,1H),6.79–6.71(m,1H),6.66–6.55(m,2H),4.11(s,1H),3.77(brs,3H),2.61(dt,J＝16.4,4.5Hz,1H),2.36(ddd,J＝16.3,10.9,5.1Hz,1H),2.27–2.15(m,1H),1.91(tdd,J＝12.8,4.9,1.8Hz,1H),1.57(s,3H)。13C NMR(126MHz,CDCl3)δ159.7,150.3,143.9,129.4,129.3,127.0,120.5,118.0,116.7,113.6,112.1,111.1,55.6,55.2,35.4,30.6,24.5。高分辨质谱：(ESI)实测值[M+H]+254.1536,C17H20NO+理论值254.1539。[α]D 20＝+221(c 1.0,CHCl3)。HPLC分析：(Chiralpak IA柱),90:10正己烷/异丙醇,流速1.0mL/min；tR＝6.5min(major),7.7min(minor),99％ee。IR(cm-1):f＝3396,2955,2926,1606,1481,1312,1260,1045,745,700。
3g:淡黄色泡沫状固体,58.5mg,产率53％。1H NMR(500MHz,CDCl3)δ7.31–7.05(m,12H),7.05–6.76(m,4H),6.63(dd,J＝8.1,2.5Hz,1H),6.40(d,J＝8.7Hz,1H),5.06(s,2H),5.02(s,2H),4.13(s,1H),3.62(s,3H),2.51–2.26(m,1H),2.26–2.10(m,1H),2.06(dt,J＝12.9,4.8Hz,1H),1.73(td,J＝12.0,4.7Hz,1H),1.42(s,3H)。13C NMR(126MHz,CDCl3)δ159.6,156.2,150.0,143.2,136.1,135.7,130.8,129.5,128.6,128.5,128.4,128.3,128.2,128.0,127.6(br),125.3(br),120.3,117.9,113.2,112.1,111.0,68.1,67.7,55.7,55.2,35.0,30.6,24.3。高分辨质谱：(ESI)实测值[M+H]+552.2485,C33H34N3O5 +理论值552.2493。[α]D 20＝-59.7(c 1.0,CHCl3)。HPLC分析：(Chiralpak IC柱),50:50正己烷/异丙醇,流速1.0mL/min；tR＝11.0min(minor),13.0min(major),84％ee。IR(cm-1):f＝3377,3294,2955,2926,1707,1504,1392,1217,1044,738,696。
2-(苯并[d][1,3]二氧代-5-基)-2-甲基-1,2,3,4-四氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA1，反应温度-50℃，反应时间24小时。
(R)-1h:白色固体,26.1mg,回收率49％。1H NMR(500MHz,CDCl3)δ7.04(t,J＝8.0Hz,1H),6.92(dd,J＝12.3,4.7Hz,2H),6.87(dd,J＝8.2,1.9Hz,1H),6.74(d,J＝8.2Hz,1H),6.66–6.56(m,2H),5.95–5.87(m,2H),4.07(brs,1H),2.62(dt,J＝16.4,4.7Hz,1H),2.39(ddd,J＝16.3,11.2,5.1Hz,1H),2.17(dt,J＝13.0,4.9Hz,1H),1.93–1.82(m,1H),1.56(s,3H)。13C NMR(126MHz,CDCl3)δ147.7,146.0,143.8,142.6,129.3,127.1,120.5,118.7,116.8,113.6,108.0,106.4,101.0,55.5,35.6,30.9,24.4。高分辨质谱：(ESI)实测值[M+H]+268.1326,C17H18NO2 +理论值268.1332。[α]D 20＝+157(c 1.0,CHCl3)。HPLC分析：(Chiralpak IA柱),90:10正己烷/异丙醇,流速1.0mL/min；tR＝6.8min(major),7.3min(minor),92％ee。IR(cm-1):f＝3297,2961,2925,1706,1503,1483,1226,1036,809,739,695。
3h:淡黄色泡沫状固体,53.4mg,产率47％。1H NMR(400MHz,CDCl3)δ7.42–7.23(m,10H),7.17(s,1H),7.06(s,1H),6.98(d,J＝8.7Hz,1H),6.86(d,J＝1.9Hz,1H),6.82(dd,J＝8.1,1.9Hz,1H),6.72(d,J＝8.1Hz,1H),6.51(d,J＝7.7Hz,1H),5.96–5.88(m,2H),5.19(s,2H),5.15(s,2H),4.18(s,1H),2.56(d,J＝17.0Hz,1H),2.33(s,1H),2.12(dt,J＝12.9,4.8Hz,1H),1.89–1.76(m,1H),1.53(s,3H)。13C NMR(101MHz,CDCl3)δ156.2,147.7,146.1,143.1,142.3,136.1,135.7,135.6,130.8,128.7,128.6,128.5,128.3,128.1,120.4,118.6,113.3,108.0,106.3,101.1,68.2,67.8,55.6,35.2,30.9,24.4。高分辨质谱：(ESI)实测值[M+H]+566.2277,C33H32N3O6 +理论值566.2286。[α]D 20＝-60.7(c 1.0,CHCl3)。HPLC分析：(Chiralpak IC柱),50:50正己烷/异丙醇,流速1.0mL/min；tR＝17.0min(minor),18.2min(major),95％ee。IR(cm-1):f＝3369,3297,2961,2925,1706,1503,1483,1226,1036,809,739,695。
2-乙基-2-苯基-1,2,3,4-四氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA1，反应温度-40℃，反应时间20小时。
(R)-1i:白色固体,21.1mg,回收率45％。1H NMR(400MHz,CDCl3)δ7.29–7.17(m,4H),7.14–7.07(m,1H),6.95(td,J＝7.8,1.7Hz,1H),6.84–6.75(m,1H),6.57(dd,J＝8.0,1.2Hz,1H),6.50(td,J＝7.3,1.2Hz,1H),4.17(s,1H),2.48(dt,J＝16.2,4.3Hz,1H),2.22(ddd,J＝16.5,12.1,5.1Hz,1H),2.10(dt,J＝12.9,5.1,3.7Hz,1H),1.94–1.73(m,3H),0.72(t,J＝7.4Hz,3H)。13C NMR(101MHz,CDCl3)δ146.6,144.0,129.3,128.4,127.0,126.3,126.1,121.0,116.7,113.6,58.6,35.5,33.8,24.2,7.8。高分辨质谱：(ESI)实测值[M+H]+238.1588,C17H20N+理论值238.1590。[α]D 20＝+213(c 1.0,CHCl3)。HPLC分析：(Chiralpak IB柱),97:3正己烷/异丙醇,流速1.0mL/min；tR＝6.7min(minor),7.3min(major),98％ee。IR(cm-1):f＝3399,2964,2927,1602,1478,1308,1256,1079,747,703。
3i:淡黄色泡沫状固体,51.6mg,产率49％。1H NMR(400MHz,CDCl3)δ7.35–6.61(m,18H),6.48(d,J＝8.5Hz,1H),5.08(s,2H),5.04(s,2H),4.27(brs,1H),2.52–2.24(m,1H),2.23–2.10(m,1H),2.06(dt,J＝12.9,4.3Hz,1H),1.93–1.70(m,3H),0.69(t,J＝7.4Hz,3H)。13C NMR(126MHz,CDCl3)δ156.2,146.3,143.3,136.1,135.7,130.7,128.7,128.6,128.5,128.4,128.4,128.3,128.1,127.7(br),126.4,126.0,125.2(br),120.9,113.4,68.2,67.8,58.7,35.5,33.4,24.1,7.8。高分辨质谱：(ESI)实测值[M+H]+536.2541,C33H34N3O4 +理论值536.2544。[α]D 20＝-56.9(c 1.0,CHCl3)。HPLC分析：(Chiralpak IA柱),70:30正己烷/异丙醇,流速1.0mL/min；tR＝14.4min(major),16.8min(minor),83％ee。IR(cm-1):f＝3383,3287,2961,2931,1706,1504,1392,1301,1217,1060,750,696。
2-烯丙基-2-苯基-1,2,3,4-四氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA1，反应温度-40℃，反应时间17小时。
(S)-1j:白色固体,23.5mg,回收率47％。1H NMR(400MHz,CDCl3)δ7.39–7.22(m,4H),7.22–7.11(m,1H),7.01(t,J＝7.6Hz,1H),6.86(d,J＝7.4Hz,1H),6.68–6.49(m,2H),5.46(dtd,J＝17.3,9.8,5.0Hz,1H),5.21–4.99(m,2H),4.34(brs,1H),2.83(dd,J＝13.7,5.0Hz,1H),2.61–2.37(m,2H),2.33–2.17(m,2H),1.93(td,J＝12.9,12.3,4.8Hz,1H)。13CNMR(101MHz,CDCl3)δ146.3,143.7,133.5,129.2,128.5,127.1,126.4,126.1,120.7,119.4,116.7,113.5,57.4,47.9,34.4,24.1。高分辨质谱：(ESI)实测值[M+H]+250.1587,C18H20N+理论值250.1590。[α]D 20＝+132(c 1.0,CHCl3)。HPLC分析：(Chiralpak IB柱),95:5正己烷/异丙醇,流速1.0mL/min；tR＝5.1min(minor),5.6min(major),92％ee。IR(cm-1):f＝3402,2928,2915,1606,1481,1444,1314,915,744,702。
3j:淡黄色泡沫状固体,57.8mg,产率53％。1H NMR(500MHz,CDCl3)δ7.43–7.04(m,16H),6.98(brs,1H),6.85(brs,1H),6.44(d,J＝8.7Hz,1H),5.44–5.27(m,1H),5.20–4.86(m,6H),4.35(s,1H),2.73(dd,J＝13.7,5.0Hz,1H),2.47–2.23(m,2H),2.20–2.00(m,2H),1.80(td,J＝13.7,7.3Hz,1H)。13C NMR(126MHz,CDCl3)δ156.2,145.9,143.0,136.1,135.7,133.3,130.7,128.6,128.6,128.5,128.3,128.2,128.0,127.7(br),126.5,126.0,125.2(br),120.6,119.5,113.2,68.1,67.8,57.5,47.8,34.0,23.9。高分辨质谱：(ESI)实测值[M+H]+548.2537,C34H34N3O4 +理论值548.2544。[α]D 20＝-41.5(c 1.0,CHCl3)。HPLC分析：(Chiralpak IG柱),60:40hexanes:isopropanol,流速1.0mL/min；tR＝17.2min(minor),20.0min(major),85％ee。IR(cm-1):f＝3373,3287,3031,2930,1707,1504,1392,1298,1218,1057,737,695。
2-苄基-2-苯基-1,2,3,4-四氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA1，反应温度-40℃，反应时间16小时。
(S)-1k:白色固体,29.7mg,回收率50％。1H NMR(500MHz,CDCl3)δ7.34–7.12(m,8H),7.03(t,J＝7.6Hz,1H),6.90(d,J＝7.3Hz,1H),6.86–6.78(m,2H),6.67–6.52(m,2H),4.18(brs,1H),3.38(d,J＝13.1Hz,1H),3.05(d,J＝13.1Hz,1H),2.64(dt,J＝16.2,4.2Hz,1H),2.50(ddd,J＝12.8,5.3,3.2Hz,1H),2.35(ddd,J＝16.8,12.1,5.2Hz,1H),2.10(td,J＝12.4,5.0Hz,1H)。13C NMR(126MHz,CDCl3)δ145.7,143.6,136.2,130.6,129.3,128.4,128.1,127.0,126.8,126.6,126.5,120.9,116.9,113.8,58.6,49.8,34.7,24.2。高分辨质谱：(ESI)实测值[M+H]+300.1743,C22H22N+理论值300.1747。[α]D 20＝+120(c 1.0,CHCl3)。HPLC分析：(Chiralpak IB柱),95:5正己烷/异丙醇,流速1.0mL/min；tR＝6.3min(minor),7.0min(major),89％ee。IR(cm-1):f＝3418,2960,2921,1606,1478,1313,1123,1080,1029,774,747,701。
3k:淡黄色泡沫状固体,59.4mg,产率50％。1H NMR(400MHz,CDCl3)δ7.38–6.99(m,19H),6.93(brs,1H),6.85(brs,1H),6.67(d,J＝7.0Hz,2H),6.35(d,J＝8.5Hz,1H),5.04(s,2H),5.00(s,2H),4.16(s,1H),3.22(d,J＝13.0Hz,1H),2.87(d,J＝13.1Hz,1H),2.54–2.25(m,2H),2.25–2.02(m,1H),1.90(td,J＝12.7,4.8Hz,1H)。13C NMR(126MHz,CDCl3)δ156.2,145.4,142.9,136.1,135.9,135.7,130.9,130.5,128.6,128.5,128.4,128.2,128.1,127.6(br),126.8,126.7,126.5,125.1(br),120.8,113.5,68.1,67.8,58.7,49.6,34.2,24.1。高分辨质谱：(ESI)实测值[M+H]+598.2695,C38H36N3O4 +理论值598.2700。[α]D 20＝-49.4(c 1.0,CHCl3)。HPLC分析：(Chiralpak IA柱),60:40正己烷/异丙醇,流速1.0mL/min；tR＝11.1min(minor),16.5min(major),90％ee。IR(cm-1):f＝3374,3286,3029,2927,1707,1504,1391,1299,1216,1056,749,696。
实施例3
消旋二氢喹啉的动力学拆分
本实施例中使用到的手性磷酸催化剂结构如下：
二氢喹啉类底物的动力学拆分的通用方法：
氮气氛围下，消旋底物(0.2毫摩尔)、磷酸催化剂(0.02毫摩尔，10mol％)和
分子筛(100毫克)加入8毫升玻璃瓶内，加入2毫升干燥的氯仿。把带但气球的玻璃瓶放入一定温度的冷浴里搅拌3分钟。再向其中滴加溶解偶氮二甲酸二苄酯(36毫克，0.12毫摩尔，0.6当量)的2毫升干燥氯仿。通过手性高效液相色谱检测发现原料已经转化了大约50％的时候，向反应体系里加入20微升三乙胺淬灭反应。然后经过硅藻土过滤后，二氯甲烷洗硅藻土，旋蒸溶剂，再经柱色谱分离(石油醚/乙酸乙酯40/1到4/1)回收手性原料和胺化的产物。
2-甲基-2-苯基-1,2-二氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA2，反应温度-40℃，反应时间18小时。
(R)-1l:无色油状液体,21.8mg,回收率49％。1H NMR(500MHz,CDCl3)δ7.59–7.48(m,2H),7.34(t,J＝7.7Hz,2H),7.26–7.20(m,1H),7.00(td,J＝7.6,1.5Hz,1H),6.91(dd,J＝7.3,1.5Hz,1H),6.60(td,J＝7.4,1.1Hz,1H),6.45(d,J＝7.9Hz,1H),6.34(d,J＝9.7Hz,1H),5.60(d,J＝9.7Hz,1H),4.04(brs,1H),1.73(s,3H)。13C NMR(126MHz,CDCl3)δ149.1,142.7,129.9,129.0,128.1,127.0,126.9,125.5,123.5,119.2,117.3,112.5,57.5,30.3。高分辨质谱：(ESI)实测值[M+H]+300.1743,C22H22N+理论值300.1747。高分辨质谱：(ESI)实测值[M+H]+222.1274,C16H16N+理论值222.1277。[α]D 20＝+339(c 1.0,CHCl3)。HPLC分析：(Chiralpak IA柱),95:5正己烷/异丙醇,流速1.0mL/min；tR＝5.9min(major),6.4min(minor),98％ee。IR(cm-1):f＝3384,3030,2968,1603,1470,1317,1234,1126,1027,741,696。
3l:淡黄色泡沫状固体,52.3mg,产率50％.1H NMR(500MHz,CDCl3)δ7.43(d,J＝1.5Hz,1H),7.41(s,1H),7.33–7.10(m,13H),7.07–6.65(m,3H),6.29(d,J＝9.0Hz,1H),6.20(d,J＝9.7Hz,1H),5.51(d,J＝9.7Hz,1H),5.11(s,2H),5.08(s,2H),4.04(s,1H),1.64(s,3H)。13C NMR(126MHz,CDCl3)δ156.2,148.8,141.9,136.1,135.7,131.3,130.2,128.6,128.5,128.5,128.4,128.3,128.1,127.9(br),127.0,125.5,125.0(br),122.9,119.0,112.2,68.3,67.9,57.6,30.3。高分辨质谱：(ESI)实测值[M+H]+520.2226,C32H30N3O4 +理论值520.2231。[α]D 20＝-94.5(c1.0,CHCl3)。HPLC分析：(Chiralpak IB柱),50:50正己烷/异丙醇,流速1.0mL/min；tR＝8.6min(major),10.6min(minor),96％ee。IR(cm-1):f＝3369,3284,3032,2962,1705,1497,1397,1341,1219,1165,1027,755,733,695。
2-(4-甲氧基苯基)-2-甲基-1,2-二氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA2，反应温度-40℃，反应时间18小时。
(R)-1m:白色固体,25.1mg,回收率50％。1H NMR(500MHz,CDCl3)δ7.48–7.41(m,2H),6.98(td,J＝7.7,1.5Hz,1H),6.90(dd,J＝7.5,1.5Hz,1H),6.88–6.83(m,2H),6.58(td,J＝7.4,1.1Hz,1H),6.42(d,J＝7.9Hz,1H),6.32(d,J＝9.7Hz,1H),5.55(d,J＝9.7Hz,1H),3.99(s,1H),3.79(s,3H),1.70(s,3H)。13C NMR(126MHz,CDCl3)δ158.5,142.7,141.5,130.2,129.0,126.9,126.8,123.2,119.2,117.2,113.7,112.4,57.0,55.4,30.2。高分辨质谱：(ESI)实测值[M+H]+252.1381,C17H18NO+理论值252.1383。[α]D 20＝+195(c 1.0,CHCl3)。HPLC分析：(Chiralpak IA柱),90:10正己烷/异丙醇,流速1.0mL/min；tR＝6.9min(major),7.8min(minor),95％ee。IR(cm-1):f＝3355,3032,2966,1639,1599,1465,1233,1178,1114,1019,806,775,745,643。
3m:淡黄色泡沫状固体,54.4mg,产率50％.1H NMR(500MHz,CDCl3)δ7.30(d,J＝8.8Hz,2H),7.27–7.05(m,11H),6.90(brs,2H),6.74(d,J＝8.8Hz,2H),6.21(d,J＝8.4Hz,1H),6.17–5.97(m,1H),5.43(d,J＝9.8Hz,1H),5.07(s,2H),5.03(s,2H),4.02(s,1H),3.66(s,3H),1.57(s,3H)。13C NMR(126MHz,CDCl3)δ158.5,156.2,141.9,141.2,136.1,135.7,131.2,130.5,128.6,128.5,128.4,128.2,128.1,127.8(br),126.8,124.9(br),122.6,118.9,113.7,112.1,68.2,67.8,57.1,55.3,30.2。高分辨质谱：(ESI)实测值[M+H]+550.2327,C33H32N3O5 +理论值550.2336。[α]D 20＝-92.7(c 1.0,CHCl3)。HPLC分析：(ChiralpakIB柱),50:50正己烷/异丙醇,流速1.0mL/min；tR＝9.8min(major),11.6min(minor),95％ee。IR(cm-1):f＝3387,3278,3034,2961,1745,1666,1499,1409,1347,1221,1168,1029,823,750,696。
2-(3-甲氧基苯基)-2-甲基-1,2-二氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA2，反应温度-40℃，反应时间16小时。
(R)-1n:白色固体,24.1mg,回收率48％。1H NMR(500MHz,CDCl3)δ7.26(t,J＝8.1Hz,1H),7.13–7.06(m,2H),6.99(td,J＝7.7,1.5Hz,1H),6.90(dd,J＝7.4,1.5Hz,1H),6.77(ddd,J＝8.2,2.6,0.9Hz,1H),6.59(td,J＝7.4,1.1Hz,1H),6.45(d,J＝7.9Hz,1H),6.33(d,J＝9.6Hz,1H),5.59(d,J＝9.7Hz,1H),4.04(brs,1H),3.78(s,3H),1.71(s,3H)。13CNMR(126MHz,CDCl3)δ159.7,150.8,142.7,129.8,129.5,129.0,127.0,123.6,119.3,117.8,117.4,112.5,112.0,111.8,57.5,55.3,30.3。高分辨质谱：(ESI)实测值[M+H]+252.1380,C17H18NO+理论值252.1383。[α]D 20＝+311(c 1.0,CHCl3)。HPLC分析：(ChiralpakIA柱),90:10正己烷/异丙醇,流速1.0mL/min；tR＝6.6min(minor),7.0min(major),99％ee。IR(cm-1):f＝3381,3005,2965,1062,1470,1317,1251,1042,742,697。
3n:淡黄色泡沫状固体,53.7mg,产率49％。1H NMR(500MHz,CDCl3)δ7.34–7.04(m,12H),7.03–6.74(m,4H),6.66(dd,J＝8.1,2.5Hz,1H),6.24(d,J＝8.9Hz,1H),6.18–5.98(m,1H),5.47(d,J＝9.7Hz,1H),5.07(s,2H),5.03(s,2H),4.07(s,1H),3.65(s,3H),1.57(s,3H)。13C NMR(126MHz,CDCl3)δ159.7,156.2,150.5,141.9,136.1,135.7,129.5,128.6,128.6,128.5,128.4,128.2,128.1,127.8(br),124.1(br),123.0,119.0,117.8,112.2,112.0,111.8,68.2,67.8,57.6,55.3,30.3。高分辨质谱：(ESI)实测值[M+H]+550.2319,C33H32N3O4 +理论值550.2336。[α]D 20＝-102(c 1.0,CHCl3)。HPLC分析：(Chiralpak IC柱),50:50正己烷/异丙醇,流速1.0mL/min；tR＝12.7min(major),15.2min(minor),96％ee。IR(cm-1):f＝3386,3285,3035,2968,1745,1667,1606,1500,1412,1349,1219,1169,1040,779,756,639,698。
2-甲基-2-(2-萘基)-1,2-二氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA2，反应温度-40℃，反应时间28小时。
(R)-1o:黄色油状液体,24.0mg,回收率44％。1H NMR(500MHz,CDCl3)δ7.90(d,J＝1.9Hz,1H),7.88–7.80(m,3H),7.76(dd,J＝8.7,1.9Hz,1H),7.53–7.46(m,2H),7.05(td,J＝7.7,1.5Hz,1H),6.96(dd,J＝7.4,1.5Hz,1H),6.64(td,J＝7.4,1.1Hz,1H),6.50(d,J＝7.9Hz,1H),6.41(d,J＝9.7Hz,1H),5.69(d,J＝9.7Hz,1H),4.13(s,1H),1.85(s,3H)。13CNMR(126MHz,CDCl3)δ146.1,142.7,133.2,132.4,129.7,129.1,128.4,128.4,127.6,127.1,126.3,126.0,124.8,123.8,123.3,119.3,117.4,112.6,57.6,30.2。高分辨质谱：(ESI)实测值[M+H]+,C20H18N+272.1429理论值272.1434。[α]D 20＝+350(c 1.0,CHCl3)。HPLC分析：(Chiralpak IA柱),90:10正己烷/异丙醇,流速1.0mL/min；tR＝7.1min(major),7.8min(minor),99％ee。IR(cm-1):f＝3386,3053,2968,1600,1470,1318,1127,817,792,740。
3o:黄色泡沫状固体,56.4mg,产率49％。1H NMR(400MHz,CDCl3)δ7.89–7.75(m,4H),7.71(dd,J＝8.6,1.9Hz,1H),7.54–7.41(m,2H),7.41–7.24(m,9H),7.18–6.70(m,3H),6.58–6.10(m,2H),5.66(s,1H),5.20(s,2H),5.17(s,3H),4.23(brs,1H),1.83(s,3H)。13CNMR(101MHz,CDCl3)δ156.2,145.8,141.9,136.0,135.7,133.1,132.4,131.3,130.0,128.6,128.5,128.4,128.4,128.2,128.1,127.8,127.6,126.3,126.1,124.8,123.3,118.9,112.2,68.2,67.8,57.8,30.2。高分辨质谱：(ESI)实测值[M+H]+,C36H32N3O4 +570.2377理论值570.2387。[α]D 20＝-80.8(c1.0,CHCl3)。HPLC分析：(Chiralpak ID柱),50:50正己烷/异丙醇,流速1.0mL/min；tR＝16.3min(minor),20.3min(major),92％ee。IR(cm-1):f＝3359,3287,3032,2964,1705,1497,1392,1222,1163,1057,818,744,695。
2-甲基-2-(3-噻吩基)-1,2-二氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA3，反应温度-20℃，反应时间36小时。
(R)-1p:黄色油状液体,18.7mg,回收率41％。1H NMR(500MHz,CDCl3)δ7.28(dd,J＝5.1,2.9Hz,1H),7.20(dd,J＝5.1,1.4Hz,1H),7.16(dd,J＝3.0,1.4Hz,1H),7.02(td,J＝7.6,1.6Hz,1H),6.95(dd,J＝7.4,1.5Hz,1H),6.64(t,J＝7.4Hz,1H),6.44(d,J＝7.9Hz,1H),6.37(d,J＝9.7Hz,1H),5.60(d,J＝9.6Hz,1H),4.06(s,1H),1.74(s,3H)。13C NMR(126MHz,CDCl3)δ150.7,142.6,129.5,129.0,127.0,126.3,126.2,123.6,119.5,119.4,117.5,112.6,55.6,30.5。高分辨质谱：(ESI)实测值[M+H]+228.0839,C14H14NS+理论值228.0841。[α]D 20＝+240(c 1.0,CHCl3)。HPLC分析：(Chiralpak IA柱),90:10正己烷/异丙醇,流速1.0mL/min；tR＝5.7min(major),6.3min(minor),87％ee。IR(cm-1):f＝3377,3031,2964,1602,1469,1316,1126,1083,857,776,742,652。
3p:黄色泡沫状固体,49.2mg,产率47％.1H NMR(500MHz,CDCl3)δ7.19(d,J＝6.7Hz,12H),7.03(d,J＝5.1Hz,1H),6.99(d,J＝3.0Hz,1H),6.96–6.67(m,2H),6.18(dd,J＝26.5,9.1Hz,2H),5.44(d,J＝9.7Hz,1H),5.07(s,2H),5.03(s,2H),4.06(s,1H),1.58(s,3H)。13C NMR(126MHz,CDCl3)δ156.2,150.4,141.8,136.0,135.7,131.4,129.8,128.6,128.5,128.4,128.2,128.1,127.8,126.3,126.2,123.0,119.6,119.1,112.3,68.2,67.8,55.7,30.5。高分辨质谱：(ESI)实测值[M+H]+526.1788,C30H28N3O4S+理论值526.1795。[α]D 20＝-68.1(c 1.0,CHCl3)。HPLC分析：(Chiralpak IB柱),50:50正己烷/异丙醇,流速1.0mL/min；tR＝11.0min(major),13.3min(minor),97％ee。IR(cm-1):f＝3356,3278,3032,2962,1705,1497,1393,1217,1163,1057,779,734,695,656。
2-异丁基-2-甲基-1,2-二氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA3，反应温度-40℃，反应时间18小时。
(S)-1q:无色油状液体,17.1mg,回收率43％。1H NMR(400MHz,CDCl3)δ6.94(td,J＝7.6,1.6Hz,1H),6.85(dd,J＝7.3,1.5Hz,1H),6.53(t,J＝7.4Hz,1H),6.35(d,J＝7.9Hz,1H),6.26(d,J＝9.8Hz,1H),5.39(d,J＝9.8Hz,1H),3.50(s,1H),2.00–1.86(m,1H),1.50–1.34(m,2H),1.27(s,3H),0.95(d,J＝6.7Hz,6H)。13C NMR(126MHz,CDCl3)δ143.5,130.3,128.7,126.7,124.1,119.6,116.8,112.3,55.7,53.0,31.6,25.0,24.7,24.6。高分辨质谱：(ESI)实测值[M+H]+202.1585,C14H20N+理论值202.1590。[α]D 20＝+7.7(c 1.0,CHCl3)。HPLC分析：(Chiralpak IB柱),99:1正己烷/异丙醇,流速1.0mL/min；tR＝5.9min(minor),6.3min(major),92％ee。IR(cm-1):f＝3366,3032,2953,1705,1498,1394,1219,1162,1059,734,695。
3q:黄色泡沫状固体,45.4mg,产率45％。1H NMR(500MHz,CDCl3)δ7.43–7.01(m,11H),7.00–6.56(m,2H),6.29–5.91(m,2H),5.30(s,1H),5.09(s,2H),5.05(s,2H),3.51(s,1H),1.90–1.77(m,1H),1.40–1.24(m,2H),1.16(s,3H),0.85(d,J＝6.7Hz,6H)。13C NMR(126MHz,CDCl3)δ156.2,142.8,136.1,135.7,128.6,128.5,128.4,128.3,128.1,127.7,127.6,124.7,123.6,119.3,111.9,68.2,67.8,55.9,53.1,31.8,24.9,24.6,24.5。高分辨质谱：(ESI)实测值[M+H]+500.2531,C32H34N3O4 +理论值500.2544。[α]D 20＝-4.1(c 1.0,CHCl3)。HPLC分析：(Chiralpak IB柱),60:40正己烷/异丙醇,流速1.0mL/min；tR＝9.7min(major),12.2min(minor),93％ee。IR(cm-1):f＝3365,3285,3033,2952,1705,1498,1391,1339,1220,1161,1059,733,695。
2,3-二甲基-2-苯基-1,2-二氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA2，反应温度-40℃，反应时间16小时。
(R)-1r:无色油状液体,21.9mg,回收率47％。1H NMR(500MHz,CDCl3)δ7.63(d,J＝7.0Hz,2H),7.37(t,J＝7.8Hz,2H),7.28(t,J＝7.5Hz,1H),6.97(td,J＝7.7,1.5Hz,1H),6.94–6.86(m,1H),6.63(t,J＝7.4Hz,1H),6.38(d,J＝7.9Hz,1H),6.25(s,1H),3.89(s,1H),1.79(s,3H),1.62(s,3H)。13C NMR(126MHz,CDCl3)δ147.3,142.0,136.3,128.3,128.1,127.2,126.6,125.9,121.9,120.3,117.3,112.0,60.8,26.3,19.7。高分辨质谱：(ESI)实测值[M+H]+236.1425,C17H18N+理论值236.1434。[α]D 20＝+72.4(c 1.0,CHCl3)。HPLC分析：(Chiralpak IB柱),90:10正己烷/异丙醇,流速1.0mL/min；tR＝6.0min(minor),7.9min(major),98％ee。IR(cm-1):f＝3374,3020,2970,1603,1475,1318,1283,1185,1025,743,698,617。
3r:淡黄色泡沫状固体,54.4mg,产率51％.1H NMR(500MHz,CDCl3)δ7.48(d,J＝7.7Hz,2H),7.42–7.11(m,13H),7.11–6.55(m,3H),6.41–5.82(m,2H),5.11(s,2H),5.08(s,2H),3.87(brs,1H),1.67(s,3H),1.52(brs,3H)。13C NMR(126MHz,CDCl3)δ156.2,147.0,141.2,136.8,136.1,135.7,131.4,128.6,128.5,128.4,128.3,128.3,128.1,127.8(br),127.2,126.5,123.9(br),121.5,120.0,111.6,68.2,67.8,60.9,26.4,19.6。高分辨质谱：(ESI)实测值[M+H]+534.2397,C33H32N3O4 +理论值534.2387。[α]D 20＝-10.0(c 1.0,CHCl3)。HPLC分析：(Chiralpak IB柱),50:50正己烷/异丙醇,流速1.0mL/min；tR＝14.6min(major),21.5min(minor),94％ee。IR(cm-1):f＝3356,3288,3030,2967,1705,1500,1392,1341,1217,1056,738,696。
4-甲氧基-2-甲基-2-苯基-1,2-二氢喹啉的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA2，反应温度-40℃，反应时间16小时。
(R)-1s:浅黄色固体,21.2mg,回收率42％。1H NMR(500MHz,CDCl3)δ7.57(d,J＝8.6Hz,2H),7.40(dd,J＝8.1,1.4Hz,1H),7.36(t,J＝7.7Hz,2H),7.29–7.21(m,1H),7.12–7.00(m,1H),6.67(t,J＝7.4Hz,1H),6.50(d,J＝7.9Hz,1H),4.74(s,1H),4.10(s,1H),3.71(s,3H),1.78(s,3H)。13C NMR(126MHz,CDCl3)δ150.0,149.9,143.4,129.5,128.4,126.8,125.4,122.3,117.2,116.8,112.6,100.3,57.8,54.6,31.4。高分辨质谱：(ESI)实测值[M+H]+252.1375,C17H18NO+理论值252.1383。[α]D 20＝+137(c 1.0,CHCl3)。HPLC分析：(Chiralpak IB柱),80:20正己烷/异丙醇,流速1.0mL/min；tR＝7.0min(minor),8.4min(major),97％ee。IR(cm-1):f＝3380,3056,2963,1647,1603,1476,1363,1272,1239,1142,1103,1027,743,697。
3s:黄色固体,54.8mg,产率50％。1H NMR(500MHz,CDCl3)δ7.52(d,J＝7.7Hz,2H),7.46–7.19(m,14H),7.19–6.73(m,2H),6.41(d,J＝8.7Hz,1H),5.20(s,2H),5.17(s,2H),4.70(brs,1H),4.16(s,1H),3.65(s,3H),1.75(s,3H)。13C NMR(126MHz,CDCl3)δ156.2,149.8,149.2,142.6,136.1,135.7,131.3,128.7,128.6,128.5,128.5,128.3,128.1,127.7(br),126.9,125.4,120.5(br),116.5,112.4,100.6,68.3,67.9,58.1,54.6,31.5。高分辨质谱：(ESI)实测值[M+H]+550.2322,C33H32N3O5 +理论值550.2336。[α]D 20＝-34.6(c 1.0,CHCl3)。HPLC分析：(Chiralpak IA柱),50:50正己烷/异丙醇,流速1.0mL/min；tR＝8.2min(major),9.2min(minor),86％ee。IR(cm-1):f＝3362,3288,3032,2959,1708,1501,1219,1105,1027,741,695。
6-甲基-6-苯基-5,6-二氢菲啶的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA2，反应温度-40℃，反应时间36小时。
(S)-1t:灰色固体,24.7mg,回收率46％。1H NMR(500MHz,CDCl3)δ7.67(dd,J＝7.9,1.3Hz,1H),7.60(dd,J＝7.8,1.4Hz,1H),7.45–7.37(m,2H),7.25–7.16(m,3H),7.16–7.10(m,1H),7.07(td,J＝7.6,1.3Hz,1H),7.01(td,J＝7.6,1.4Hz,1H),6.85(dd,J＝7.8,1.3Hz,1H),6.71(td,J＝7.6,1.2Hz,1H),6.55(dd,J＝7.9,1.2Hz,1H),4.16(brs,1H),1.76(s,3H)。13C NMR(126MHz,CDCl3)δ147.5,143.2,140.2,130.9,129.1,128.2,127.3,127.3,127.2,127.1,126.0,123.4,122.6,121.0,118.9,115.3,59.8,28.7。高分辨质谱：(ESI)实测值[M+H]+272.1430,C20H18N+理论值272.1434。[α]D 20＝-48.5(c 1.0,CHCl3)。HPLC分析：(Chiralpak IC柱),90:10正己烷/异丙醇,流速1.0mL/min；tR＝5.4min(minor),6.1min(major),98％ee。IR(cm-1):f＝3407,2989,2972,1603,1490,1441,1266,772,750,740,723,699。
3t:黄色固体,59.0mg,产率52％。1H NMR(500MHz,CDCl3)δ7.66(brs,1H),7.54(brs,1H),7.40(d,J＝7.7Hz,2H),7.36–6.89(m,17H),6.81(d,J＝7.8Hz,1H),6.50(s,1H),5.13(s,2H),5.09(s,2H),4.28(brs,1H),1.76(s,3H)。13C NMR(126MHz,CDCl3)δ156.3,147.3,142.2,139.9,136.0,135.7,135.6,132.9,130.1,128.6,128.6,128.4,128.4,128.3,128.2,127.8(br),127.4,127.3,127.2,127.2,125.9,122.7,121.6,120.7,115.1,68.3,67.9,59.8,28.8。高分辨质谱：(ESI)实测值[M+H]+570.2380,C36H32N3O4 +理论值570.2387。[α]D 20＝+28.5(c 1.0,CHCl3)。HPLC分析：(Chiralpak IC柱),50:50正己烷/异丙醇,流速1.0mL/min；tR＝8.3min(major),14.4min(minor),88％ee。IR(cm-1):f＝3355,3289,3031,2968,1705,1499,1443,1390,1329,1295,1217,1058,907,730,695。
9-甲氧基-6-甲基-6-苯基-5,6-二氢菲啶的动力学拆分：
反应规模为0.2毫摩尔，催化剂用CPA2，反应温度-40℃，反应时间21小时。
(S)-1u:浅黄色固体,28.8mg,回收率48％。1H NMR(500MHz,CDCl3)δ7.69(dd,J＝7.9,1.4Hz,1H),7.59–7.46(m,3H),7.37–7.27(m,3H),7.24–7.17(m,1H),7.10(td,J＝7.6,1.5Hz,1H),6.83–6.71(m,2H),6.51(dd,J＝7.8,1.3Hz,1H),3.93(s,1H),3.34(s,3H),1.99(s,3H)。13C NMR(126MHz,CDCl3)δ156.4,150.0,142.5,132.6,129.3,129.2,128.3,127.6,126.5,126.3,123.9,119.5,118.1,115.3,114.3,111.7,58.8,55.4,27.2。高分辨质谱：(ESI)实测值[M+H]+302.1528,C21H20NO+理论值302.1539。[α]D 20＝-73.4(c 1.0,CHCl3)。HPLC分析：(Chiralpak IA柱),70:30正己烷/异丙醇,流速1.0mL/min；tR＝4.7min(minor),5.1min(major),98％ee。IR(cm-1):f＝3361,2967,2930,1593,1467,1433,1254,1085,1018,799,756,745,700。
3u:浅黄色固体,60.7mg,产率51％。1H NMR(500MHz,CDCl3)δ7.77–7.51(m,1H),7.38(d,J＝7.7Hz,2H),7.32–6.79(m,17H),6.63(d,J＝8.0Hz,1H),6.31(s,1H),5.13(s,2H),5.09(s,2H),3.97(brs,1H),3.21(s,3H),1.85(s,3H)。13C NMR(126MHz,CDCl3)δ156.3,149.9,141.6,136.1,135.7,132.1,131.8,129.0,128.6,128.6,128.4,128.3,128.3,128.2,127.9(br),127.6,126.5,126.3,122.1(br),119.1,115.4,114.1,112.1,68.3,67.9,58.9,55.4,27.2。高分辨质谱：(ESI)实测值[M+H]+600.2476,C37H34N3O5 +理论值600.2493。[α]D 20＝+40.4(c 1.0,CHCl3)。HPLC分析：(Chiralpak IB柱),70:30正己烷/异丙醇,流速1.0mL/min；tR＝15.1min(major),17.6min(minor),95％ee。IR(cm-1):f＝3356,3290,3031,2960,1707,1575,1506,1467,1329,1255,1217,1027,737,695。
实施例4
消旋苯并双杂原子杂环的动力学拆分
本实施例中使用到的手性磷酸催化剂结构如下：
二氢喹啉类底物的动力学拆分的通用方法：
通用方法：反应瓶中加入S1(0.2mmol)、催化剂(5mol％)以及3A分子筛100mg，加入3.5mL氯仿并置于对应低温环境中(-40℃或-60℃)，S2溶于0.5mL氯仿中，在低温条件下缓慢滴加，结束后低温反应。TLC或HPLC监测反应结束后0.3mL三乙胺加入中低温搅拌15min后提至室温，旋蒸除去溶剂，经柱层析纯化得到相应手性原料和产物。
苯并六元氮氧杂环的动力学拆分：
通用方法：反应瓶中加入S1(0.2mmol)、催化剂(5mol％)以及3A分子筛100mg，加入3.5mL氯仿并置于对应低温环境中(-40℃或-60℃)，S2溶于0.5mL氯仿中，在低温条件下缓慢滴加，结束后低温反应。TLC或HPLC监测反应结束后0.3mL三乙胺加入中低温搅拌15min后提至室温，旋蒸除去溶剂，经柱层析纯化得到相应手性原料和产物。
条件：-60℃，S1:S2＝1：0.55，0.2mmol规模，12h，S＝75.7。
3-甲基-3-苯基-3,4-二氢-2H-苯并[b][1,4]恶嗪：22mg，49％回收率，85.5％ee，白色固体。1H NMR(500MHz,Chloroform-d)δ7.42(d,J＝7.7Hz,2H),7.29(t,J＝7.6Hz,2H),7.23–7.15(m,1H),6.79–6.71(m,2H),6.68–6.53(m,2H),4.08(d,J＝10.5Hz,1H),3.90(d,J＝10.6Hz,1H),1.54(s,3H).m/z HRMS(ESI)发现[M+H]+226.1221，C15H16NO+理论226.1226.
1-(3-甲基-3-苯基-3,4-二氢-2H-苯并[b][1,4]恶嗪-7-基)肼-1,2-二羧酸二苄酯：50mg，48％产率，93％ee，白色泡沫。1H NMR(400MHz,Chloroform-d)δ7.51–7.40(m,2H),7.37–7.11(m,14H),7.07–6.71(m,2H),6.67–6.38(m,1H),5.14(d,J＝16.0Hz,4H),4.20–3.95(m,2H),3.90(d,J＝10.5Hz,1H),1.55(s,3H).m/z HRMS(ESI)发现[M+H]+524.2172，C31H30N3O5 +理论524.2180.
苯并六元氮硫杂环的动力学拆分：
条件：-40℃，S1:S2＝1：0.55，0.2mmol规模，12h，S＝212.4。
3-甲基-3-苯基-3,4-二氢-2H-苯并[b][1,4]噻嗪：22mg，47％回收率，98.5％ee，白色固体。1H NMR(500MHz,Chloroform-d)δ7.46–7.40(m,2H),7.37–7.31(m,2H),7.29–7.26(m,1H),7.00(dd,J＝7.7,1.5Hz,1H),6.96(td,J＝7.6,1.5Hz,1H),6.69–6.58(m,2H),4.18(s,1H),3.14(d,J＝12.7Hz,1H),2.94(d,J＝12.7Hz,1H),1.71(s,3H).m/z HRMS(ESI)发现[M+H]+242.0992，C15H16NS+理论242.0998.
1-(3-甲基-3-苯基-3,4-二氢-2H-苯并[b][1,4]噻嗪-7-基)肼-1,2-二羧酸二苄酯:54mg，50％产率，95.5％ee，白色泡沫。1H NMR(400MHz,Chloroform-d)δ7.56–6.73(m,19H),6.51(s,1H),5.31–4.96(m,4H),4.16(s,1H),3.09(d,J＝12.7Hz,1H),2.88(d,J＝12.9Hz,1H),1.67(s,3H).m/z HRMS(ESI)发现[M+H]+540.1949，C31H30N3O4S+理论540.1952.
苯并氮氮杂环的动力学拆分：
条件：室温，S1:S2＝1：0.55，0.05mmol规模，12h，S＝38.3。
2,3-二甲基-3-苯基-3,4-二氢喹喔啉-1(2H)-羧酸叔丁酯：7mg，47％回收率，80％ee，白色固体。1H NMR(500MHz,Chloroform-d)δ7.73–7.44(m,3H),7.39(t,J＝7.6Hz,2H),7.29(t,J＝7.3Hz,1H),7.06–6.88(m,1H),6.80–6.58(m,2H),4.73(s,1H),4.08(s,1H),1.56(s,9H),1.51(s,3H),0.69(d,J＝6.8Hz,3H).m/z HRMS(ESI)发现[M+H]+339.2061，C21H27N2O2 +理论339.2068.
1-(4-(叔丁氧基羰基)-2,3-二甲基-2-苯基-1,2,3,4-四氢喹喔啉-6-基)肼-1,2-二羧酸二苄酯：15mg，47％产率，80％ee，棕色胶状。1H NMR(500MHz,Chloroform-d)δ7.49(d,J＝7.7Hz,3H),7.45–7.27(m,13H),7.21–6.52(m,3H),5.28–5.03(m,4H),4.71(s,1H),4.19(s,1H),1.51(d,J＝11.8Hz,9H),1.34–1.21(m,3H),0.69(d,J＝6.7Hz,3H).m/z HRMS(ESI)发现[M+H]+637.3012，C37H41N4O6 +理论637.3021.
苯并氮氧七元环动力学拆分：
条件：-40℃，S1:S2＝1：1，0.2mmol规模，14h，S＝153.9。
11-甲基-11-苯基-10,11-二氢二苯并[b，f][1,4]奥氮平:28mg，49％回收率，96％ee，白色固体。1H NMR(400MHz,Chloroform-d)δ7.48(dd,J＝7.8,1.7Hz,1H),7.33–7.15(m,7H),7.11(dd,J＝7.9,1.4Hz,1H),6.95–6.83(m,2H),6.69–6.57(m,2H),4.24(s,1H),1.85(s,3H).m/z HRMS(ESI)发现[M+H]+288.1377，C20H18NO+理论288.1383.
1-(11-甲基-11-苯基-10,11-二氢二苯并[b，f][1,4]恶唑啉-7-基)肼-1,2-二羧酸二苄酯：59mg，50％产率，95％ee，白色泡沫。1H NMR(400MHz,Chloroform-d)δ7.56–6.41(m,25H),5.25–4.98(m,4H),4.34(s,1H),1.80(s,3H).m/z HRMS(ESI)发现[M+H]+586.2331，C36H32N3O5 +理论586.2336.
苯并氮硫七元环动力学拆分：
条件：-40℃，S1:S2＝1：1，0.2mmol规模，72h，S＝47。
11-甲基-11-苯基-10,11-二氢二苯并[b，f][1,4]噻氮平:29mg，48％回收率，87.5％ee，黄色泡沫。1H NMR(500MHz,Chloroform-d)δ7.46(d,J＝7.4Hz,1H),7.40(d,J＝7.7Hz,1H),7.30–7.18(m,7H),7.15(d,J＝7.6Hz,1H),7.00(t,J＝7.6Hz,1H),6.67(t,J＝7.5Hz,1H),6.58(d,J＝8.0Hz,1H),4.19(s,1H),1.89(s,3H).m/z HRMS(ESI)发现[M+H]+304.1149，C20H18NS+理论304.1154.
1-(11-甲基-11-苯基-10,11-二氢二苯并[b，f][1,4]噻唑啉-7-基)肼-1,2-二羧酸二苄酯:59mg，49％回收率，88.5％ee，白色泡沫。1H NMR(400MHz,Chloroform-d)δ7.90–6.18(m,25H),5.31–4.91(m,4H),4.31(s,1H),1.84(s,3H).m/z HRMS(ESI)发现[M+H]+602.2101，C36H32N3O4S+理论602.2109.
实施例5
反应催化剂减量和反应放大
二氢喹啉底物的克级别放大反应
氮气氛围下50毫升蛋形瓶里计入搅拌子、消旋底物1l(1.0克，4.52毫摩尔)和手性磷酸CPA2(12.4毫克，0.0225毫摩尔，0.5mol％)和
分子筛320毫克。加入13毫升干氯仿后，体系温度降低到-30℃，往里滴加含偶氮二甲酸二苄酯(714毫克，2.40毫摩尔，0.53当量)的10毫升干氯仿，继续在-30℃下搅拌60小时，然后加入加入100微升三乙胺淬灭反应。用硅藻土过滤，旋蒸溶剂，柱层析分离(洗脱剂：石油醚/乙酸乙酯40/1到4/1)，回收原料(R)-1l(487毫克，49％，97％ee)，得到产物3l(1.17克，50％，94％ee)。
实施例6
二氢喹啉底物胺化反应的脱氨基反应：
氮气氛围下，原料3l(52.0毫克，0.1毫摩尔，94％ee)溶于乙醇/水溶液(乙醇/水＝40/1)2毫升，加入氢氧化钾(66.0毫克，85％，10.0当量)，然后75摄氏度加热14小时。用乙酸乙酯稀释，饱和食盐水洗两次。有机相用无水硫酸钠干燥，旋蒸溶剂，柱层析得到产物(S)-1l(18.2毫克，产率82％，93％ee)。
综上所述，本发明有效克服了现有技术中的种种缺点而具高度产业利用价值。
上述实施例仅例示性说明本发明的原理及其功效，而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下，对上述实施例进行修饰或改变。因此，举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变，仍应由本发明的权利要求所涵盖。
Claims (10)
1.一种手性α-叔胺的拆分合成方法，包括：
将消旋的式A化合物在催化剂存在的条件下与偶氮二甲酸酯进行不对称亲电芳香取代反应，以提供(R)或(S)构型的式A化合物和与式A化合物相反构型的式C化合物，反应方程式如下：
其中，R1、R2各自独立地选自H，C1-C8烷基，C1-C8烯基，C1-C8炔基，取代基选自卤素、C1-C6烷基、C1-C6烷氧基的取代或未取代的芳基，芳基烷基，杂芳基，-OC(O)R’，R’选自H、C1-C6烷基；
X选自NR”，O，S，C(O)OR”’，C(O)R”’，或不存在，R”选自H，C1-C6烷基，R”’选自C1-C6烷基；
Y选自C，或不存在；
R3、R6各自独立地选自H，C1-C6烷基，C1-C6烷氧基，或与它们所连接的原子一起形成稠合的取代基选自C1-C6烷氧基的取代或未取代的芳基；
R4选自H、C1-C8烷基、芳基、卤素、C1-C6烷氧基；
R5选自C1-C8烷基、芳基、芳基烷基；
所述催化剂选自手性磷酸催化剂。
2.如权利要求1所述的一种手性α-叔胺的拆分合成方法，其特征在于，R1选自取代基选自卤素、C1-C6烷基、C1-C6烷氧基的取代或未取代的芳基，杂芳基；
R2选自C1-C8烷基、C1-C8烯基、芳基，芳基烷基；
X选自NR”，O，S，或不存在，R”选自H，C1-C6烷基；
Y选自C，或不存在；
R3、R6各自独立地选自H，C1-C6烷基，C1-C6烷氧基，或与它们所连接的原子一起形成稠合的取代基选自C1-C6烷氧基的取代或未取代的芳基；
R4选自H；
R5选自芳基烷基。
3.如权利要求1所述的一种手性α-叔胺的拆分合成方法，其特征在于，所述式A化合物选自化学结构式如下之一所示的化合物：
4.如权利要求1所述的一种手性α-叔胺的拆分合成方法，其特征在于，所述手性磷酸催化剂为
酸催化剂。
5.如权利要求4所述的一种手性α-叔胺的拆分合成方法，其特征在于，所述手性磷酸催化剂具有SPINOL骨架、BINOL骨架、或H8-BINOL骨架。
6.如权利要求5所述的一种手性α-叔胺的拆分合成方法，其特征在于，所述手性磷酸催化剂选自化学结构式如下之一所示的化合物，或这些催化剂的对映体：
其中，Rcat1和Rcat2为相同基团或不同的基团；
Rcat1和Rcat2各自独立地选自苯基、2,4,6-三甲基苯基、2,4,6-三环己基苯基、2,4,6-三异丙基苯基、1-萘基、2-萘基、9-蒽基、9-菲基。
7.如权利要求1所述的一种手性α-叔胺的拆分合成方法，其特征在于，不对称亲电芳香取代反应在溶剂存在的条件下进行，优选的，不对称亲电芳香取代反应中所使用的溶剂选自非质子溶剂；
和/或，式A化合物与偶氮二甲酸酯的摩尔比为1：0.5～1.1，优选的，式A化合物与偶氮二甲酸酯的摩尔比为1：0.55～0.65；
和/或，不对称亲电芳香取代反应在无水条件下进行；
和/或，不对称亲电芳香取代反应的反应温度为-80℃～50℃，优选的，不对称亲电芳香取代反应的反应温度为-40℃～-20℃；
和/或，所述不对称亲电芳香取代反应的后处理包括：淬灭、脱除溶剂，纯化以提供(R)或(S)构型的式A化合物以及与式A化合物相反构型的式C化合物。
8.如权利要求1所述的一种手性α-叔胺的拆分合成方法，其特征在于，所述方法还包括：通过式C化合物提供与其相同构型的式A化合物，反应方程式如下所示：
9.如权利要求8所述的一种手性α-叔胺的拆分合成方法，其特征在于，通过式C化合物提供与其相同手性构型的式A化合物的方法具体为：将式C化合物在碱存在的条件下进行脱肼基反应，以提供与其相同手性构型的式A化合物。
10.如权利要求9所述的一种手性α-叔胺的拆分合成方法，其特征在于，所述脱肼基反应中，所述碱选自有机碱和/或无机碱，无机碱优选为碱金属、碱土金属的氢氧化物和碳酸盐中的一种或多种的组合，更优选为氢化化钾、氢氧化钠、氢氧化锂、碳酸钾、碳酸钠、碳酸锂、碳酸铯中的一种或多种的组合，有机碱优选为季铵碱、碱金属的醇盐中的一种或多种的组合，优选为氢氧化四甲基铵、叔丁醇钾、叔丁醇钠、叔丁醇锂、DBU(1,8-二氮杂二环十一碳-7-烯)中的一种或多种的组合，有机碱更优选为季铵碱；
和/或，所述脱肼基反应在溶剂存在的条件下进行，优选的，所述脱肼基反应中，溶剂选自水、醇类溶剂、醚类溶剂、酰胺类溶剂、砜类溶剂、芳香烃类溶剂中的一种或多种的组合；
和/或，所述脱肼基反应的反应温度为20～100℃，优选的，所述脱肼基反应的反应温度为60～80℃。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010010359A2 (en) * | 2008-07-24 | 2010-01-28 | Cilpa Limited | A process for the preparation of cinacalcet and its salts |
| CN111423332A (zh) * | 2020-05-25 | 2020-07-17 | 上海科技大学 | 一种拆分手性化合物的方法 |
| CN111517964A (zh) * | 2020-05-25 | 2020-08-11 | 上海科技大学 | 一种拆分手性化合物的方法 |
| CN112694376A (zh) * | 2020-12-25 | 2021-04-23 | 浙江工业大学 | 一种手性磷酸催化的烯丙基叔醇动力学拆分方法 |
-
2020
- 2020-11-27 CN CN202011361366.3A patent/CN112409253B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010010359A2 (en) * | 2008-07-24 | 2010-01-28 | Cilpa Limited | A process for the preparation of cinacalcet and its salts |
| CN111423332A (zh) * | 2020-05-25 | 2020-07-17 | 上海科技大学 | 一种拆分手性化合物的方法 |
| CN111517964A (zh) * | 2020-05-25 | 2020-08-11 | 上海科技大学 | 一种拆分手性化合物的方法 |
| CN112694376A (zh) * | 2020-12-25 | 2021-04-23 | 浙江工业大学 | 一种手性磷酸催化的烯丙基叔醇动力学拆分方法 |
Non-Patent Citations (3)
| Title |
|---|
| GRIGORY A. SHEVCHENKO, ET AL: "Catalytic Asymmetric α-Amination of α-Branched Ketones via Enol Catalysis", 《SYNLETT.》 * |
| SHOU-GUO WANG, ET AL: "Asymmetric Dearomatization of β-Naphthols through an Amination Reaction Catalyzed by a Chiral Phosphoric Acid", 《ANGEWANDTE CHEMIE, INTERNATIONAL EDITION》 * |
| 刘财路 等: "手性磷酸催化己内酯的动力学拆分", 《中国科技论文》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115340514A (zh) * | 2022-08-31 | 2022-11-15 | 中国科学院化学研究所 | 一种手性胺类化合物及其制备方法 |
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