CN116283956A - 基于金鸡纳碱骨架的手性双齿氮配体、制备方法及应用 - Google Patents
基于金鸡纳碱骨架的手性双齿氮配体、制备方法及应用 Download PDFInfo
- Publication number
- CN116283956A CN116283956A CN202310115723.5A CN202310115723A CN116283956A CN 116283956 A CN116283956 A CN 116283956A CN 202310115723 A CN202310115723 A CN 202310115723A CN 116283956 A CN116283956 A CN 116283956A
- Authority
- CN
- China
- Prior art keywords
- bidentate nitrogen
- chiral bidentate
- chiral
- ligand
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title claims abstract description 122
- 239000003446 ligand Substances 0.000 title claims abstract description 104
- 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 62
- 241000157855 Cinchona Species 0.000 title claims abstract description 36
- 235000021513 Cinchona Nutrition 0.000 title claims abstract description 35
- 150000003797 alkaloid derivatives Chemical group 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 86
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 25
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 22
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 13
- 229930013930 alkaloid Natural products 0.000 claims abstract description 10
- -1 alkaloid compounds Chemical class 0.000 claims description 53
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- 239000000706 filtrate Substances 0.000 claims description 20
- 239000002808 molecular sieve Substances 0.000 claims description 17
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 17
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 16
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 15
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 15
- 239000012279 sodium borohydride Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000012074 organic phase Substances 0.000 claims description 12
- 230000002829 reductive effect Effects 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 11
- 238000004440 column chromatography Methods 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- 230000000171 quenching effect Effects 0.000 claims description 6
- 229910052723 transition metal Inorganic materials 0.000 claims description 6
- 150000003624 transition metals Chemical class 0.000 claims description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
- 229920002554 vinyl polymer Polymers 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 238000011065 in-situ storage Methods 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 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 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 29
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000006555 catalytic reaction Methods 0.000 abstract description 4
- 239000007795 chemical reaction product Substances 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 27
- 238000003786 synthesis reaction Methods 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 150000002576 ketones Chemical class 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 6
- WYJOVVXUZNRJQY-UHFFFAOYSA-N 2-Acetylthiophene Chemical compound CC(=O)C1=CC=CS1 WYJOVVXUZNRJQY-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229910052741 iridium Inorganic materials 0.000 description 3
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 3
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N pentanal Chemical compound CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical class O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- KTYAQHYBYRVCGD-UHFFFAOYSA-N [Ir].COC1=CC=CCCCC1 Chemical group [Ir].COC1=CC=CCCCC1 KTYAQHYBYRVCGD-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 2
- FXHGMKSSBGDXIY-UHFFFAOYSA-N heptanal Chemical compound CCCCCCC=O FXHGMKSSBGDXIY-UHFFFAOYSA-N 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- ULBXWWGWDPVHAO-UHFFFAOYSA-N Chlorbufam Chemical compound C#CC(C)OC(=O)NC1=CC=CC(Cl)=C1 ULBXWWGWDPVHAO-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- VEQOALNAAJBPNY-UHFFFAOYSA-N antipyrine Chemical class CN1C(C)=CC(=O)N1C1=CC=CC=C1 VEQOALNAAJBPNY-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- QWMUDOFWQWBHFI-UHFFFAOYSA-N hydroxy-imino-diphenoxy-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1OP(=O)(N)OC1=CC=CC=C1 QWMUDOFWQWBHFI-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910017464 nitrogen compound Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 229960005222 phenazone Drugs 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- ZSKGQVFRTSEPJT-UHFFFAOYSA-N pyrrole-2-carboxaldehyde Chemical compound O=CC1=CC=CN1 ZSKGQVFRTSEPJT-UHFFFAOYSA-N 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 125000003003 spiro 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
- C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1825—Ligands comprising condensed ring systems, e.g. acridine, carbazole
- B01J31/183—Ligands comprising condensed ring systems, e.g. acridine, carbazole with more than one complexing nitrogen atom, e.g. phenanthroline
- B01J31/1835—Ligands comprising condensed ring systems, e.g. acridine, carbazole with more than one complexing nitrogen atom, e.g. phenanthroline comprising aliphatic or saturated rings
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/40—Radicals substituted by oxygen atoms
- C07D307/42—Singly bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/28—Halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/56—Radicals substituted by oxygen atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/827—Iridium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及不对称催化技术领域,具体涉及基于金鸡纳碱骨架的手性双齿氮配体、制备方法及应用。该化合物用于催化杂环芳香酮的不对称氢化反应。采用该手性配体与非手性膦配体共修饰的金属催化反应产物具有高转化率,对映选择性可达到99.9%。该手性双齿氮配体采用金鸡纳碱为原料制备而得,原料便宜易得,制备反应过程简单,在空气环境中稳定,具有极高的应用价值。
Description
技术领域
本发明涉及不对称催化技术领域,具体涉及基于金鸡纳碱骨架的手性双齿氮配体、制备方法及应用。
背景技术
在过去的几十年里,通过酮的不对称氢化反应制备手性醇已取得飞速的发展,尤其是利用合成出的各种手性配体能有效提高不对称氢化反应的对映异构体选择性。自1995年Noyori等开发的手性双齿膦配体与手性二胺配体被成功应用于酮的不对称催化氢化以来,各种各样的手性膦配体及手性氮配体被合成出来并应用于酮的不对称氢化反应,例如BICP,TolBINAP,spiro diphosphines,hemisalen type ligands,ferrocene-based配体,aminoalcohols等,但这些配体的合成受限于步骤多,反应复杂且膦配体易氧化等问题。此外杂环芳香酮的不对称氢化一直是该研究方向的一大难点,通常加氢活性低,对映异构体选择性差等。因此利用手性天然产物直接合成新型的多齿手性氮配体,并结合非手性膦配体共修饰金属催化杂环芳香酮不对称氢化反应以制备手性醇具有重要的意义。
发明内容
本发明所要解决的技术问题是提供基于金鸡纳碱骨架的手性双齿氮配体、制备方法及应用。
本发明解决上述技术问题的技术方案如下:
本发明提供一种基于金鸡纳碱骨架的手性双齿氮配体,其化学式如通式(I)所示:
所述通式(I)中,R独立的表示为甲基、乙基、C3~C7的直链烷基、C3~C7的支链烷基或杂环烷基,R'独立的表示为甲氧基或氢,R〞独立的表示为乙基或乙烯基。
进一步,所述通式(I)中两个含氮杂环与氨基连接的碳原子的构型为R型或S型。
进一步,R独立的表示为甲基,丙基,戊基,庚基,吡咯烷基中的一种;R'独立的表示为甲氧基、氢中的一种;R〞为乙烯基;其化学式如通式(I I)所示:
进一步,所述手性双齿氮配体的结构式为:
本发明还提供一种如上述基于金鸡纳碱骨架的手性双齿氮配体的制备方法,先将金鸡纳碱类化合物衍生成胺类化合物,再将得到的所述胺类化合物与醛类化合物反应生成具有空间构型的所述手性双齿氮配体。
进一步,所述胺类化合物与所述醛类化合物的反应步骤为:
向所述胺类化合物中加入所述醛类化合物以及4A分子筛,再加入1,2-二氯乙烷,室温条件下搅拌24h后,过滤所述4A分子筛并收集滤液;在真空条件下除去滤液中的1,2-二氯乙烷,再加入无水甲醇,并在0℃条件下加入硼氢化钠;恢复至所述室温后搅拌4h,加水进行淬灭反应,并用二氯甲烷萃取淬灭反应后的反应体系,再采用无水硫酸钠干燥萃取后得到的有机相,干燥后再进行减压蒸馏,去除二氯甲烷;将得到的粗产物通过柱色谱分离纯化,得到所述手性双齿氮配体;
其中,所述醛类化合物的结构如通式(III)所示:
反应方程式为:
进一步,所述胺类化合物与所述醛类化合物的摩尔比为1:1.14~3.0;所述胺类化合物与所述4A分子筛的质量比为1:10;所述胺类化合物与所述1,2-二氯乙烷的质量比为1:25;所述胺类化合物与所述无水甲醇的质量比为1:20;所述胺类化合物与所述硼氢化钠的摩尔比为1:3。
本发明还提供一种如上述基于金鸡纳碱骨架的手性双齿氮配体在杂环芳香酮的不对称氢化反应中的应用,将所述手性双齿氮配体与非手性膦配体在过渡金属络合物的作用下,在有机溶剂中对所述杂环芳香酮的不对称氢化反应进行原位催化。
进一步,所述非手性膦配体的化学式如通式(Ⅳ)所示:
所述通式(Ⅳ)中,R1独立的表示为未取代的苯基、烷基取代的苯基以及烷氧基取代的苯基中的一种。
进一步,所述过渡金属络合物为[I r(COD)OMe]2;所述手性双齿氮配体、所述非手性膦配体以及[I r(COD)OMe]2的摩尔比为2~8:2~8:1。
本发明相对于现有技术的有益效果包括:
1)本发明的基于金鸡纳碱骨架的手性双齿氮配体,在其化学式9号位C连接的N上,以烷基作为取代基,不含有不稳定的磷元素,使该配体本身更加稳定和易得;
2)本发明的基于金鸡纳碱骨架的手性双齿氮配体,可以作为手性配体与非手性膦配体用于催化杂环芳香酮的不对称加氢反应,这样既能保证该配体本身的稳定性,又能保证不对称加氢反应的有效性;采用该手性配体进行催化的反应产物具有高转化率,异构体的对映选择性可达到99.9%;
3)本发明的基于金鸡纳碱骨架的手性双齿氮配体,采用金鸡纳碱原料和醛原料作为反应物,原料便宜易得,具有极高的应用价值;
4)本发明的基于金鸡纳碱骨架的手性双齿氮配体,其结构中含有金鸡纳碱骨架,金鸡纳碱是广泛存在自然界中的一种生物碱,该类化合物含有独特的手性结构,在制备手性双齿氮配体的过程中,可通过现有的化学合成方法简单地将其衍生成胺类化合物,并利用形成的手性胺制备出具有特殊空间构型的手性双齿氮配体,反应过程简单、易于操作;
5)本发明的基于金鸡纳碱骨架的手性双齿氮配体的制备方法,对制备条件的要求较低,无需在氮气或其他无氧环境中进行,更加适于推广和应用。
具体实施方式
以下对本发明的原理和特征进行描述,所举实例只用于解释本发明,并非用于限定本发明的范围。
本发明的基于金鸡纳碱为骨架的手性双齿氮配体,其结构为一种新型氮氮多齿结构,可作为手性配体应用于杂环芳香酮的不对称加氢中。
该化合物的结构中含有两个手性氮、可作为手性配体用于酮的不对称氢化中。
该化合物与铱催化剂在各类酮的不对称催化氢化中可以得到大于99%的对映选择性。相对于其他优势配体,该类型配体合成极其简单,成本低廉,结构稳定,有利于大规模合成及应用。
本发明的基于金鸡纳碱骨架的手性双齿氮配体,其化学式如通式(I)所示:
通式(I)中,R独立的表示为甲基、乙基、C3~C7的直链烷基、C3~C7的支链烷基或杂环烷基,R'独立的表示为甲氧基或氢,R〞独立的表示为乙基或乙烯基。
优选的,R〞为乙烯基时,该手性双齿氮配体的化学式如通式(I I)所示:
优选的,R独立的表示为甲基,丙基,戊基,庚基,吡咯烷基中的一种。
本发明的手性双齿氮配体的第9位碳的构型为S型或R型;在本发明的化合物作为配体产品使用时,该产品可以为(9S)-氮氮配体、(9R)-氮氮配体中的一种或是两种的混合物。
本发明的化合物首先以商业化的金鸡纳碱化合物作为原料制备出氨基衍生物,随后分别与醛类化合物通过还原胺化反应制备而成。金鸡纳碱化合物可以为辛可宁、辛可尼丁、奎宁、奎尼丁。
本发明的基于金鸡纳碱骨架的手性双齿氮配体,通过通式(I)可以看出,第9位碳的N上连接的取代基R的可选结构中,均不含有膦,这就使本发明的配体性质更加稳定。
实际上,现有的用于酮的不对称氢化反应的配体化合物的种类很多,但大部分都在上述位置使用了含膦的取代基团,虽然这样的配体化合物具有良好的转化率和高选择性,但是其本身的性质并不稳定,对制备条件的要求很高,通常要在无氧无水的条件下,避免发生氧化。这就导致了这样的化合物虽然理论上具有良好的效果,但是在实际使用中,制备成本和储存的成本高,并且难以投入大规模使用。
而本发明的上述手性双齿氮配体,一方面,将取代基R的结构进行了颠覆性的改变,使其具有良好的稳定性,大幅度降低了制备成本和储存成本,能够真正意义上的投入使用;另一方面,本发明的上述结构还能保证该配体同样具有良好的转化率和高选择性,特别是对于杂环芳香酮的不对称氢化反应,本发明将上述手性双齿氮配体与非手性膦配体相结合,使其对于杂环芳香酮的不对称氢化反应具有更高的转化率,异构体的对映选择性可达到99.9%。
具体的制备步骤如下:
1)将金鸡纳碱类化合物衍生成胺类化合物,该步骤为现有的步骤,具体为;
在N2环境下,将金鸡纳碱化合物和三苯基膦(PPh3)混合并加入经过无水无氧处理后的四氢呋喃(THF)中。将混合后的溶液转移至0℃搅拌,一次性加入偶氮二甲酸二异丙酯(D IAD)搅拌反应15分钟,将叠氨磷酸二苯酯((PhO)2P(O)3)加入到四氢呋喃中混合均匀后慢慢滴加到反应液。滴加完毕后,将反应转移至室温搅拌反应12小时,升温到50℃继续搅拌反应2小时后加入三苯基膦继续50℃搅拌反应2小时,将反应液冷却至室温加入蒸馏水继续室温反应18小时。反应结束后,减压真空浓缩反应液,浓缩液用二氯甲烷和稀盐酸萃取,收集水相,将水相继续用二氯甲烷萃取三次,丢弃有机相,水相用过量氨水调至pH至9左右,继续用二氯甲烷萃取,收集有机相用无水硫酸钠干燥,经硅胶柱层析分离纯化得到胺类化合物。
2)将得到的胺类化合物与醛类化合物反应生成具有空间构型的手性双齿氮配体
向胺类化合物中加入甲醛类化合物以及4A分子筛,再加入1,2-二氯乙烷,室温条件下搅拌24h后,过滤4A分子筛并收集滤液;在真空条件下除去滤液中的1,2-二氯乙烷,再加入无水甲醇,并在0℃条件下加入硼氢化钠,恢复至室温后搅拌4h,加水进行淬灭反应,胺类化合物在甲醇作为溶剂的环境下,在硼氢化钠的还原作用下反应生成手性氮氮化合物;反应后,用二氯甲烷萃取淬灭反应后的反应体系,无水硫酸钠干燥萃取后得到的有机相,干燥后再进行减压蒸馏,去除二氯甲烷,同时去除可能残留的甲醇溶剂,粗产物通过柱色谱分离纯化,最终得到手性双齿氮配体的纯品;上述反应过程为一锅法反应,其反应原理是甲醛类化合物和胺类化合物在1,2-二氯甲烷中经分子筛脱水形成亚胺,亚胺在被硼氢化钠还原,得到手性双齿氮配体。
所述醛类化合物的结构如通式(III)所示:
本发明的制备过程中发生的反应方程式为:
优选的,胺类化合物与醛类化合物的摩尔比为1:1.14~1.5;胺类化合物与4A分子筛的质量比为1:10;胺类化合物与1,2-二氯乙烷的质量比为1:25;胺类化合物与无水甲醇的质量比为1:20;胺类化合物与所述硼氢化钠的的摩尔比为1:3。
本发明的基于金鸡纳碱骨架的手性双齿氮配体可应用于催化杂环芳香酮的不对称氢化反应中。
优选的,不对称氢化反应具体为取代或未取代的杂环酮等。
本发明的催化剂为上述手性双齿氮配体及非手性膦配体与过渡金属络合物原位形成的配合物。
优选的,所述过渡金属络合物为铱络合物。
优选的,铱络合物为铱甲氧基环辛二烯二聚体络合物[Ir(COD)OMe]2。
优选的,手性双齿氮配体与铱甲氧基环辛二烯二聚体络合物[Ir(COD)OMe]2的摩尔比为6:1;手性双齿氮配体与非手性膦配体的摩尔比为3:1。
本发明的催化剂,可以催化以氢气为氢源的不对称加氢反应。
以下以具体的反应路线为例进行说明。反应路线I中的手性双齿氮配体为通式(II)的手性双齿氮配体;反应路线I以氢气为氢源,以氢氧化锂为碱,同时采用商业化的非手性膦配体和[Ir(COD)OMe]2配合物作为催化剂进行不对称加氢反应。
在反应路线I中,反应时,将[Ir(COD)OMe]2与手性双齿氮配体及非手性膦配体直接添加至反应中,该反应路线的方式为原位催化。
下面通过实施例对本发明加以说明,但本发明不仅限于以下实施例。
以下实施例中的胺类化合物均为由其对应的金鸡纳碱为原料通过上述反应得到。
以下实施例中,各中间体对应的手性双齿氮配体及其编号如表1所示:
表1
实施例 | 胺类化合物 | 化合物 |
实施例1 | 1a | (1) |
实施例2 | 1a | (2) |
实施例3 | 1a | (3) |
实施例4 | 1a | (4) |
实施例5 | 1b | (5) |
实施例6 | 1c | (6) |
实施例7 | 1a | (7) |
实施例1
化合物(1)的合成:
化合物(1)的合成步骤为,向一个25mL反应瓶中加入1a(0.5g,1.7mmol),多聚甲醛(3.4mmol)和4A分子筛(10g),最后加入10mL1,2-二氯乙烷。室温条件下反应24h后,过滤,滤液收集至另一25mL反应瓶中。真空条件下除去溶剂,加入10mL无水甲醇,并在0℃加入硼氢化钠(193mg,5.1mmol)。恢复至室温后反应4h,加水淬灭反应,并用二氯甲烷萃取反应体系,有机相用无水硫酸钠干燥后过滤,滤液减压条件下除去溶剂,经过柱层析分离得到(1)。
本实施例的产物质量为353mg,产率为67.5%。
产物为淡黄色油状物。1H NMR(400MHz,D2O)δ8.73(d,J=2.0Hz,1H),8.10(d,J=4.0Hz,1H),7.90(d,J=6.0Hz,1H),7.61-7.64(m,1H),7.50-7.53(m,1H),7.42(d,J=2.0Hz,1H),5.53-5.61(m,1H),5.04-5.09(m,2H),4.51(d,J=4.0Hz,1H),3.60(d,J=4.0Hz,1H),3.37(d,J=4.0Hz,3H),3.23-3.30(m,1H),2.58-2.64(m,1H),1.92(s,3H),1.63-1.84(m,3H),1.44(s,1H),0.81(d,J=4.0Hz,2H).13C{1H}NMR(100MHz,D2O)δ149.9,146.6,145.5,136.7,130.5,128.5,128.0,127.8,122.7,118.6,116.6,61.0,55.6,48.4,45.5,35.7,31.8,25.9,22.6,22.5.HRMS(ESI)calcd.for C20H26N3[M+H]+:308.2121,found:308.2123.
实施例2
化合物(2)的合成:
化合物(2)的合成步骤为,向一个25mL反应瓶中加入1a(0.5g,1.7mmo l),丙醛(197mg,3.4mmol)和4A分子筛(10g),最后加入10mL1,2-二氯乙烷。室温条件下反应24h后,过滤,滤液收集至另一25mL反应瓶中。真空条件下除去溶剂,加入10mL无水甲醇,并在0℃加入硼氢化钠(193mg,5.1mmo l)。恢复至室温后反应4h,加水淬灭反应,并用二氯甲烷萃取反应体系,有机相用无水硫酸钠干燥后过滤,滤液减压条件下除去溶剂,经过柱层析分离得到(2)。
本实施例的产物质量为335mg,产率为58.8%。
产物为淡黄色油状物。1H NMR(600MHz,CD3OD)δ8.86(s,1H),8.29-8.43(m,1H),8.08(d,J=6.0Hz,1H),7.60-7.80(m,3H),5.91(d,J=3.0Hz,1H),5.08-5.13(m,2H),2.95-3.02(m,5H),2.30-2.43(m,2H),2.14-2.18(m,1H),1.53-1.57(m,4H),1.40-1.44(m,2H),1.27-1.29(m,2H),1.11(s,1H),0.80-0.82(m,3H).13C{1H}NMR(100MHz,D2O)δ145.0,137.0,136.3,134.9,132.1,130.8,128.5,124.3,123.7,119.8,117.0,67.8,60.5,49.0,48.3,46.3,35.7,25.8,25.0,22.9,22.2,10.5.HRMS(ESI)calcd.for C22H30N3[M+H]+:336.2434,found:336.2433.
实施例3
化合物(3)的合成:
化合物(3)的合成步骤为,向一个25mL反应瓶中加入1a(0.5g,1.7mmo l),戊醛(292mg,3.4mmol)和4A分子筛(10g),最后加入10mL1,2-二氯乙烷。室温条件下反应24h后,过滤,滤液收集至另一25mL反应瓶中。真空条件下除去溶剂,加入10mL无水甲醇,并在0℃加入硼氢化钠(193mg,5.1mmo l)。恢复至室温后反应4h,加水淬灭反应,并用二氯甲烷萃取反应体系,有机相用无水硫酸钠干燥后过滤,滤液减压条件下除去溶剂,经过柱层析分离得到(3)。
本实施例的产物质量为486mg,产率为78.7%。
产物为淡黄色油状物。1H NMR(600MHz,D2O)δ9.04(d,J=3.0Hz,1H),8.45(d,J=6.0Hz,1H),8.12(d,J=3.0Hz,2H),8.03(d,J=3.0Hz,1H),7.88-7.91(m,1H),5.48(d,J=6.0Hz,1H),4.92-4.97(m,2H),4.19-4.23(m,1H),3.25-3.52(m,5H),2.59-2.66(m,2H),2.26(s,1H),1.75(d,J=15.0Hz,3H),1.22-1.34(m,3H),0.86(s,6H),0.46-0.47(m,3H).13C{1H}NMR(150MHz,D2O)δ148.2,144.6,138.5,136.0,135.8,132.0,128.6,123.5,122.3,120.8,117.1,59.6,54.7,49.4,47.3,46.9,35.4,27.6,26.1,25.5,23.3,21.7,21.3,12.8.HRMS(ESI)calcd.for C24H34N3[M+H]+:364.2747,found:364.2742.
实施例4:
化合物(4)的合成
化合物(4)的合成步骤为,向一个25mL反应瓶中加入1a(0.5g,1.7mmo l),庚醛(387mg,3.4mmol)和4A分子筛(10g),最后加入10mL1,2-二氯乙烷。室温条件下反应24h后,过滤,滤液收集至另一25mL反应瓶中。真空条件下除去溶剂,加入10mL无水甲醇,并在0℃加入硼氢化钠(193mg,5.1mmo l)。恢复至室温后反应4h,加水淬灭反应,并用二氯甲烷萃取反应体系,有机相用无水硫酸钠干燥后过滤,滤液减压条件下除去溶剂,经过柱层析分离得到(4)。
本实施例的产物质量为446mg,产率为67.0%。
产物为淡黄色油状物。1H NMR(600MHz,D2O)δ9.16(d,J=3.0Hz,1H),8.59(d,J=3.0Hz,1H),8.22-8.25(m,2H),8.13-8.16(m,1H),8.01-8.04(m,1H),5.62-5.68(m,1H),5.09-5.13(m,2H),4.27(s,1H),3.52-3.64(m,4H),2.72-2.76(m,2H),2.37-2.41(m,1H),1.83-1.95(m,3H),1.34-1.44(m,4H),0.96-1.07(m,10H),0.60-0.62(m,3H).13C{1H}NMR(150MHz,D2O)δ148.9,144.7,138.6,136.0,135.9,131.9,128.6,123.6,122.4,120.7,117.1,67.8,59.8,54.8,49.4,47.3,46.9,35.5,30.6,27.7,26.6,25.4,25.0,23.3,21.7,13.2.HRMS(ESI)calcd.for C26H38N3[M+H]+:392.3060,found:393.3054.
实施例5
化合物(5)的合成:
化合物(5)的合成步骤为,向一个25mL反应瓶中加入1b(0.55g,1.7mmo l),戊醛(292mg,3.4mmol)和4A分子筛(10g),最后加入10mL1,2-二氯乙烷。室温条件下反应24h后,过滤,滤液收集至另一25mL反应瓶中。真空条件下除去溶剂,加入10mL无水甲醇,并在0℃加入硼氢化钠(193mg,5.1mmo l)。恢复至室温后反应4h,加水淬灭反应,并用二氯甲烷萃取反应体系,有机相用无水硫酸钠干燥后过滤,滤液减压条件下除去溶剂,经过柱层析分离得到(5)。
本实施例的产物质量为385mg,产率为65.2%。
产物为淡黄色油状物。1H NMR(600MHz,D2O)δ8.98(d,J=3.0Hz,1H),8.14-8.21(m,2H),7.77-7.80(m,1H),7.69(d,J=1.5Hz,1H),5.66-5.68(m,1H),5.10-5.17(m,2H),4.34(d,J=3.0Hz,1H),3.94-3.99(m,4H),3.59-3.69(m,3H),3.45-3.50(m,1H),2.76-2.84(m,2H),2.43-2.47(m,1H),1.84-1.95(m,3H),1.35-1.53(m,3H),1.02-1.10(m,6H),0.61-0.62(m,3H).13C{1H}NMR(150MHz,D2O)δ161.6,145.8,141.1,136.2,134.8,130.7,128.7,124.0,121.1,116.9,101.7,59.8,56.9,54.9,49.4,47.2,47.0,35.1,27.7,26.1,25.2,23.2,21.8,21.3,12.9.HRMS(ESI)calcd.for C25H36N3O[M+H]+:394.2853,found:394.2846.
实施例6
化合物(6)的合成:
化合物(6)的合成步骤为,向一个25mL反应瓶中加入1c(0.5g,1.7mmo l),戊醛(292mg,3.4mmol)和4A分子筛(10g),最后加入10mL1,2-二氯乙烷。室温条件下反应24h后,过滤,滤液收集至另一25mL反应瓶中。真空条件下除去溶剂,加入10mL无水甲醇,并在0℃加入硼氢化钠(193mg,5.1mmo l)。恢复至室温后反应4h,加水淬灭反应,并用二氯甲烷萃取反应体系,有机相用无水硫酸钠干燥后过滤,滤液减压条件下除去溶剂,经过柱层析分离得到(6)。
本实施例的产物质量为336mg,产率为54.4%。
产物为淡黄色油状物。1H NMR(400MHz,D2O)δ9.16(d,J=4.0Hz,1H),8.65(d,J=6.0Hz,1H),8.22-8.27(m,2H),8.14-8.18(m,1H),8.02-8.05(m,1H),5.70-5.78(m,1H),5.07-5.13(m,2H),4.19-4.26(m,1H),3.77-3.85(m,1H),3.67-3.73(m,1H),3.37-3.52(m,2H),2.68-2.78(m,2H),2.33-2.40(m,1H),1.88-1.92(m,3H),1.58-1.74(m,2H),1.37-1.44(m,3H),0.88-1.03(m,5H),0.58-0.62(m,3H).13C{1H}NMR(150MHz,D2O)δ148.6,144.7,138.6,136.0,135.9,132.0,128.6,123.6,122.4,120.7,117.1,66.0,59.8,54.8,49.4,47.3,46.9,35.5,27.7,25.6,23.3,21.9,21.3,12.9.HRMS(ESI)calcd.for C24H34N3[M+H]+:364.2747,found:364.2745.
实施例7
化合物(7)的合成:
化合物(7)的合成步骤为,向一个25mL反应瓶中加入1c(0.5g,1.7mmo l),2-甲酰吡咯(337mg,3.4mmo l)和4A分子筛(10g),最后加入10mL1,2-二氯乙烷。室温条件下反应24h后,过滤,滤液收集至另一25mL反应瓶中。真空条件下除去溶剂,加入10mL无水甲醇,并在0℃加入硼氢化钠(193mg,5.1mmol)。恢复至室温后反应4h,加水淬灭反应,并用二氯甲烷萃取反应体系,有机相用无水硫酸钠干燥后过滤,滤液减压条件下除去溶剂,经过柱层析分离得到(7)。
本实施例的产物质量为397mg,产率为62.1%。
产物为淡黄色油状物。1H NMR(400MHz,D2O)δ9.11(d,J=2.0Hz,1H),8.62(d,J=4.0Hz,1H),8.12–8.24(m,3H),7.98–8.02(m,1H),5.75–5.84(m,1H),5.19–5.23(m,2H),3.90–4.03(m,1H),3.53–3.59(m,4H),3.36–3.44(m,1H),3.20–3.27(m,2H),2.79(d,J=2Hz,1H),2.53(d,J=2Hz,2H),1.85–1.96(m,8H),1.23–1.36(m,3H),1.10–1.13(m,1H).13CNMR(101MHz,D2O)δ157.11,143.90,137.53,136.52,135.67,131.05,128.79,124.02,121.46,119.42,116.95,61.29,59.89,55.55,48.94,47.07,46.33,44.88,35.73,27.24,25.80,22.78,22.51,22.30.HRMS(ESI)calcd.for C24H32N4[M+H]+:377.2705,found:377.2712.
实施例8
本实施例以化合物(4)及非手性膦(邻甲氧基三苯基膦)作为配体与[Ir(COD)OMe]2配合,并将其应用于2-乙酰基噻吩不对称氢化反应中,具体的步骤为:
向高压釜中加入[Ir(COD)OMe]2(1.42mg,0.0021mmol),化合物(4)(5.03mg,0.012mmol),氢氧化锂(7.2mg,0.3mmol),2-乙酰基噻吩(8.57mmol,1.018g)及乙醇2ml,用氢气将釜内空气置换三次后,调整氢气压力至6.0MPa,反应在35℃条件下进行1h,反应的转化率及对映选择性通过气相色谱进行测定。气相分析条件:色谱柱β-DEX120(30m×0.25mm):温度115℃,柱前压0.06bar,进样量0.1微升,2-乙酰基噻吩出峰时间7.3mi n,1-(2-噻吩)乙醇出峰时间tR(mi nor)=18.7mi n,tR(major)=19.2mi n。
实施例8~34为将实施例8中的配合物应用于多种酮的不对称加氢反应中。
实施例8~34的反应中,各种酮的反应收率及对映选择性参见表2所示。
表2
表2中,分离收率表示分离得到的产物质量与产物理论质量的比例,上述实验中的产率百分比取整数。对映选择性ee表示生成的产物中,一种异构体的含量占产物总量的比例。
另外,需要说明的是,本发明配体的稳定性及其易保存的特点是显然的,含有膦的配体化合物在空气中长期暴露很容易被氧化从而失去活性。一般情况下都不会开展实验去讨论。如果膦配体被氧化,该试剂则完全不能进行上述反应,因此无需特别针对稳定性进行实验。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
2.根据权利要求1所述一种基于金鸡纳碱骨架的手性双齿氮配体,其特征在于,所述通式(I)中两个含氮杂环与氨基连接的碳原子的构型为R型或S型。
5.一种如权利要求1~4任意一项所述基于金鸡纳碱骨架的手性双齿氮配体的制备方法,其特征在于,先将金鸡纳碱类化合物衍生成胺类化合物,再将得到的所述胺类化合物与醛类化合物反应生成具有空间构型的所述手性双齿氮配体。
6.根据权利要求5所述一种基于金鸡纳碱骨架的手性双齿氮配体的制备方法,其特征在于,所述胺类化合物与所述醛类化合物的反应步骤为:
向所述胺类化合物中加入所述醛类化合物以及4A分子筛,再加入1,2-二氯乙烷,室温条件下搅拌24h后,过滤所述4A分子筛并收集滤液;在真空条件下除去滤液中的1,2-二氯乙烷,再加入无水甲醇,并在0℃条件下加入硼氢化钠;恢复至所述室温后搅拌4h,加水进行淬灭反应,并用二氯甲烷萃取淬灭反应后的反应体系,再采用无水硫酸钠干燥萃取后得到的有机相,干燥后再进行减压蒸馏,去除二氯甲烷;将得到的粗产物通过柱色谱分离纯化,得到所述手性双齿氮配体;
其中,所述醛类化合物的结构如通式(III)所示:
反应方程式为:
7.根据权利要求6所述一种基于金鸡纳碱骨架的手性双齿氮配体的制备方法,其特征在于,
所述胺类化合物与所述醛类化合物的摩尔比为1:1.14~3.0;所述胺类化合物与所述4A分子筛的质量比为1:10;所述胺类化合物与所述1,2-二氯乙烷的质量比为1:25;所述胺类化合物与所述无水甲醇的质量比为1:20;所述胺类化合物与所述硼氢化钠的摩尔比为1:3。
8.一种权利要求1~5任意一项所述基于金鸡纳碱骨架的手性双齿氮配体在杂环芳香酮的不对称氢化反应中的应用,其特征在于,将所述手性双齿氮配体与非手性膦配体在过渡金属络合物的作用下,在有机溶剂中对所述杂环芳香酮的不对称氢化反应进行原位催化。
10.根据权利要求9所述基于金鸡纳碱骨架的手性双齿氮配体在杂环芳香酮的不对称氢化反应中的应用,其特征在于,所述过渡金属络合物为[Ir(COD)OMe]2;
所述手性双齿氮配体、所述非手性膦配体以及[Ir(COD)OMe]2的摩尔比为2~8:2~8:1。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310115723.5A CN116283956A (zh) | 2023-02-15 | 2023-02-15 | 基于金鸡纳碱骨架的手性双齿氮配体、制备方法及应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310115723.5A CN116283956A (zh) | 2023-02-15 | 2023-02-15 | 基于金鸡纳碱骨架的手性双齿氮配体、制备方法及应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116283956A true CN116283956A (zh) | 2023-06-23 |
Family
ID=86778843
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310115723.5A Pending CN116283956A (zh) | 2023-02-15 | 2023-02-15 | 基于金鸡纳碱骨架的手性双齿氮配体、制备方法及应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116283956A (zh) |
-
2023
- 2023-02-15 CN CN202310115723.5A patent/CN116283956A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111285901A (zh) | 基于1,1`-联-2-萘酚骨架的手性硫/硒化合物及其制备方法和应用 | |
EP1276745B1 (en) | Ruthenium-diphosphine complexes and their use as catalysts | |
EP4089097A1 (en) | Preparation method for and application of chiral spirocyclic phosphine-nitrogen-phosphine tridentate ligand and iridium catalyst thereof | |
CN114230553B (zh) | 一种左旋烟碱的不对称合成方法 | |
CN104610256A (zh) | 一种四氢化1,5-萘啶类化合物的制备方法及其制得的手性产品 | |
CN108002966B (zh) | 一种合成1,2-二芳基乙烷类化合物的方法 | |
Dindaroğlu et al. | TARTROL-derived chiral phosphine–phosphite ligands and their performance in enantioselective Cu-catalyzed 1, 4-addition reactions | |
CN113244951A (zh) | 介孔分子筛负载的催化剂及其应用 | |
CN117303993A (zh) | 一种镍催化的烯烃不对称氢芳基化方法和应用 | |
CN114213460B (zh) | 一种用于酮不对称氢化反应或转移加氢反应的手性氮氮膦化合物、制备方法及应用 | |
Barbaro et al. | Synthesis and characterization of chiral bis-ferrocenyl triphosphine Ni (II) and Rh (III) complexes and their use as catalyst precursors for acetalization reactions | |
CN116283956A (zh) | 基于金鸡纳碱骨架的手性双齿氮配体、制备方法及应用 | |
CN114315917B (zh) | 手性二茂铁pnno四齿配体及其在不对称氢化反应中的应用 | |
CN113583046B (zh) | 双齿膦配体及其制备方法、应用 | |
Saper et al. | Synthesis of chiral heterobimetallic tris (phosphinoamide) Zr/Co complexes | |
CN112552343B (zh) | 一种轴手性萘-吲哚类膦催化剂及其制备方法与应用 | |
CN111100124B (zh) | 一种线性邻菲咯啉化合物及其制备方法和应用 | |
CN111116450B (zh) | 一种轴手性萘胺方酰胺类有机催化剂及其制备方法和应用 | |
CN114907404A (zh) | 5-(2-(二取代膦基)苯基)-1-烷基-1h-吡唑膦配体及其制备方法和应用 | |
CN111217847A (zh) | 一种硫代硅烷配体及其制备方法和在芳基硼化催化反应中的应用 | |
CN115466288B (zh) | 一类基于手性双膦配体合成硒/硫类配体的方法 | |
CN115155658B (zh) | 一类基于vapol合成硒硫类化合物的合成方法 | |
CN117820316B (zh) | 一种手性吲哚并二氢吡啶并吲哚类化合物及其合成方法 | |
US9340519B2 (en) | Paracyclophane-based ligands, their preparation and use in catalysis | |
CN112300220B (zh) | 手性二茂铁p,n配体衍生物及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |