CN111233913A - 一种制备区分和识别对映异构体的含氟试剂 - Google Patents
一种制备区分和识别对映异构体的含氟试剂 Download PDFInfo
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- 229910052731 fluorine Inorganic materials 0.000 title claims abstract description 57
- 239000011737 fluorine Substances 0.000 title claims abstract description 57
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 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 title claims abstract description 21
- 239000003153 chemical reaction reagent Substances 0.000 title abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 45
- 239000000523 sample Substances 0.000 claims abstract description 35
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- 150000004292 cyclic ethers Chemical class 0.000 claims abstract description 5
- 238000001228 spectrum Methods 0.000 claims description 37
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- -1 cyclic alcohols Chemical class 0.000 claims description 25
- 238000004293 19F NMR spectroscopy Methods 0.000 claims description 21
- 238000006467 substitution reaction Methods 0.000 claims description 18
- 239000012491 analyte Substances 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 238000012937 correction Methods 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000006736 (C6-C20) aryl group Chemical group 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 238000005259 measurement Methods 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 8
- 230000007935 neutral effect Effects 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
- DVWQNBIUTWDZMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-ol Chemical group C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=CC=CC2=C1 DVWQNBIUTWDZMW-UHFFFAOYSA-N 0.000 claims description 5
- 229910052796 boron Inorganic materials 0.000 claims description 5
- 150000002170 ethers Chemical class 0.000 claims description 5
- 229910052733 gallium Inorganic materials 0.000 claims description 5
- 229910052738 indium Inorganic materials 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 125000005555 sulfoximide group Chemical group 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- 229910052720 vanadium Inorganic materials 0.000 claims description 5
- UPULOMQHYQDNNT-UHFFFAOYSA-N 5h-1,3-oxazol-2-one Chemical class O=C1OCC=N1 UPULOMQHYQDNNT-UHFFFAOYSA-N 0.000 claims description 4
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- 150000004657 carbamic acid derivatives Chemical class 0.000 claims description 4
- 150000001735 carboxylic acids Chemical class 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 239000002879 Lewis base Substances 0.000 claims description 2
- 150000003950 cyclic amides Chemical class 0.000 claims description 2
- 150000003997 cyclic ketones Chemical class 0.000 claims description 2
- 150000007527 lewis bases Chemical class 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 14
- 150000001412 amines Chemical class 0.000 abstract description 6
- 238000010521 absorption reaction Methods 0.000 abstract description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 57
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 239000007787 solid Substances 0.000 description 23
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- 238000001514 detection method Methods 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 239000000126 substance Substances 0.000 description 10
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000001212 derivatisation Methods 0.000 description 4
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- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 238000013461 design Methods 0.000 description 3
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- 238000011160 research Methods 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 108091027076 Spiegelmer Proteins 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 239000011903 deuterated solvents Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000806 fluorine-19 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000012521 purified sample Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VIYKYVYAKVNDPS-HKGPVOKGSA-N (2s)-2-azanyl-3-[3,4-bis(oxidanyl)phenyl]propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 VIYKYVYAKVNDPS-HKGPVOKGSA-N 0.000 description 1
- AJKNNUJQFALRIK-UHFFFAOYSA-N 1,2,3-trifluorobenzene Chemical compound FC1=CC=CC(F)=C1F AJKNNUJQFALRIK-UHFFFAOYSA-N 0.000 description 1
- KCOPAESEGCGTKM-UHFFFAOYSA-N 1,3-oxazol-4-one Chemical compound O=C1COC=N1 KCOPAESEGCGTKM-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- WXCPOOYYSDHTPQ-UHFFFAOYSA-N 3-bromo-2-phenylmethoxybenzaldehyde Chemical compound BrC1=CC=CC(C=O)=C1OCC1=CC=CC=C1 WXCPOOYYSDHTPQ-UHFFFAOYSA-N 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- HUOFUOCSQCYFPW-UHFFFAOYSA-N [4-(trifluoromethoxy)phenyl]boronic acid Chemical compound OB(O)C1=CC=C(OC(F)(F)F)C=C1 HUOFUOCSQCYFPW-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical class [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 230000007321 biological mechanism Effects 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
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
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- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
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- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
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- 229960003638 dopamine Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- 239000000706 filtrate Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 238000012216 screening Methods 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
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 239000003579 shift reagent Substances 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 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
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/06—Aluminium compounds
- C07F5/069—Aluminium compounds without C-aluminium linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
- G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
- G01N24/087—Structure determination of a chemical compound, e.g. of a biomolecule such as a protein
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- High Energy & Nuclear Physics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Molecular Biology (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种制备区分和识别对映异构体的含氟试剂,具体地,本发明提供了一种含氟探针配合物,所述配合物具有下式I或II所示的结构。所述的试剂可以对醇,胺,酰胺,羧酸,亚砜,环醚等大量不同的手性分子进行快速区分检测,不需要样品具有紫外吸收或结晶性。该方法也可以用于对手性分子绝对构型的快速判断及在复杂体系中同时检测多种不同的手性分子。
Description
技术领域
本发明属于分析化学领域。具体地,本发明设计合成了一系列手性的含氟探针分子。当探针分子和不同构型的手性分析物络合时会产生不同的氟谱信号从而实现手性分子的区分检测。本方法可以对醇,胺,酰胺,羧酸,亚砜,环醚、氨基甲酸酯、噁唑啉酮、亚砜亚胺等大量不同的手性分子进行快速区分检测,不需要样品具有紫外吸收或结晶性。方法也可以用于对手性分子绝对构型的快速判断及在复杂体系中同时检测多种不同的手性分子。
背景技术
手性分子在医药,材料及生命科学等领域中具有极其重要的地位,因为对映异构体在手性环境中常表现出不同功能和性质,所以快速可靠的方法来鉴定对映异构体具有十分重要的研究价值。目前,鉴定对映异构体的方法主要手性高效液相色谱和X-射线单晶衍射等手段。这些方法通常需要纯化的样品,对样品的光吸收性质或结晶性也有一定要求。同时,单晶的培养及色谱分离条件的筛选较为耗时,难于用于大量样品的快速区分和检测。
与色谱法不同,核磁共振波谱是一种不基于分离的测试手段。由于其检测仅依靠能量很低的射频辐射,不具有破坏性,目前已经广泛用于生物机制研究及疾病诊断等领域。利用核磁共振分析手性分子的方法已经有不少报道,主要是利用手性化学衍生化试剂或手性化学位移试剂与待测手性分子形成一对非对映异构体。利用非对映异构体核磁共振信号存在的差异实现区分检测。因为这些方法通常基于分子的氢谱信号,通常需要氘代溶剂和纯化后的样品。在分析复杂结构时,信号重叠常常给谱图解析带来困难,使其难于应用于复杂体系中手性物质的直接检测。同时,衍生化反应也会使分析检测方法变得复杂,难于广泛应用。
综上所述,需要开发新型高效,快速,适用范围广适用的手性分子区分检测手段,弥补传统方法不足。
发明内容
本发明的目的是提供一种可以用于快速区分检测手性分析物的探针分子。发明内容也包括探针分子及其前体分子的合成方法。
本发明的第一方面,提供了一种含氟探针配合物,所述配合物具有下式I或II所示的结构:
式中,R1为选自下组的基团:取代或未取代的C1~C10的烷基,取代或未取代的C6~C20的芳基,取代或未取代的5~20元杂芳基;其中,所述的杂芳基骨架上具有选自N、O或S的1-8个杂原子;
R2选自下组:取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C6~C20芳基、取代或未取代的5~20元杂芳基;其中,所述的杂芳基骨架上具有选自N、O或S的1-8个杂原子;其中,所述的取代指集团上的一个或多个氢原子被选自下组的取代基取代:卤素,C1-C4卤代烷基;
L为路易斯碱中性配位分子;
M选自下组:Al、B、Ga、In或V;
所述的联萘酚骨架既可以为R构型,也可以为S构型;
除非特别说明,所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素,C1-C4烷基、C1-C4卤代烷基。
在另一优选例中,L为选自下组的分子:C1-C6的链状或环状醇,C1-C6的链状或环状醚,C1-C6的链状或环状酰胺,C1-C6的链状或环状亚砜,C1-C6的链状或环状砜,C1-C6的链状或环状醛,C1-C6的链状或环状酮,C1-C6的链状或环状羧酸。
在另一优选例中,所述的L为选自下组的分子:四氢呋喃、甲醇,乙醇,异丙醇,叔丁醇,乙醚,环戊基甲基醚,乙腈,丙酮,2-甲基四氢呋喃,二甲基亚砜,N,N-二甲基甲酰胺。
在另一优选例中,所述的R2选自下组:三氟甲基、三氟甲氧基、九氟叔丁氧基,或三氟甲基、三氟甲氧基、九氟叔丁氧基取代的选自下组的基团:C6~C20的芳基、5~20元杂芳基。
在另一优选例中,所述的配合物具有选自下组的结构:
本发明的第二方面,提供了一种配体,其特征在于,所述配体具有下式III或IV所示的结构:
式中,R1为选自下组的基团:取代或未取代的C1~C10的烷基,取代或未取代的C6~C20的芳基,取代或未取代的5~20元杂芳基;其中,所述的杂芳基骨架上具有选自N、O或S的1-8个杂原子;
R2选自下组:取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C6~C20芳基、取代或未取代的5~20元杂芳基;其中,所述的杂芳基骨架上具有选自N、O或S的1-8个杂原子;其中,所述的取代指集团上的一个或多个氢原子被选自下组的取代基取代:卤素,C1-C4卤代烷基;
L为中性配位分子;
M选自下组:Al、B、Ga、In或V;
所述的联萘酚骨架既可以为R构型,也可以为S构型;
除非特别说明,所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素,C1-C4烷基、C1-C4卤代烷基。
在另一优选例中,所述的R2选自下组:三氟甲基、三氟甲氧基、九氟叔丁氧基,或三氟甲基、三氟甲氧基、九氟叔丁氧基取代的选自下组的基团:C6~C20的芳基、5~20元杂芳基。
在另一优选例中,所述的配合物具有选自下组的结构:
本发明的第三方面,提供了一种区分和识别对映异构体的方法,所述的方法包括步骤:
(1)在惰性溶剂中,用如本发明第一方面中的式I或式II配合物与待测的手性对映异构体混合,得到第二配合物;
(2)对所述的第二配合物进行19F NMR,分别得到氟谱信号I(left)和I(right);
其中,I(left)指测定中左侧的氟谱积分值,I(right)指测定中右侧的氟谱积分值;
(3)通过所述步骤(2)中得到的氟谱信号确定待测的手性对映异构体构型。
在另一优选例中,所述的方法还包括如下的误差校正步骤:
(i)确定矫正因子α,所述的矫正因子α=I0(left)/I0(right);
其中,I0(left)指在该方法下,分析物为外消旋体时左侧的氟谱积分值,I0(right)指在该方法下,分析物为外消旋体时右侧的氟谱积分值;
(ii)通过以下方法计算得出ee值:
ee=(I(left)-αI(right))/(I(leftt)+αI(right))
其中,I(left)指测定中左侧的氟谱积分值,I(right)指测定中右侧的氟谱积分值。
在另一优选例中,所述待测的手性对映异构体选自下组:醚、胺醇、酰胺、亚砜、氮氧化物、羧酸、氨基甲酸酯、噁唑啉酮、亚砜亚胺。
在另一优选例中,述的惰性溶剂为有机溶剂,较佳地选自下组:氯仿、二氯甲烷、甲苯、正己烷、苯、石油醚、四氯化碳、乙腈、乙酸乙酯或其他溶剂。
在另一优选例中,所述的待测的手性对映异构体为碳原子数为C1-C50的分子。
在另一优选例中,所述的溶剂可以为氘代溶剂或非氘代溶剂。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1为本申请的探针分子用于识别检测的示意图。其中,当构型为R和S的分析物分辨与手性含氟探针分子络合时会产生化学位移不同的氟谱信号,从而能够实现手性分子的区分能识别。例如图中的红色及蓝色的氟谱信号分别由不同构型的分析物产生。
图2为探针分子A1区分和识别对映异构体的效果图。
图3为探针分子A1对不同手性醇的区分识别效果图。
图4为探针分子A1对不同种类的对映异构体的区分和识别效果图。
图5为探针分子6a对烷基醇和芳基醇的区分和识别效果图,其中,图5a、图5b,图5d,图5e为光学纯构型的19F NMR图谱,图5c与图5f为消旋体的19F NMR图谱。
图6为对映体过量矫正原理示意图。
图7为通过对映体矫正方法测量对映体过量的结果图。
具体实施方式
能够用于区分和识别对映异构体的试剂。用所述的试剂进行对映异构体进行区分和识别,只需要将试剂与对映异构体混合测其19F NMR,通过分析氟谱得化学位移就能够快速便捷的鉴定手性醇,手性胺,手性酰胺,手性醚,手性亚砜等中性有机化合物;而且通过分析其氟谱的积分并矫正之后便能准确测得性醇,手性胺,手性酰胺,手性醚,手性亚砜等中性有机化合物对映体过量。且该试剂制备的反应条件温和,成本低,非常适合用于工业化,大规模地生产。
术语
如本文所用,术语“C1~C10烷基”指具有1~10个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基,或类似基团。
术语“C6~C20芳基”指具有6~20个碳原子的芳基,包括单环或多环芳基,例如苯基、萘基,或类似基团。一种优选的实施例中,所述的芳基可以是C6-C10芳基。
术语“5-20元杂芳基”指具有5~20个环原子的杂芳基(骨架上具有选自N、O或S的1-8个杂原子),例如吡咯基、吡啶基、呋喃基,或类似基团。一种优选的实施例中,所述的杂芳基可以是5-12元杂芳基。
术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代:C1~C10烷基、C3~C10环烷基、C1~C10烷氧基、卤素、羟基、羧基(-COOH)、C1~C10醛基、C2~C10酰基、C2~C10酯基、氨基、苯基;所述的苯基包括未取代的苯基或具有1-3个取代基的取代苯基,所述取代基选自:卤素、C1-C10烷基、氰基、OH、硝基、C3~C10环烷基、C1~C10烷氧基、氨基。
一种能识别对映异构体的试剂的合成
本发明设计合成了一系列手性的含氟探针分子。当探针分子和不同构型的手性分析物络合时会产生不同的氟谱信号从而实现手性分子的区分检测。本方法可以对醇,胺,酰胺,羧酸,亚砜,环醚等大量不同的手性分子进行快速区分检测,不需要样品具有紫外吸收或结晶性。方法也可以用于对手性分子绝对构型的快速判断及在复杂体系中同时检测多种不同的手性分子。由于这些优点,该方法在手性物质分辨,质量控制,药物分子光学纯度测定及构型确定等方面具有广泛的应用。
含氟探针分子的合成设计路线:当手性胺和芳香醛的反应比例不同,可以得到下列两类手性含氟探针。
具体地,所述的手性含氟探针分子具有如下式I或式II所示的结构:
式中,R1为选自下组的基团:取代或未取代的C1~C10的烷基,取代或未取代的C6~C20的芳基,取代或未取代的5~20元杂芳基;其中,所述的杂芳基骨架上具有选自N、O或S的1-8个杂原子;
R2选自下组:取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C6~C20芳基、取代或未取代的5~20元杂芳基;其中,所述的杂芳基骨架上具有选自N、O或S的1-8个杂原子;其中,所述的取代指集团上的一个或多个氢原子被选自下组的取代基取代:卤素,C1-C4卤代烷基
L为中性配位分子;
M选自下组:Al、B、Ga、In或V;
所述的联萘酚骨架既可以为R构型,也可以为S构型;
除非特别说明,所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素,C1-C4烷基、C1-C4卤代烷基。
应立即,本发明的式I和式II可以用以下两种不同形式表述,当用以下两种形式书写时,均意在代指式I或式II的化合物:
一种对映异构体的区分和检测的方法
对映异构体的独特之处在于其通常具有相同的物理及化学性质,但在手性环境中却常常表现出功能上的显著差异。例如用于帕金森病药物治疗的L-多巴(L-DOPA)可以在脱羧酶的作用下转化为多巴胺,其对紊乱的神经系统活动进行调节。其镜像异构体则不能在酶的作用下脱羧,导致该异构体在体内积累,产生毒害作用,不能用于医疗。所以快速便捷的区分和识别对映异构体具有极为重要的应用价值。
本发明的对映异构体的区分和检测原理为:本发明提供的手性含氟探针是一种有活性配位点的光学纯络合物,它的其中一个配体可以与对映异构体实现动态交换,当对映异构体与该试剂配位,就会生成一对非对映异构体,即会诱导出两个化学位移不同的氟信号。因此,根据所产生的化学位移不同的信号就可以实现手性分析物的区分和检测,检测原理示意图如图1所示。
具体地,本发明提供了一种快速便捷地测定对映体过量的方法,所述方法包括:
(1)在惰性溶剂中,用如本发明的第一方面中的式I或式II配合物与待测的手性对映异构体按照一定比例混合,得到第二配合物;
(2)对所述的第二配合物进行19F NMR,得到氟谱信号;
(3)通过所述步骤(2)中得到的氟谱信号分析其峰的归属,确定对应的构型。然后通过对氟谱积分的分析,并矫正之后计算出对映体过量。
在另一优选例中,上所述的溶剂为有机溶剂,较佳的选自下组:氯仿、二氯甲烷、甲苯、正己烷、苯、石油醚、四氯化碳、乙腈、乙酸乙酯或其氘代溶剂。
所述的对映异构体可以为醚、胺醇、酰胺、亚砜、氮氧化物、羧酸、氨基甲酸酯、噁唑啉酮、亚砜亚胺等大量不同种类的手性分子。
在另一优选例中,上所述的溶剂为有机溶剂,较佳的选自下组:氯仿、二氯甲烷、甲苯、正己烷、苯、石油醚、四氯化碳、乙腈、乙酸乙酯或其氘代溶剂。
所述的对映异构体可以为醚、胺醇、酰胺、亚砜、氮氧化物、羧酸、氨基甲酸酯、噁唑啉酮、亚砜亚胺等大量不同种类的手性分子。
上述方法中,含氟试剂与对映异构体的混合比例没有一定的限制。
上述方法中,核磁的测试温度为-78-80℃。
本发明的含氟探针对分析对映体过量的原理为:本发明提供的手性含氟探针可以与对映异构体络合,因为与不同构型的光学纯分析物络合会产生不同化学位移的氟信号,通过分析不同氟信号的积分,就可以确定对映体之间的比例,从而可以计算出对映体过量。
发明人在研究中发现,本发明提供的手性含氟探针有一个手性口袋的光学纯络合物,其对不同的构型的对映体具有一定选择性,造成与对映异构体之间的络合强度差异。考虑到直接根据氟谱信号积分来分析对映体过量所产生的部分误差,因此,在分析氟谱的时候,进一步对其积分进行矫正,减少误差,该误差校正的原理如图6所示。
具体地,所述的误差校正包括步骤:
(i)确定过量的对映异构体的构型;
(ii)确定矫正因子α,所述的矫正因子α=I0(left)/I0(right);
其中,I0(left)指在该方法下,分析物为外消旋体时左侧的氟谱积分值,I0(right)指在该方法下,分析物为外消旋体时右侧的氟谱积分值;
(iii)通过以下方法计算得出ee值:
ee=(I(left)-αI(right))/(I(leftt)+αI(right))
其中,I(left)指测定中左侧的氟谱积分值,I(right)指测定中右侧的氟谱积分值。
本发明的主要优点:
(1)本发明的试剂能够高效率、快捷的鉴定对映异构体,分析数据简单。
(2)本发明试剂制法简单,易于获得。
(3)本发明的方法能够广泛地应用于多类手性化合物的鉴定合成,在药物设计和合成、农药制备等领域都具有极大的应用价值。
(4)本发明对待测物的紫外吸收性质和结晶性没有要求。
(5)本发明方法不经分离化学衍生化可以同时对多种手性分析物实现区分检测。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
合成例
通用方法酚羟基保护
将(6.0g,18.3mmol,1.0equiv)和Cs2CO3(11.9g,36.5mmol,2.0equiv)加入反应瓶中,然后加入乙腈(100mL)并搅拌,然后再加入溴化苄(4.1g,23.8mmol,1.3equiv),让这反应体系在室温下搅拌3小时.滤去沉淀,旋转蒸发去除溶剂,经柱层析得白色固体(7.2g,17.2mmol,yield:94%).M.P.:98–100℃.IR:3358,3058,2842,1684,1617,1584,1497,1454,1265,1181,1075,1019,995,808,746,686,545cm-1.1H NMR(400MHz,Chloroform-d)δ10.4(s,1H),8.6(s,1H),8.1(dd,J=12.0,8.7Hz,2H),7.9(d,J=8.3Hz,1H),7.5–7.4(m,2H),7.4–7.3(m,2H),7.3(td,J=7.5,6.6,1.4Hz,2H),7.3–7.1(m,4H),6.8–6.7(m,2H),4.6(q,2H),3.8(s,3H).13C NMR(101MHz,Chloroform-d)δ190.8,155.3,155.1,137.3,136.2,133.9,130.7,130.5,130.3,130.2,129.1,129.07,129.06,128.35,128.33,128.1,127.1,127.0,125.86,125.85,125.0,123.9,117.9,113.4,77.0,56.5.HRMS(ESI):计算值C29H23O3[M+H]+419.1642,实际值:419.1633.
采用类似方法制备得到化合物3。
白色固体(Yield:93%).M.P.:35–37℃.IR:2943,2843,1716,1506,1472,1456,1362,1251,1195,1171,1114,1075,1052,966,757,696,556cm-1.1H NMR(400MHz,Chloroform-d)δ10.18(s,1H),7.74(dd,J=7.8,1.7Hz,1H),7.54(m,1H),7.37(s,5H),7.22(t,J=8.0,1H),5.19(s,2H).19F NMR(376MHz,Chloroform-d)δ-57.71(s,3F).13C NMR(101MHz,Chloroform-d)δ188.6,153.5,142.6,142.6,135.3,131.4,129.0,128.8,128.2,126.5,124.5,120.6(q,J=259.2Hz),77.7.HRMS(ESI):计算值C15H11O3F3Na[M+Na]+319.0553,实际值:319.0552.
在氮气氛围下,将(2.0g,3.91mmol)溶于无水THF(20mL)中并将反应体系降温至78℃,然后缓慢滴加正丁基锂(2.5M in hexane,1.88mL,1.2equiv)并维持搅拌30分钟.加入无水DMF(1.51mL,5.0equiv),然后让反应体系缓慢升温至室温,加入盐酸(20mL,3N)并搅拌1小时,用乙酸乙酯(3×50mL)萃取.合并有机相并用无水Na2SO4干燥,旋转蒸发去除溶剂,经柱层析得白色固体(1.49g,3.26mmol,yield:83%).M.P.:93–95℃.IR:2861,1690,1610,1576,1510,1467,1379,1370,1260,1137,1137,而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常Chloroform-d)δ9.9(s,1H),7.5–7.5(m,1H),7.4–7.3(m,4H),7.3-7.2(m,2H),5.1(s,2H),2.4(s,3H).19FNMR(376MHz,Chloroform-d)δ-69.3(s,9F).13CNMR(101MHz,Chloroform-d)δ188.9,152.3,146.5,135.0,134.8,131.2,129.7,129.1,128.9,128.7,126.3,119.9(q,J=292.7Hz),81.7(deca,J=28.28Hz),77.9,20.8.HRMS(ESI):计算值C19H14O3F9[M+H]+461.0794,实际值:461.0788.
在氮气氛围下,将2-(苄氧基)-3-溴苯甲醛(3.0g,10.3mmol,1.0equiv),4-(三氟甲氧基)苯硼酸(2.55g,12.37mmol,1.2equiv),K2CO3(5.7g,41.22mmol,4.0equiv)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯加入250mL得反应瓶中,然后加入乙二醇二甲醚(100mL)。让该反应80℃条件下搅拌过夜。过滤,旋转蒸发去除溶剂,经柱层析得白色固体(3.10g,8.33mmol,yield:80%).M.P.:83–85℃.IR:3347,3072,2860,1692,1576,1510,1462,1443,1271,1218,1156,1068,961,853,805,794,704,674,649,641,578,564cm-1.1H NMR(400MHz,Chloroform-d)δ10.33(d,J=0.9Hz,1H),7.85(dd,J=7.7,1.8Hz,1H),7.65–7.55(m,3H),7.36–7.19(m,5H),7.04–6.96(m,2H),4.55(s,2H).19F NMR(376MHz,Chloroform-d)δ-57.82(s,3F).13C NMR(101MHz,Chloroform-d)δ189.9,159.0,148.9,136.9,135.8,135.2,130.7,130.3,128.8,128.7,128.5,128.08,124.3,121.8,119.2(q,J=255.6Hz),99.9,77.7.HRMS(ESI):计算值C21H16O3F3[M+H]+373.1046,实际值:373.1040.
通用方法 肟的制备
将(2.0g,4.8mmol,1.0equiv)溶于乙醇(50mL),将NaOH(573mg,14.3mmol,3.0equiv)和盐酸羟胺(830mg,12.0mmol,2.5equiv)溶于水(5mL)中,然后将水溶液缓慢滴加入乙醇溶液中并搅拌3小时。旋转蒸发去除溶剂,乙酸乙酯(100×3mL)萃取.合并有机相,无水硫酸钠干燥,经柱层析得白色固体(1.78g,4.11mmol,yield:85%).M.P.:90 92℃.IR:3064,2837,1959,1621,1591,1507,1497,1353,1332,1263,1246,1147,1103,1077,1044,975,861,807,746,700,628,610,532cm-1.1H NMR(400MHz,Chloroform-d)δ8.63(s,1H),8.45(s,1H),8.04(d,J=9.1Hz,1H),7.95(d,J=8.1Hz,1H),7.90(s,1H),7.49–7.38(m,2H),7.35(m,1H),7.32–7.08(m,7H),6.77–6.69(m,2H),4.71–4.43(m,2H),3.78(s,3H).13C NMR(101MHz,Chloroform-d)δ155.0,153.1,147.4,136.6,135.0,134.0,130.7,130.1,129.1,128.8,128.18,128.11,128.0,127.8,127.1,126.9,126.8,126.3,125.7,125.5,125.4,125.2,123.8,118.5,113.5,76.2,56.5.HRMS(ESI)计算值C29H24O3N[M+H]+434.1751,实际值:434.1739.
采用类似方法制备得到化合物S6b-S6d。
白色固体(yield:92%).M.P.:61–63℃.IR:3229,2873,2358,2334,1625,1459.6,1305,1258,1202,1151,1074,967,900,887,782,745,693,654,585cm-1.1H NMR(400MHz,Chloroform-d)δ8.3(s,1H),7.7(dd,J=7.9,1.5Hz,1H),7.5(s,1H),7.4–7.3(m,6H),7.1(t,J=8.0Hz,1H),5.0(s,2H).19F NMR(376MHz,Chloroform-d)δ-57.6(s,3F).13C NMR(101MHz,Chloroform-d)δ149.3,145.6,142.7,142.7,135.9,128.7,128.6,128.0,124.7,124.6,123.7,119.3(q,J=259.6Hz),76.9.HRMS(ESI):计算值C15H13O3NF3[M+H]+312.0842,实际值:312.0835.
白色固体(yield:86%).M.P.:95–97℃.IR:3275,2359,1591,1507,1455,1433,1400,1258,1214,1196,1165,968,953,915,853,800,765,752,696,634,607,530cm-1.1HNMR(400MHz,Chloroform-d)δ8.46(s,1H),7.78(dd,J=7.8,1.7Hz,1H),7.62–7.53(m,2H),7.37(dd,J=7.6,1.8Hz,1H),7.33(s,1H),7.31–7.16(m,7H),7.07–6.94(m,2H),4.43(s,2H).19F NMR(376MHz,Chloroform-d)δ-57.83(s,3F).13C NMR(101MHz,Chloroform-d)δ154.7,148.8,148.7,146.5,136.5,135.7,134.8,132.6,130.7,128.6,128.4,126.5,126.3,124.9,120.9,120.6(q,J=257.0Hz),76.75.HRMS(ESI):计算值C21H17O3NF3[M+H]+388.1155,实际值:388.1147.
白色固体(yield:90%).M.P.:95–97℃.IR:3374,2357,1684,1617,1583,1469,1249,1139,1075,967,808,695,609,570,536cm-1.1H NMR(400MHz,Chloroform-d)δ8.2(s,1H),7.5–7.4(s,1H),7.4–7.3(m,6H),7.1(d,J=2.0Hz,1H),4.9(s,2H),2.3(s,3H).19FNMR(376MHz,Chloroform-d)δ-69.3(s,9F).13C NMR(101MHz,Chloroform-d)δ148.2,146.5,145.8,135.9,134.6,128.6,128.5,128.5,127.5,125.3,124.8,120.0(q,J=292.6Hz),81.6(deca,J=29.8Hz),77.2,21.0.HRMS(ESI):计算值C19H15O3NF9[M+H]+476.0903,实际值:476.0891.
通用方法 伯胺的制备
将(1.5g,3.5mmol,1.0equiv)溶于无水乙醚(20mL)中,LiAlH4(328mg,8.65mmol,2.5equiv)按份缓慢加入,搅拌2小时,缓慢滴加水.过滤去除固体,滤液用乙醚(50×3mL)萃取.将有机相合并,无水Na2SO4干燥,经柱层析得淡黄色固体(870mg,2.1mmol,yield:59%).M.P.:64 65℃.IR:3069,3010,2913,2835,1621,1591,1506,1455,1429,1354,1263,1246,1229,1146,1101,1077,1018,979,806,745,698,610,527cm-1.1H NMR(400MHz,Chloroform-d)δ8.01(d,J=9.0Hz,1H),7.87(d,J=8.6Hz,3H),7.48–7.05(m,10H),6.75(d,J=7.0Hz,2H),4.51(d,J=2.9Hz,2H),4.03(d,J=3.4Hz,2H),3.77(s,3H).13C NMR(101MHz,Chloroform-d)δ155.0,153.8,137.2,134.0,133.4,130.9,130.0,129.1,128.1,128.0,127.9,127.9,127.8,127.7,127.3,126.8,125.8,125.4,125.3,125.2,124.9,123.7,119.3,113.6,75.0,56.5,42.9.HRMS(ESI):计算值C21H17O3NF3[M+H]+419.1885,实际值:419.1878.
采用类似方法制备得到化合物2b-2d。
淡黄色液体(yield:64%).IR:3032,2886,1635,1497,1470,1247,1225,1161,1077,970,914,858,794,753,695,633,557cm-1.1H NMR(400MHz,Chloroform-d)δ7.45–7.28(m,5H),7.26–7.16(m,3H),7.08(t,J=7.9Hz,1H),5.04(s,2H),3.76(s,2H).19F NMR(376MHz,Chloroform-d)δ-57.49(s,3F).13CNMR(101MHz,Chloroform-d)δ148.6,142.3,139.0,136.7,128.6,128.4,128.4,127.0,124.3,120.9,119.4(q,J=259.4Hz),75.9,41.7.HRMS(ESI):计算值C15H15O2NF3[M+H]+298.1049,实际值:298.1048.
黄色油状液体(yield:53%).IR:3109,3031,2876,2359,1508,1455,1251,1204,1160,1104,1077,1018,977,918,851,793,762,738,696,559cm-1.1HNMR(400MHz,Chloroform-d)δ7.69–7.58(m,2H),7.46–7.13(m,8H),7.11–6.99(m,2H),4.41(s,2H),3.89(s,2H).19F NMR(376MHz,Chloroform-d)δ-57.82(s,3F).13C NMR(101MHz,Chloroform-d)δ154.1,148.5,137.4,137.3,136.5,134.1,130.7,129.7,128.5,128.46,128.44,128.2,124.7,120.8,120.5(q,J=258.56Hz),75.3,42.2.HRMS(ESI):计算值C21H19O2NF3[M+H]+374.1362,实际值:374.1358.
黄色油状液体(yield:71%).IR:2883,2359,2338,1843,1771,1683,1521,1456,1269,1225,1172,1051,1003,969,915,856,737,697,527cm-1.1H NMR(400MHz,Chloroform-d)δ7.4–7.3(m,5H),7.0–7.0(m,2H),4.9(s,2H),3.6(s,2H),2.3(s,3H).19FNMR(376MHz,Chloroform-d)δ-69.3(s,9F).13C NMR(101MHz,Chloroform-d)δ147.3,146.2,138.5,136.8,134.3,128.5,128.4,128.3,127.6,122.1,120.0(q,J=292.6Hz),81.5(deca,J=29.8Hz),76.0,41.6,20.9.HRMS(ESI):计算值C19H17O2NF9[M+Na]+462.1110,实际值:462.1104.
通用方法 三级胺的制备
将(300mg,1.45mmol,1equiv)和(1.33g,3.19mmol,2.2equiv)溶于无水THF(20mL)之中,在60℃的条件下搅拌3小时.然后将反应体系降至室温,然后加入三乙酰基硼氢化钠(920.8mg,4.34mmol,3.0equiv).缓慢加入饱和的NaHCO3(50mL)溶液,然后用乙酸乙酯(50×3mL)萃取.合并有机相,然后用无水Na2SO4干燥,经柱层析得白色固体(1.17g,1.06mmol,yield:73%).M.P.:92–94℃.IR:3509,2935,2836,1621,1592,1508,1469,1430,1345,1262,1246,1172,1147,1074,979,904,858,806,746,696,628,557cm-1.1H NMR(400MHz,Chloroform-d)δ8.44(s,2H),8.05(d,J=9.0Hz,2H),7.93(d,J=8.1Hz,5H),7.53–7.41(m,4H),7.41–7.13(m,17H),7.11–6.97(m,6H),6.62(d,J=6.9,1.5Hz,4H),5.00(s,2H),4.51(q,J=10.8Hz,4H),4.04(q,J=21.6Hz,4H),3.93(dd,J=10.8Hz,J=21.6Hz 2H),3.78(s,6H).19F NMR(376MHz,Chloroform-d)δ-57.29(s,3F).13C NMR(101MHz,Chloroform-d)δ155.0,154.1,149.0,142.5,142.4,137.2,136.7,135.9,134.1,133.2,133.0,131.1,129.8,129.1,128.4,128.3,128.19,128.15,127.9,127.90,127.8,127.4,126.8,125.6,124.6,125.5,125.4,125.3,124.7,124.3,123.6,122.0,120.4(q,J=259.4Hz),119.4,113.5,75.7,75.0,56.4,53.4,52.7.HRMS(ESI):计算值C73H59O6NF3[M+H]+1102.4289,实际值:1102.4283.
采用类似方法制备得到化合物4,S7c和S7d。
白色固体(yield:68%).M.P.:59–61℃.IR:3032,2933,2360,1507,1455,1248,1224,1190,1170,1097,1077,978,913,807,750,697,631,528cm-1.1H NMR(400MHz,Chloroform-d)δ8.28(s,1H),8.08(d,J=9.0Hz,1H),8.01–7.91(m,2H),7.78(dd,J=7.8,1.6Hz,2H),7.48(m,2H),7.44–7.37(m,5H),7.37–7.25(m,12H),7.20–7.07(m,5H),6.73–6.66(m,2H),5.02(s,4H),4.66–4.44(m,2H),4.02–3.71(m,9H).19F NMR(376MHz,Chloroform-d)δ-57.27(s,6F).13C NMR(101MHz,Chloroform-d)δ155.1,154.2,149.2,142.55,142.53,137.3,136.8,135.6,134.1,133.4,132.7,131.1,130.0,129.2,128.5,128.5,128.4,128.3,128.1,128.0,127.9,127.8,127.6,126.9,125.8,125.62,125.59,125.4,124.9,124.4,123.4,120.8(q,J=258.56Hz),120.6,119.4,113.5,75.9,75.1,56.4,53.5,52.5.HRMS(ESI):计算值C59H48O6NF6[M+H]+980.3380,实际值:980.3383.
白色固体(yield:83%).M.P.:118-120℃.IR:3058,2925,2358,2343,1621,1591,1508,1454,1353,1247,1219,1147,1074,1042,1018,980,906,851,806,746,696,643,571cm-1.1H NMR(400MHz,Chloroform-d)δ8.5(s,2H),8.0(t,J=8.8Hz,3H),7.9(d,J=8.2Hz,2H),7.8(d,J=8.2Hz,2H),7.6–7.5(m,2H),7.4(dd,J=8.7,4.9Hz,4H),7.3–7.1(m,14H),7.1–6.8(m,11H),6.6–6.5(m,4H),4.5(q,J=10.8Hz,4H),4.3(s,2H),4.1–4.0(m,6H),3.7(s,6H).19F NMR(376MHz,Chloroform-d)δ-57.7(s,3F).13C NMR(101MHz,Chloroform-d)δ155.0,154.5,154.2,148.4,137.6,137.2,136.5,134.2,134.1,134.0,133.2,131.1,130.8,129.8,129.4,129.3,129.1,128.5,128.4,128.2,128.1,128.0,127.97,127.90,127.8,127.4,126.8,125.6,125.54,125.51,125.4,124.8,124.5,123.6,121.0,120.7,120.6(q,J=264.6),119.4,113.5,75.5,75.0,56.4,53.5,53.0.HRMS(ESI):计算值C79H63O6NF3[M+H]+1178.4602,实际值:1178.4598.
白色固体(yield:68%).M.P.:99–101℃.IR:3056,2935,2836,2359,1948,1807,1621,1592,1508,1497,1453,1308,1262,1246,1177,1146,1074,967,806,746,696,571,528cm-1.1H NMR(400MHz,Chloroform-d)δ8.3(s,2H),8.0(d,J=9.0Hz,2H),7.8(d,J=8.2Hz,4H),7.6(d,J=2.1Hz,1H),7.4(dd,J=8.6,4.4Hz,4H),7.3–7.1(m,12H),7.1–7.0(m,6H),7.0–6.9(m,4H),6.5(d,J=6.9,1.4Hz,4H),4.9(s,2H),4.5–4.4(m,4H),4.0–3.9(m,4H),3.7(s,8H),2.3(s,3H).19F NMR(376MHz,Chloroform-d)δ-69.1(s,9F).13C NMR(101MHz,Chloroform-d)δ155.0,154.2,147.9,146.2,137.2,136.7,135.2,134.1,134.0,133.3,133.0,131.1,129.8,129.1,128.9,128.8,128.3,128.2,128.1,127.98,127.94,127.8,127.7,127.4,126.7,125.6,125.55,125.51,125.4,124.7,123.6,121.9,120.1(q,J=293.91Hz),119.5,113.5,81.7(deca,J=29.7Hz),75.9,75.0,56.4,53.1,52.3,21.3.HRMS(ESI):计算值C77H61O6NF9[M+H]+1266.4350,实际值:1266.4346.
通用方法去苄基保护.
将(1.0g,0.91mmol,1.0equiv)和氢氧化钯(300mg,10%on carbon,0.23equiv)溶于乙酸乙酯中,在氢气(1atm)氛围下搅拌24小时。过滤,旋蒸去除溶剂,经柱层析得淡黄色固体(530mg,0.64mmol,yield:70%).M.P.:142–144℃.IR:3511,3062,2874,2834,2358,2335,1684,1618,1591,1497,1469,1454,1351,1335,1248,1147,1041,1019,997,907,808,781,746,726,686,667,611,545,512cm-1.1H NMR(400MHz,Chloroform-d)δ8.05(d,J=9.1Hz,2H),7.89(t,J=4.2Hz,4H),7.84(d,J=8.1Hz,2H),7.46(d,J=9.1Hz,2H),7.38–7.28(m,4H),7.18(m,9H),7.06(d,J=8.4Hz,2H),4.22(d,J=13.1Hz,2H),4.11(d,J=13.7Hz,1H),4.03(d,J=13.1Hz,2H),3.93(d,J=13.7Hz,1H),3.62(s,6H).19F NMR(376MHz,Chloroform-d)δ-57.72(s,3F).13C NMR(101MHz,Chloroform-d)δ155.8,151.0,151.0,149.3,136.8,134.0,133.8,130.9,130.7,129.4,128.6,128.4,128.0,127.9,127.1,126.3,125.6,125.1,124.7,124.0,123.3,121.3,120.8(q,257.5Hz),118.9,116.3,116.0,114.0,56.6,55.4,53.5.HRMS(ESI):计算值C52H41O6NF3[M+H]+832.2880,实际值:832.2877.
白色固体(yield:65%).M.P.:151–153℃.IR:3585,3289,2385,1620,1593,1473,1280,1259,1222,1167,1144,1105,1077,942,832,755,610,542cm-1.1HNMR(400MHz,Chloroform-d)δ8.10(d,J=9.1Hz,1H),7.94(d,J=8.1Hz,1H),7.88–7.80(m,2H),7.53(d,J=9.1Hz,1H),7.44–7.15(m,2H),7.11(d,J=7.8Hz,4H),7.08–7.01(m,1H),6.79(t,J=7.9Hz,2H),4.07(d,J=12.9Hz,1H),4.02–3.84(m,5H),3.83(s,3H).19F NMR(376MHz,Chloroform-d)δ-57.88(s,6F).13C NMR(101MHz,Chloroform-d)δ155.9,150.4,148.2,136.7,134.0,133.7,131.2,131.2,129.4,128.7,128.6,128.2,127.9,127.3,126.5,125.2,124.9,124.8,124.7,124.2,123.6,121.0,120.7(q,J=258.56Hz),119.3,116.0,115.2,113.8,56.6,55.6,54.8.HRMS(ESI):计算值C38H30O6NF6[M+H]+710.1972,实际值:710.1974.
采用类似方法制备得到化合物5c和5d。
白色固体(yield:56%).M.P.:150–152℃.IR:3520,3052,2974,2936,2834,2358,2335,1684,1619,1592,1507,1454,1351,1264,1248,1180,1075,1041,1019,996,889,808,745,611,571cm-1.1H NMR(400MHz,Chloroform-d)δ8.02(d,J=9.1Hz,2H),7.87(d,J=8.3Hz,2H),7.82(s,2H),7.78(d,J=8.1Hz,2H),7.40(d,J=9.1Hz,2H),7.27(m,7H),7.20–7.10(m,7H),7.05–6.95(m,7H),6.87(t,J=7.5Hz,1H),4.13(dt,J=28.8,14.3Hz,6H),3.99(d,J=13.6Hz,1H),3.49(s,6H).19F NMR(376MHz,Chloroform-d)δ-57.62(s,3F).13CNMR(101MHz,Chloroform-d)δ155.7,154.2,150.7,147.8,137.1,133.9,130.9,130.7,130.6,129.7,129.4,129.3,128.6,127.9,127.3,127.0,126.2,125.3,125.1,124.7,123.9,123.5,120.2,120.4(q,J=298.2Hz),119.3,116.2,116.05,116.03,113.9,56.8,56.5,55.7.HRMS(ESI):计算值C58H45O6NF3[M+H]+908.3193,实际值:908.3193.
白色固体(yield:65%).M.P.:138 140℃.IR:3355,3050,2842,2358,2343,1684,1591,1469,1351,1265,1248,1147,1101,1075,1019,997,808,746,726,610,545cm-1.1HNMR(400MHz,Chloroform-d)δ8.03(d,J=9.1Hz,2H),7.88(t,J=4.2Hz,4H),7.80(d,J=8.2Hz,2H),7.44(d,J=9.1Hz,2H),7.30(m,4H),7.18(dd,J=12.6,5.6Hz,6H),7.02(d,J=8.4Hz,2H),6.91(d,J=17.9Hz,2H),4.20(d,J=13.3Hz,2H),4.05(d,J=13.7Hz,1H),3.97(d,J=13.3Hz,2H),3.85(d,J=13.7Hz,1H),3.60(s,6H),2.19(s,3H).19F NMR(376MHz,Chloroform-d)δ-69.43(s,9F).13C NMR(101MHz,Chloroform-d)δ155.7,151.2,147.3,140.3,134.0,133.6,130.65,130.62,129.4,129.1,128.6,128.3,128.0,127.9,127.0,126.2,125.19,125.12,124.7,124.6,123.9,123.2,122.0,120.1(d,J=292.9Hz),116.5,115.8,114.1,81.5(d,J=29.3Hz),56.6,55.0,54.7,20.6.HRMS(ESI):计算值C56H43O6NF9[M+H]+996.2941,实际值:996.2944.
通用方法 制备铝络合物
将(200mg,0.24mmol,1.0equiv)溶于无水THF中,然后向反应液中缓慢滴加三甲基铝(1.0M solution in heptane,0.25mL,0.25mmol,1.05equiv).该反应体系在室温下搅拌2小时.旋蒸去除溶剂,用二氯加绒重新溶解,然后用过滤去除不溶固体杂质,然后旋蒸去除溶剂,并用正己烷重结晶得白色固体6b(177mg,0.19mmol,yield:79%).M.P.:214–216℃.IR:3063,2933,2834,1620,1490,1457,1359,1318,1289,1262,1231,1147,1116,1081,1147,1081,1046,961,792,773,745,684,666,625,603,575cm-1.1H NMR(400MHz,DMSO-d6)δ8.00–7.61(m,9H),7.46(d,J=9.1Hz,1H),7.39–6.87(m,12H),6.74(d,J=8.5Hz,2H),6.64(t,J=7.8Hz,1H),4.37–3.86(m,3H),3.59–3.17(m,13H),1.76–1.59(m,4H).19F NMR(376MHz,DMSO-d6)δ-56.76(s,3F).13C NMR(101MHz,DMSO-d6)δ155.6,155.3,155.2,155.1,151.8,138.2,134.7,134.7,134.0,133.9,129.3,129.0,128.9,128.4,128.4,128.2,128.2,128.0,128.0,127.2,127.2,126.3,126.3,126.2,126.1,125.8,125.6,125.4,124.5,124.4,123.8,123.5,122.7,122.7,121.7,120.9,120.6(q,J=208.06Hz)119.6,117.8,117.8,116.8,115.7,114.6,67.4,57.9,57.1,56.6,56.4,56.3,25.5.HRMS(ESI):计算值C39H30NO7F6NaAl[M+Na]+910.25427,实际值:910.25320
采用类似方法制备得到化合物6a,6c和6d。
浅黄色固体(yield:78%).M.P.:164–166℃.IR:3056,2926,2848,2355,1609,1495,1458,1437,1381,1361,1319,1291,1257,1207,1148,1116,1069,1047,1019,959,872,743,658,603,574,519cm-1.1H NMR(400MHz,DMSO-d6)δ8.18–7.68(m,4H),7.56(d,J=9.1Hz,1H),7.42–6.95(m,9H),6.95–6.59(m,3H),4.09–3.25(m,13H),1.75(s,4H).19F NMR(376MHz,DMSO-d6)δ56.70(s,6F).13C NMR(101MHz,DMSO-d6)δ155.3,154.9,151.4,138.2,134.6,134.0,129.2,129.1,128.5,128.3,128.0,127.3,126.4,125.9,125.8,125.4,125.0,124.9,124.5,123.6,122.7,122.6,122.3,121.0,119.5(d,J=300.1Hz),118.0,117.1,115.0,67.4,57.9,57.1,57.0,56.3,26.7,25.5.HRMS(ESI):计算值C39H30NO7F6NaAl[M-THF+CH3OH+Na]+788.16341,实际值:788.16330.
浅黄色固体(yield:72%).M.P.:220–222oC.IR:3066,2936,2901,2834,1621,1592,1499,1456,1434,1260,1246,1219,1147,1082,1018,960,914,879,849,792,746,726,676,651,579cm-1.1H NMR(400MHz,DMSO-d6)δ8.0–7.7(m,10H),7.5(d,J=9.0Hz,1H),7.4–6.9(m,15H),6.8–6.7(m,3H),4.3(m,3H),3.9–3.1(m,13H),1.8–1.6(m,4H).19F NMR(376MHz,DMSO-d6)δ-56.89(s,3F).13C NMR(101MHz,DMSO-d6)δ156.4,155.2,147.0,138.7,134.7,134.7,134.0,133.9,131.1,129.8,129.5,129.4,129.1,128.9,128.5,128.2,128.0,127.3,126.4,126.3,125.9,125.7,125.4,123.8,123.5,123.1,122.2,121.8,121.3,120.6(q,J=256.54Hz),119.3,117.8,117.8,114.9,67.5,58.0,57.8,56.8,56.5,25.6.HRMS(ESI):计算值C59H45NO7F3NaAl[M-THF+CH3OH+Na]+986.28557,实际值:986.28438.
浅黄色固体(yield:81%).M.P.:260–262℃.IR:3061,2974,2829,1622,1593,1498,1472,1457,1431,1328,1359,1324,1261,1130,1117,1048,1109,964,855,772,647,603,580,517cm-1.1H NMR(400MHz,DMSO-d6)δ8.01–7.75(m,8H),7.50(d,J=9.0Hz,1H),7.40–7.33(m,1H),7.32–7.24(m,2H),7.21–6.98(m,7H),6.91–6.83(m,2H),6.73(d,J=8.4Hz,2H),4.37(d,J=13.2Hz,1H),4.10(dd,J=22.4,13.5Hz,2H),3.63–3.59(m,4H),3.57–3.30(m,9H),2.18(s,3H),1.76(td,J=6.5,5.9,2.6Hz,4H).19F NMR(376MHz,DMSO-d6)δ-68.98(s,9F).13C NMR(101MHz,DMSO-d6)δ155.6,155.3,155.2,155.1,150.3,150.1,141.7,141.6,134.7,134.7,134.0,133.9,129.5,129.2,128.9,128.9,128.4,128.3,128.2,128.2,127.9,127.1,126.5,126.3,126.1,125.9,125.8,125.5,125.4,125.1,124.9,124.7,124.2,123.9,123.7,123.0,122.1,122.1,121.8,121.5,120.09(d,J=292.4Hz),118.6,117.8,117.6,116.3,115.6,115.0,114.9,81.4(deca,J=29.7Hz),67.4,58.0,57.6,57.1,56.9,25.5,20.5.HRMS(ESI):计算值C57H43NO7F9NaAl[M-THF+CH3OH+Na]+1074.26034,实际值:1074.26014.
测试例1探针分子A1区分和识别对映异构体的效果图
将1mg A1探针分子与1-2mg分析物溶解在0.5mL的CDCl3中,测试其氟谱,结果如图2所示。
图2和图3中显示了探针分子对不同手性醇的区分识别效果。可以看出,不同构型分析物络合时给出的氟谱型号的差异。每个信号分别和相应构型的对映异构体对应,不经分离及化学衍生化就可以实现手性分析物的快速分析检测。具有R构型的手性醇的型号相对于S构型出现在左边,可以用于绝对构型的快速判定。该方法对于不同的手性醇,例如伯醇、仲醇和叔醇均可使用。
测试例2探针分子A1区分和识别对映异构体的效果图
将1mg A1分子与0.5-2mg分析物溶解在0.5mL的CDCl3中,测试其氟谱,测试结果如图4中所示,结果表明,当A1与不同一对对应异构体络合后会产生两个化学位移不同的氟谱型号。其中图4表明探针分子可以用于酰胺,亚砜,醚等大量不同的手性分析物的区分检测。图4中的w表明探针分子可以同时区分检测多种不同的手性分析物(例如图4w中的三组分混合物)。
测试例3探针分子A1测量分析物对映体过量
将1mg探针分子与0.5-2mg分析物溶于0.5mLCDCl3中,测其氟谱。测试结果进行进一步矫正,最终结果如图7中所示。结果表明,当A1与不同一对对应异构体络合后,通过对于其计算结果进行矫正后,能够更加准确地测量出分析物的对映体过量,而且该方法可以应用于多种分析物的测量,如醇、酰胺、亚砜等,具有良好的普适性。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种含氟探针配合物,其特征在于,所述配合物具有下式I或II所示的结构:
式中,R1为选自下组的基团:取代或未取代的C1~C10的烷基,取代或未取代的C6~C20的芳基,取代或未取代的5~20元杂芳基;其中,所述的杂芳基骨架上具有选自N、O或S的1-8个杂原子;
R2选自下组:取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C6~C20芳基、取代或未取代的5~20元杂芳基;其中,所述的杂芳基骨架上具有选自N、O或S的1-8个杂原子;其中,所述的取代指集团上的一个或多个氢原子被选自下组的取代基取代:卤素,C1-C4卤代烷基
L为路易斯碱中性配位分子;
M选自下组:Al、B、Ga、In或V;
所述的联萘酚骨架既可以为R构型,也可以为S构型;
除非特别说明,所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素,C1-C4烷基、C1-C4卤代烷基。
2.如权利要求1所述的配合物,其特征在于,L为选自下组的分子:C1-C6的链状或环状醇,C1-C6的链状或环状醚,C1-C6的链状或环状酰胺,C1-C6的链状或环状亚砜,C1-C6的链状或环状砜,C1-C6的链状或环状醛,C1-C6的链状或环状酮,C1-C6的链状或环状羧酸。
3.如权利要求1所述的配合物,其特征在于,所述的R2选自下组:三氟甲基、三氟甲氧基、九氟叔丁氧基,或三氟甲基、三氟甲氧基、九氟叔丁氧基取代的选自下组的基团:C6~C20的芳基、5~20元杂芳基。
5.一种配体,其特征在于,所述配体具有下式III或IV所示的结构:
式中,R1为选自下组的基团:取代或未取代的C1~C10的烷基,取代或未取代的C6~C20的芳基,取代或未取代的5~20元杂芳基;其中,所述的杂芳基骨架上具有选自N、O或S的1-8个杂原子;
R2选自下组:取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C6~C20芳基、取代或未取代的5~20元杂芳基;其中,所述的杂芳基骨架上具有选自N、O或S的1-8个杂原子;其中,所述的取代指集团上的一个或多个氢原子被选自下组的取代基取代:卤素,C1-C4卤代烷基;
L为中性配位分子;
M选自下组:Al、B、Ga、In或V;
所述的联萘酚骨架既可以为R构型,也可以为S构型;
除非特别说明,所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素,C1-C4烷基、C1-C4卤代烷基。
6.如权利要求1所述的配体,其特征在于,所述的R2选自下组:三氟甲基、三氟甲氧基、九氟叔丁氧基,或三氟甲基、三氟甲氧基、九氟叔丁氧基取代的选自下组的基团:C6~C20的芳基、5~20元杂芳基。
8.一种区分和识别对映异构体的方法,其特征在于,所述的方法包括步骤:
(1)在惰性溶剂中,用如权利要求1中的式I或式II配合物与待测的手性对映异构体混合,得到第二配合物;
(2)对所述的第二配合物进行19F NMR,分别得到氟谱信号I(left)和I(right);
其中,I(left)指测定中左侧的氟谱积分值,I(right)指测定中右侧的氟谱积分值;
(3)通过所述步骤(2)中得到的氟谱信号确定待测的手性对映异构体构型。
9.如权利要求8所述的方法,其特征在于,所述的方法还包括如下的误差校正步骤:
(i)确定矫正因子α,所述的矫正因子α=I0(left)/I0(right);
其中,I0(left)指在该方法下,分析物为外消旋体时左侧的氟谱积分值,I0(right)指在该方法下,分析物为外消旋体时右侧的氟谱积分值;
(ii)通过以下方法计算得出ee值:
ee=(I(left)-αI(right))/(I(leftt)+αI(right))
其中,I(left)指测定中左侧的氟谱积分值,I(right)指测定中右侧的氟谱积分值。
10.如权利要求8或9所述的方法,其特征在于,所述待测的手性对映异构体选自下组:醚、胺醇、酰胺、亚砜、氮氧化物、羧酸、氨基甲酸酯、噁唑啉酮、亚砜亚胺。
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CN113834829A (zh) * | 2021-09-18 | 2021-12-24 | 厦门大学 | 一种识别手性α-羟基酸的方法 |
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