CN107141227A - A kind of preparation method and applications of chiral 4 amido cyclopentenone - Google Patents
A kind of preparation method and applications of chiral 4 amido cyclopentenone Download PDFInfo
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- CN107141227A CN107141227A CN201610802636.7A CN201610802636A CN107141227A CN 107141227 A CN107141227 A CN 107141227A CN 201610802636 A CN201610802636 A CN 201610802636A CN 107141227 A CN107141227 A CN 107141227A
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- chiral
- cyclopentenone
- amidos
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- -1 amido cyclopentenone Chemical compound 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 66
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000003960 organic solvent Substances 0.000 claims abstract description 36
- 239000003054 catalyst Substances 0.000 claims abstract description 32
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 18
- 150000004982 aromatic amines Chemical class 0.000 claims abstract description 15
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006467 substitution reaction Methods 0.000 claims abstract description 10
- 125000003003 spiro group Chemical group 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 claims description 63
- 239000001257 hydrogen Substances 0.000 claims description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 230000000694 effects Effects 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 239000012298 atmosphere Substances 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000000746 allylic group Chemical group 0.000 claims description 6
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 6
- 230000031709 bromination Effects 0.000 claims description 6
- 238000005893 bromination reaction Methods 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 4
- 229910002651 NO3 Inorganic materials 0.000 claims description 4
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000002240 furans Chemical class 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims 1
- 238000006462 rearrangement reaction Methods 0.000 abstract description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract description 8
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 6
- 150000002596 lactones Chemical class 0.000 abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- NWZXFAYYQNFDCA-UHFFFAOYSA-N cyclopenten-1-ol Chemical compound OC1=CCCC1 NWZXFAYYQNFDCA-UHFFFAOYSA-N 0.000 abstract 1
- 125000001725 pyrenyl group Chemical group 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 94
- 239000000047 product Substances 0.000 description 83
- 238000005481 NMR spectroscopy Methods 0.000 description 47
- 238000004458 analytical method Methods 0.000 description 47
- 238000001228 spectrum Methods 0.000 description 47
- 238000001819 mass spectrum Methods 0.000 description 45
- 238000004587 chromatography analysis Methods 0.000 description 32
- 239000007791 liquid phase Substances 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000003921 oil Substances 0.000 description 23
- 239000002994 raw material Substances 0.000 description 18
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 16
- 238000004364 calculation method Methods 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 16
- 230000014759 maintenance of location Effects 0.000 description 16
- 238000004293 19F NMR spectroscopy Methods 0.000 description 15
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 15
- 229910052731 fluorine Inorganic materials 0.000 description 15
- 239000011737 fluorine Substances 0.000 description 15
- 238000002329 infrared spectrum Methods 0.000 description 15
- 239000010409 thin film Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 239000000376 reactant Substances 0.000 description 13
- 239000007788 liquid Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000006555 catalytic reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012263 liquid product Substances 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000001555 benzenes Chemical group 0.000 description 4
- 238000005574 benzylation reaction Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000011259 mixed 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
- 229910019020 PtO2 Inorganic materials 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 0 *[C@@](C1[Al]I)C=CC1=O Chemical compound *[C@@](C1[Al]I)C=CC1=O 0.000 description 2
- 239000007848 Bronsted acid Substances 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 2
- 230000037429 base substitution Effects 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical class NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 238000006220 Baeyer-Villiger oxidation reaction Methods 0.000 description 1
- 229910020323 ClF3 Inorganic materials 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentenylidene Natural products C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PURITTXNCHNYEP-UHFFFAOYSA-N mukoenine a Chemical compound N1C2=CC=CC=C2C2=C1C(CC=C(C)C)=C(O)C(C)=C2 PURITTXNCHNYEP-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical group 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- 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
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0255—Phosphorus containing compounds
- B01J31/0257—Phosphorus acids or phosphorus acid esters
- B01J31/0258—Phosphoric acid mono-, di- or triesters ((RO)(R'O)2P=O), i.e. R= C, R'= C, H
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- 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
- C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
The invention provides a kind of preparation method of chiral 4 amido cyclopentenone, comprise the following steps：Aromatic amine and catalyst CPA shown in offer 2 furan alcohols as shown in Equation 1, formula 2, wherein, the CPA is the phosphoric acid for the chiral spiro skeleton that 1 pyrenyl replaces, the aromatic amine and the CPA are dissolved in after the first organic solvent, 05 DEG C are cooled to, the solution of the first organic solvent of 2 furan alcohol is then added, azepine Piancatelli rearrangement reactions between asymmetric molecult are carried out under the conditions of being stirred at room temperature, obtain the chiral 4 amido cyclopentenone shown in formula 3
Description
Technical field
The invention belongs to asymmetry catalysis synthesis technical field, more particularly to a kind of preparation of chiral 4- amidos cyclopentenone
Method and its application.
Background technology
Chiral 4- amidos cyclopentenone is a kind of structure being widely present in bioactive natural product and drug molecule.It is known
Chiral 4- amidos cyclopentenone synthetic method generally require multi-step chemical conversion.Intermolecular azepine Piancatelli resets anti-
Should be a kind of method of direct synthesis racemic 4- amido cyclopentenones, however, the condition of the reaction excessively harshness is, it is necessary to add
With stronger Lewis acid such as lanthanide series metal reagent D y (OTf) under heat condition3Catalysis can be realized, it is impossible to pass through asymmetry catalysis
Synthesis, limits chiral 4- amidos cyclopentenone and synthesizes on a large scale and then have impact on it and further apply.Therefore, research and develop a kind of
The intermolecular azepine Piancatelli rearrangement reactions of mild condition and the preparation for being applied to chiral 4- amidos cyclopentenone
It is particularly important.
The content of the invention
It is an object of the invention to provide a kind of preparation method and applications of chiral 4- amidos cyclopentenone, it is intended to solves
Existing chiral 4- amidos cyclopentenone preparation method step is tediously long, cumbersome, and then limits its extensive synthesis and apply
The problem of.
The present invention is achieved in that a kind of preparation method of chiral 4- amidos cyclopentenone, comprises the following steps：
Aromatic amine and catalyst CPA shown in offer 2- furan alcohols as shown in Equation 1, formula 2, wherein, the CPA is 1- pyrenes
The phosphoric acid of the chiral spiro skeleton of base substitution,
The aromatic amine and the CPA are dissolved in after the first organic solvent, 0-5 DEG C is cooled to, the 2- is then added
The solution of first organic solvent of furan alcohol, carries out azepine Piancatelli weights between asymmetric molecult under the conditions of being stirred at room temperature
Row's reaction, obtains the chiral 4- amidos cyclopentenone shown in formula 3,
And, a kind of application of chiral 4- amidos cyclopentenone comprises the following steps：
Chiral 4- amidos cyclopentenone shown in offer formula 3, is dissolved in second organic by the chiral 4- amidos cyclopentenone
After solvent, K is sequentially added2CO3, iodide and BnBr, reaction obtains the Benzylation productions of α shown in formula 4 under the conditions of being stirred at room temperature
Thing,
A kind of application of chiral 4- amidos cyclopentenone, comprises the following steps：
Chiral 4- amidos cyclopentenone shown in offer formula 3, is dissolved in the 3rd organic by the chiral 4- amidos cyclopentenone
After solvent, allylic bromination magnesium is added dropwise, stirring reaction obtains product shown in formula 5 under the conditions of -75 DEG C to -78 DEG C,
A kind of application of chiral 4- amidos cyclopentenone, comprises the following steps：
Chiral 4- amidos cyclopentenone shown in offer formula 3, is dissolved in the 4th organic by the chiral 4- amidos cyclopentenone
In solvent, hydrogen activity catalyst, under an atmosphere of hydrogen stirring reaction are added；
Product is dissolved in the 5th organic solvent, mCPBA is then added, stirring reaction is obtained shown in formula 6 at normal temperatures
Product,
A kind of application of chiral 4- amidos cyclopentenone, comprises the following steps：
Chiral 4- amidos cyclopentenone shown in offer formula 7, is dissolved in the 6th organic by the chiral 4- amidos cyclopentenone
In solvent, hydrogen activity catalyst, under an atmosphere of hydrogen stirring reaction are added, intermediate shown in formula 8 is obtained；
Intermediate shown in formula 8 is dissolved in the 7th organic solvent, 0-5 DEG C is cooled to, sulfuric acid and ammonium ceric nitrate is then added
Afterwards, isothermal reaction, obtains product shown in formula 9,
The preparation method for the chiral 4- amidos cyclopentenone that the present invention is provided, utilizes aryl or the 2- furan alcohols of heterocyclic substituted
With aromatic amine as reaction substrate while, be catalyzed using chiral phosphoric acid catalyst, occur azepine between asymmetric molecult
Piancatelli rearrangement reactions, efficiently obtain chiral 4- amidos cyclopentenone product with high selectivity.The preparation method is not only anti-
Answer condition simple and easy to control, and selectivity is high, and obtained product purity is high.
The application for the chiral 4- amidos cyclopentenone that the present invention is provided, can be by the chirality prepared according to the method described above
4- amidos cyclopentenone carries out chemical conversion, and cyclopentanone, cyclopentanol and the lactone of chiral amino substitution can be realized with diversity
Etc. useful chemical constitution.
Embodiment
In order that technical problems, technical solutions and advantageous effects to be solved by the present invention are more clearly understood, below in conjunction with
Embodiment, the present invention will be described in further detail.It should be appreciated that specific embodiment described herein is only to explain
The present invention, is not intended to limit the present invention.
It is Protic Acid Catalyzed based on chirality due to many restrictions in terms of reactivity and zinc bromide, at normal temperatures
Azepine Piancatelli rearrangement reactions between asymmetric molecult are realized, there is bigger difficulty, be in particular in following side
Face：
First, during using amine as reactant, the alkalescence of amido can neutralize chiral Bronsted acid, be urged so that it loses
Change is acted on；
Second：From the point of view of reaction mechanism, positive oxygen ion intermediate is formed after 2- furans dehydration of alcohols, the intermediate has many
Individual site can receive the attack of nucleopilic reagent, therefore, and the control of the chemo-selective of the reaction has very big challenge；
3rd：There are two adjacent chiral centres in the reaction product, the control of cis-selectivity has very big challenge；
4th：The reaction product contains the stronger secondary amine structure of alkalescence, and product can be competed with the amido of raw material,
So as to being smoothed out for disturbing reaction.
Above-mentioned factor is based on, so far, the asymmetric Piancatelli rearrangement reactions of organic catalysis turn into hardly possible
With the problem captured, also there is not been reported for the asymmetric Piancatelli rearrangement reactions of organic catalysis.
In view of this, inventor utilizes azepine between the asymmetric molecult of catalysis by concentrating on studies
Piancatelli rearrangement reactions one-step synthesis chirality 4- amido cyclopentenones, with important application value.
The embodiments of the invention provide a kind of preparation method of chiral 4- amidos cyclopentenone, comprise the following steps：
S01., 2- furan alcohols as shown in Equation 1, aromatic amine and catalyst CPA shown in formula 2 are provided, wherein, the CPA is
The phosphoric acid of the chiral spiro skeleton of 1- pyrenyls substitution,
S02. the aromatic amine and the CPA are dissolved in after the first organic solvent, are cooled to 0-5 DEG C, then add institute
The solution of the first organic solvent of 2- furan alcohols is stated, azepine between asymmetric molecult is carried out under the conditions of being stirred at room temperature
Piancatelli rearrangement reactions, obtain the chiral 4- amidos cyclopentenone shown in formula 3,
Specifically, in above-mentioned steps S01, in the structure of formula 1 of the 2- furan alcohols, the Ar1For phenyl ring or substituted benzene ring,
One kind in condensed ring or substitution condensed ring, heterocycle.More specifically, in the substituted benzene ring, the substitution condensed ring, substituted radical includes
But halogen, methyl, methoxyl group, sulfydryl are not limited to, the heterocycle includes but is not limited to furans, thiophene.
In the structure of formula 2 of the aromatic amine, the Ar2For in phenyl ring or substituted benzene ring, and the substituted benzene ring, substituent
Group includes but is not limited to trifluoromethyl, itrile group, nitro, halogen, methyl, methoxyl group.
In the embodiment of the present invention, on present in chiral intermolecular azepine Piancatelli rearrangement reaction processes
State technological difficulties and understand that the selection of catalyst plays important reuse to the success or failure entirely reacted.The embodiment of the present invention uses 1- pyrenes
The phosphoric acid of the chiral spiro skeleton of base substitution can be overcome in conventional chiral Bronsted acid and alkaline amido as chiral catalyst
With the problem of causing catalyst failure.
It is preferred that, the addition of the CPA is the 5-20mol% of the 2- furan alcohols mole dosage.If the CPA's adds
Dosage is very few to cause the reduction of ee values, yield reduction；If the addition of the CPA can excessively cause side reaction many, yield reduction.
In above-mentioned steps S02, the aromatic amine and the CPA are dissolved in the first organic solvent, described first is organic molten
For that can dissolve the aromatic amine, the CPA simultaneously the organic solvent of chemistry does not occur with reactant for agent, including but does not limit
One kind in 1,2- dichloroethanes, dichloromethane, chloroform, toluene.First organic solvent such as 1,2- dichloroethanes adds
The concentration that dosage meets the 2- furan alcohols is 0.020-0.2mol/L, more preferably 0.025mol/L.If described first is organic
The adding too much of solvent is too low, then the concentration of the 2- furan alcohols accordingly can be reduced or raised, and causes the reduction of ee values, yield
Reduction.The mixed solution obtained after dissolving is cooled to 0-5 DEG C, speed is added to reactant to reduce the 2- furans alcoholic solution
The influence of system.
Further, the 2- furan alcohols are added in the mixed solution after cooling treatment.In the step, the present invention is implemented
Example is then added in mixed solution after the 2- furan alcohols are dissolved in into first organic solvent.Because the mixed solution passes through
Temperature is relatively low after cooling treatment, on this condition, and the 2- furan alcohols are very low with arylamine reaction speed, can ignore, and treat that it is stirred
It is warmed to room temperature after mixing uniformly and starts reaction.
Under conditions of reaction raw materials provided in an embodiment of the present invention and special catalyst, carried out under the conditions of being stirred at room temperature
Azepine Piancatelli rearrangement reactions between asymmetric molecult, obtain the chiral 4- amidos cyclopentenone shown in formula 3, reaction equation is such as
Shown in lower：
In the embodiment of the present invention, the normal temperature is room temperature, concretely 13-30 DEG C instantly.
The preparation method of chiral 4- amidos cyclopentenone provided in an embodiment of the present invention, utilizes aryl or the 2- of heterocyclic substituted
Furan alcohol and aromatic amine as reaction substrate while, be catalyzed using chiral phosphoric acid catalyst, occur between asymmetric molecult
Azepine Piancatelli rearrangement reactions, efficiently obtain chiral 4- amidos cyclopentenone product with high selectivity.The preparation method is not
Only reaction condition is simple and easy to control, and selectivity is high, and obtained product purity is high.
And, the embodiment of the present invention additionally provides a kind of application of chiral 4- amidos cyclopentenone, comprises the following steps：
Chiral 4- amidos cyclopentenone shown in offer formula 3, is dissolved in second organic by the chiral 4- amidos cyclopentenone
After solvent, K is sequentially added2CO3, iodide and BnBr, reaction obtains the Benzylation productions of α shown in formula 4 under the conditions of being stirred at room temperature
Thing,
Specifically, second organic solvent is that can effectively dissolve reactant and not chemically reacted with reactant
Organic solvent, preferably DMF.In reaction system of the embodiment of the present invention, the K2CO3, can be by carbonyl alkene as alkaline matter
Alcoholization, preferable reactiveness is provided for follow-up reaction；And the iodide can more hold with BnBr reaction generation BnI, the latter
Benzylation reaction needed for easily occurring, wherein, the iodide are preferably KI, NaI.By being stirred at room temperature, the chiral 4- amine
Cyclopentene ketone and BnBr reactions obtain the α benzylated products shown in formula 4, and reaction equation is as follows：
And, the embodiment of the present invention additionally provides a kind of application of chiral 4- amidos cyclopentenone, comprises the following steps：
Chiral 4- amidos cyclopentenone shown in offer formula 3, is dissolved in the 3rd organic by the chiral 4- amidos cyclopentenone
After solvent, allylic bromination magnesium is added dropwise, stirring reaction obtains product shown in formula 5 under the conditions of -75 DEG C to -78 DEG C,
It is preferred that, in order to ensure the reliable and stable of reaction, the embodiment of the present invention is in -75 DEG C to -78 DEG C conditions by the hand
Property 4- amido cyclopentenones be dissolved in the 3rd organic solvent, further addition allylic bromination magnesium reacted.Specifically, described
Three organic solvents do not chemically react for that can dissolve chiral 4- amidos cyclopentenone, allylic bromination magnesium with reactant
Organic solvent, preferably THF, ether.By stirring reaction, product shown in formula 5 is obtained, its reaction equation is as follows：
And, the embodiment of the present invention additionally provides a kind of application of chiral 4- amidos cyclopentenone, comprises the following steps：
Chiral 4- amidos cyclopentenone shown in offer formula 3, is dissolved in the 4th organic by the chiral 4- amidos cyclopentenone
In solvent, hydrogen activity catalyst, under an atmosphere of hydrogen stirring reaction are added；Product is dissolved in the 5th organic solvent, then
MCPBA is added, stirring reaction obtains product shown in formula 6 at normal temperatures,
Specifically, the 4th organic solvent is can dissolve reactant, and having of not chemically reacted with reactant
Machine solvent, preferably ethyl acetate.The hydrogen activity catalyst can with adsorbed hydrogen, hydrogen atom and double bond is reacted, it is raw
IntoIt is preferred that, the hydrogen activity catalyst includes PtO2, 10%Pd/C, Raney Ni (Raney's nickel), Rh
(PPh3)3Cl。
Further, the product that above-mentioned steps are obtained is dissolved in the 5th organic solvent, then adds mCPBA, normal
The lower stirring reaction of temperature obtains product shown in formula 6, and reaction equation is as follows：
Preferably, the 5th organic solvent is dichloromethane.Further, it is in order to increase reactivity, product is molten
Solution adds NaHCO in after the 5th organic solvent3Or pyridine and mCPBA, the NaHCO3Or pyridine is acted on the mCPBA,
So as to promote the progress of reaction.
And, the embodiment of the present invention additionally provides a kind of application of chiral 4- amidos cyclopentenone, comprises the following steps：
Chiral 4- amidos cyclopentenone shown in offer formula 7, is dissolved in the 6th organic by the chiral 4- amidos cyclopentenone
In solvent, Pd/C, under an atmosphere of hydrogen stirring reaction are added, intermediate shown in formula 8 is obtained；
Intermediate shown in formula 8 is dissolved in the 7th organic solvent, 0-5 DEG C is cooled to, sulfuric acid and ammonium ceric nitrate is then added
Afterwards, isothermal reaction, obtains product shown in formula 9,
Specifically, the 6th organic solvent is having for can dissolving reactant and not chemically reacted with reactant
Machine solvent, preferably ethyl acetate.The chiral 4- amidos cyclopentenone occurs following anti-in hydrogen activity catalyst, atmosphere of hydrogen
Should,
The hydrogen activity catalyst can with adsorbed hydrogen, hydrogen atom and double bond is reacted.It is preferred that, the hydrogen activity
Catalyst includes PtO2, 10%Pd/C, Raney Ni (Raney's nickel), Rh (PPh3)3Cl.Further, obtained centre will be reacted
Body is cooled to 0-5 DEG C after being dissolved in the 7th organic solvent, to avoid exothermic heat of reaction excessively violent, wherein, the 7th organic solvent
It is that can effectively dissolve reactant and the organic solvent not chemically reacted with reactant, preferably acetonitrile.Then sulphur is added
After acid and ammonium ceric nitrate, reaction obtains product shown in formula 9, and reaction equation is as follows：
The application of chiral 4- amidos cyclopentenone provided in an embodiment of the present invention, will can be prepared according to the method described above
Chiral 4- amidos cyclopentenone carry out chemical conversion, can be realized with diversity chiral amino substitution cyclopentanone, cyclopentanol
And the useful chemical constitution such as lactone.
Illustrated with reference to specific embodiment.
Embodiment 1
Using Ar1For Ph 2- furan alcohols and Ar2For 3,5- (CF3)2C6H3Arylamine as reaction raw materials, use chiral phosphoric acid
Catalyst is reacted, and specific implementation process is as follows：
The 5-trifluoromethylanilines of 3,5- bis- (172mg, 0.75mmol) and catalyst (35.7mg, 0.05mmol) are dissolved in 1,
Be cooled to 0 DEG C in 2- dichloroethanes (10mL), after 30 minutes, be slowly added dropwise phenyl substitution 2- furan alcohols (87.0mg,
1,2- dichloroethanes (10mL) solution 0.5mmol)；Afterwards, it is placed in stirring at normal temperature 75 hours.Its reaction equation is as follows：
Reaction solution is directly used in silica gel column chromatography and obtains brown oil product 126mg, it is 66% to calculate yield.
After the step prepares completion, in order to further verify purified obtained compound really in the present embodiment
Purpose product to be prepared, is analyzed resulting oil product, and the means of analysis are using determining specific rotatory power, efficiently
Liquid-phase chromatographic analysis determines ee values, nuclear magnetic resonance.Wherein, test is analyzed as follows：
1st, the specific rotatory power [α] that D lines are determined at 23 DEG CD 23:- 24.8 (c=1.1, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelIC posts；3%i-PrOHin
hexanes；1.0mL/min；Retention time:12.0min(major),20.4min(minor).Result of calculation is 90%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum, fluorine spectrum：
1H NMR(400MHz,CDCl3) δ 7.73 (dd, J=2.0Hz, 5.6Hz, 1H), 7.39-7.32 (m, 3H), 7.17
(s, 1H), 7.11 (d, J=7.6Hz, 2H), 6.81 (s, 2H), 6.51 (d, J=5.6Hz, 1H), 4.79 (dd, J=1.6Hz,
8.0Hz, 1H), 4.53 (d, J=8.0Hz, 1H), 3.35 (d, J=2.4Hz, 1H)
13C NMR(100MHz,CDCl3) δ 205.8,160.0,146.9,137.4,135.7,132.6 (q, J=
32.6Hz), 129.3,127.8 (2C), 123.2 (q, J=270.9Hz), 112.9,111.4,63.1,60.5.
19F NMR(376.5MHz,CDCl3)δ-63.4。
Detect that data are consistent with the data of the above-claimed cpd of document report.
Embodiment 2
Using Ar1=Ph 2- furan alcohols and Ar2=2,5- (CF3)2C6H3Arylamine as reaction raw materials, with 10% hand
Property phosphoric acid catalyst reacted, according to same steps described in examples detailed above 1, react 22 hours, obtain yellow oily liquid production
Thing 95mg, it is 83% to calculate yield.
Equally, after the step prepares completion, resulting oil product is analyzed, the means of analysis are using survey
Determine specific rotatory power, efficient liquid phase chromatographic analysis and determine ee values, nuclear magnetic resonance, infrared and high resolution mass spectrum.Wherein, test analysis
Data are as follows：
1st, the specific rotatory power [α] that D lines are determined at 23 DEG CD 23:- 37.9 (c=1.4, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelIC posts；3%i-PrOHin
hexanes；1.0mL/min；Retention time:17.2min(major),25.7min(minor).Result of calculation is 94%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum, fluorine spectrum：
1H NMR(400MHz,CDCl3) δ 7.72 (d, J=2.0Hz, 1H), 7.56 (d, J=8.0Hz, 1H), 7.40-7.33
(m, 3H), 7.14-7.12 (m, 2H), 7.0 (d, J=8.0Hz, 1H), 6.62 (s, 1H), 6.52 (dd, J=1.6Hz, 6.0Hz,
1H), (d, J=2.4Hz, the 1H) of 4.85 (d, J=7.6Hz, 1H), 4.82 (d, J=1.6Hz, 1H), 3.37
13C NMR(100MHz,CDCl3) δ 205.4,159.5,144.2,137.3,136.0,135.2 (q, J=
32.1Hz), 129.3,127.8 (2C), 127.6 (q, J=5.5Hz), 125.0 (q, J=104.1Hz), 122.2 (q, J=
104.5Hz), 117.0 (q, J=28.7Hz), 113.8 (q, J=3.7Hz), 110.1 (q, J=3.7Hz), 63.2,60.6.
19F NMR(376.5MHz,CDCl3)δ-62.9,-63.9.
4th, infrared spectrum：IR(thin film)3405,3071,2924,1716,1627,1593,1535,1488,1446,
1332,1271,1176,1127,1035,928,869,815,751,700,539,444cm-1.
5th, high resolution mass spectrum：HRMS m/z(CI)calcd.for C19H13F6NO(M)+385.0901,
found385.0901.
It can be seen that its Theoretical Mass is 385.0901 from the result, and the observation that peak is found in actual mass spectrum is
385.0901；Specific rotatory power in conjunction with nuclear magnetic resonance and infrared elementary analysis, and standard can determine product structure such as
Under：
For the product of the present embodiment.
Embodiment 3
Using Ar1=Ph 2- furan alcohols and Ar2=2-CF3-3-ClC6H3Arylamine as reaction raw materials, with 10% hand
Property phosphoric acid catalyst reacted, according to same steps described in examples detailed above 1, react 34 hours, obtain yellow oily liquid production
Thing 161mg, it is 92% to calculate yield.
Equally, after the step prepares completion, resulting oil product is analyzed, the means of analysis are using survey
Determine specific rotatory power, efficient liquid phase chromatographic analysis and determine ee values, nuclear magnetic resonance, infrared and high resolution mass spectrum.Wherein, test analysis
Data are as follows：
1st, the specific rotatory power [α] that D lines are determined at 23 DEG CD 23:- 78.0 (c=1.3, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelIC posts；5%i-PrOHin
hexanes；1.0mL/min；Retention time:15.8min(major),25.0min(minor).Result of calculation is 89%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum, fluorine spectrum：
1H NMR(400MHz,CDCl3) δ 7.73-7.71 (m, 1H), 7.44 (d, J=2.4Hz, 1H), 7.39-7.30 (m,
3H), 7.15-7.12 (m, 3H), 6.47 (dd, J=1.6Hz, 5.6Hz, 1H), 6.38 (d, J=8.8Hz, 1H), 4.76 (dd, J
=1.6Hz, 7.6Hz, 1H), 4.62 (d, J=7.6Hz, 1H), 3.37 (d, J=2.4Hz, 1H)
13C NMR(100MHz,CDCl3)δ205.4,160.0,142.4,137.6,135.6,132.9,129.1,127.8,
(q, J=5.6Hz), 127.6,126.8 124.0 (q, J=271.1Hz), 122.4,115.5 (q, J=30.1Hz), 114.7,
63.1,60.2.
19F NMR(376.5MHz,CDCl3)δ-62.4.
4th, infrared spectrum：IR(thin film)3406,3072,2922,1597,1510,1419,1317,1259,1110,
1046,888,806,698,653,533,481cm-1.
5th, high resolution mass spectrum：HRMS m/z(CI)calcd.for C18H13ClF3NO(M)+351.0638,found
351.0636.
It can be seen that its Theoretical Mass is 351.0638 from the result, and the observation that peak is found in actual mass spectrum is
351.0636；Specific rotatory power in conjunction with nuclear magnetic resonance and infrared elementary analysis, and standard can determine product structure such as
Under：
Embodiment 4
Using Ar1=Ph 2- furan alcohols and Ar2=3-CF3-4-NO2C6H3Arylamine as reaction raw materials, with 10%
Chiral phosphoric acid catalyst is reacted, according to same steps described in examples detailed above 1, is reacted 21 hours, is obtained yellow oily liquid
Product 66mg, it is 92% to calculate yield.
Equally, after the step prepares completion, resulting oil product is analyzed, the means of analysis are using survey
Determine specific rotatory power, efficient liquid phase chromatographic analysis and determine ee values, nuclear magnetic resonance, infrared and high resolution mass spectrum.Wherein, test analysis
Data are as follows：
1st, the specific rotatory power [α] that D lines are determined at 23 DEG CD 23:- 35.5 (c=0.4, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelAD-H posts；10%i-PrOH
in hexanes；1.0mL/min；Retention time:13.6min(major),20.5min(minor).Result of calculation is 90%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum, fluorine spectrum：
1H NMR(400MHz,CDCl3) δ 7.87 (d, J=8.8Hz, 1H), 7.71 (dd, J=2.0Hz, 5.6Hz, 1H),
7.40-7.32 (m, 3H), 7.11 (dd, J=1.2Hz, 6.4Hz, 2H), 6.77 (d, J=1.6Hz, 1H), 6.51 (dd, J=
1.2Hz, 5.6Hz, 2H), 5.15 (br s, 1H), 4.84 (s, 1H), 3.37 (d, J=2.4Hz, 1H)
13C NMR(100MHz,CDCl3)δ205.1,159.1,150.0,137.7,137.1,136.0,129.4,128.8,
(q, J=33.3Hz), 128.0,127.8,126.6 121.9 (q, J=272Hz), 113.9,112.1 (q, J=6.2Hz),
62.8,60.3.
19F NMR(376.5MHz,CDCl3)δ-60.4.
4th, infrared spectrum：IR(thin film)3739,3620,3353,3071,2922,2858,2358,1709,1601,
1508,1440,1330,1266,1144,1031,920,876,833,754,697cm-1.
5th, high resolution mass spectrum：HRMS m/z(CI)calcd.for C18H13F3N2O3(M)+362.0878,
found362.0873.
It can be seen that its Theoretical Mass is 362.0878 from the result, and the observation that peak is found in actual mass spectrum is
362.0873；Specific rotatory power in conjunction with nuclear magnetic resonance and infrared elementary analysis, and standard can determine product structure such as
Under：
For the product of the present embodiment.
Embodiment 5
Using Ar1=4-FC6H42- furan alcohols and Ar2=3,5- (CF3)2C6H3Arylamine as reaction raw materials, with 10%
Chiral phosphoric acid catalyst reacted, according to same steps described in examples detailed above 1, react 70 hours, obtain brown oil liquid
Body product 153mg, it is 76% to calculate yield.
Equally, after the step prepares completion, resulting oil product is analyzed, the means of analysis are using survey
Determine specific rotatory power, efficient liquid phase chromatographic analysis and determine ee values, nuclear magnetic resonance, infrared and high resolution mass spectrum.Wherein, test analysis
Data are as follows：
1st, the specific rotatory power [α] that D lines are determined at 23 DEG CD 23:- 15.3 (c=0.6, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelAD-H posts；5%i-PrOH in
hexanes；1.0mL/min；Retention time:7.0min(major),10.1min(minor).Result of calculation is 88%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum, fluorine spectrum：
1H NMR(400MHz,CDCl3) δ 7.71 (d, J=6.0Hz, 1H), 7.18 (s, 1H), 7.12-7.03 (m, 4H),
6.80 (s, 2H), 6.48 (d, J=5.6Hz, 1H), 4.74 (d, J=7.6Hz, 1H), 4.65 (d, J=8.4Hz, 1H), 3.34
(d, J=2.0Hz, 1H)
13C NMR(100MHz,CDCl3) δ 205.5,162.3 (d, J=245.4), 159.9,146.9,135.6,133.2
(d, J=3.5Hz), 132.6 (q, J=32.8Hz), 129.5 (d, J=8.1Hz), 123.2 (q, J=271.1Hz), 116.2
(d, J=21.5Hz), 112.9,111.5 (d, J=4.1Hz), 63.0,59.8.
19F NMR(376.5MHz,CDCl3)δ-63.4,-114.2.
4th, infrared spectrum：IR(thin film)3368,3082,2924,2856,2359,1713,1617,1514,1473,
1438,1393,1350,1279,1231,1175,1130,991,946,864,820,768,690,584,534cm-1.
5th, high resolution mass spectrum：HRMS m/z(CI)calcd.for C19H12F7NO(M)+403.0807,
found403.0804.
It can be seen that its Theoretical Mass is 403.0807 from the result, and the observation that peak is found in actual mass spectrum is
403.0804；Specific rotatory power in conjunction with nuclear magnetic resonance and infrared elementary analysis, and standard can determine product structure such as
Under：
For the product of the present embodiment.
Embodiment 6
Using Ar1=4-ClC6H42- furan alcohols and Ar2=3,5- (CF3)2C6H3Arylamine be used as reaction raw materials, use
10% chiral phosphoric acid catalyst is reacted, according to same steps described in examples detailed above 1, is reacted 70 hours, is obtained yellow oil
Shape product liquid 142mg, it is 68% to calculate yield.
Equally, after the step prepares completion, resulting oil product is analyzed, the means of analysis are using survey
Determine specific rotatory power, efficient liquid phase chromatographic analysis and determine ee values, nuclear magnetic resonance, infrared and high resolution mass spectrum.Wherein, test analysis
Data are as follows：
1st, the specific rotatory power [α] that D lines are determined at 23 DEG CD 23:- 47.7 (c=0.7, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelAD-H posts；5%i-PrOH in
hexanes；1.0mL/min；Retention time:7.4min(major),11.2min(minor).Result of calculation is 88%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum, fluorine spectrum：
1H NMR(400MHz,CDCl3) δ 7.71 (dd, J=2.0Hz, 5.6Hz, 1H), 7.33 (dt, J=2.4Hz,
8.4Hz, 2H), 7.19 (s, 1H), 7.04 (dt, J=2.4Hz, 8.8Hz, 2H), 6.80 (s, 2H), 6.48 (dd, J=1.6Hz,
5.6Hz, 1H), 4.75 (dd, J=2.0Hz, 6.0Hz, 1H), 4.63 (d, J=8.4Hz, 1H), 3.33 (d, J=2.8Hz, 1H)
13C NMR(100MHz,CDCl3) δ 205.1,159.9,146.8,135.8,135.6,133.9,132.7 (q, J=
32.8Hz), 129.4,129.2,123.2 (q, J=271.1Hz), 112.9,111.6 (q, J=3.8Hz), 62.9,59.8.
19F NMR(376.5MHz,CDCl3)δ-63.4.
4th, infrared spectrum：IR(thin film)3371,3085,2924,2856,2359,1713,1620,1531,1482,
1439,1393,1350,1278,1176,1131,1003,947,864,814,783,691,550cm-1.
5th, high resolution mass spectrum：HRMS m/z(CI)calcd.for C19H12ClF6NO(M)+419.0512,
found419.0513.
It can be seen that its Theoretical Mass is 419.0512 from the result, and the observation that peak is found in actual mass spectrum is
419.0513；Specific rotatory power in conjunction with nuclear magnetic resonance and infrared elementary analysis, and standard can determine product structure such as
Under：
For the product of the present embodiment.
Embodiment 7
Using Ar1=4-OMeC6H42- furan alcohols and Ar2=3,5- (CF3)2C6H3Arylamine be used as reaction raw materials, use
10% chiral phosphoric acid catalyst is reacted, and is reacted 37 hours, is obtained at subzero 20 DEG C according to same steps described in examples detailed above 1
To brown oil product liquid 135mg, it is 65% to calculate yield.
Equally, after the step prepares completion, resulting oil product is analyzed, the means of analysis are using survey
Determine specific rotatory power, efficient liquid phase chromatographic analysis and determine ee values, nuclear magnetic resonance, infrared and high resolution mass spectrum.Wherein, test analysis
Data are as follows：
1st, the specific rotatory power [α] that D lines are determined at 23 DEG CD 23:- 46.2 (c=1.0, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelAD-H posts；5%i-PrOH in
hexanes；1.0mL/min；Retention time:10.2min(major),13.9min(minor).Result of calculation is 88%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum, fluorine spectrum：
1H NMR(400MHz,CDCl3) δ 7.68 (dd, J=2.4Hz, 6.0Hz, 1H), 7.26 (s, 1H), 7.02 (d, J=
8.4Hz, 2H), 6.88 (d, J=8.8Hz, 2H), 6.81 (s, 2H), 6.47 (d, J=5.6Hz, 1H), 4.72 (dd, J=
1.6Hz, 8.0Hz, 1H), 4.64 (s, 1H), 3.79 (s, 3H), 3.29 (d, J=2.8Hz, 1H)
13C NMR(100MHz,CDCl3) δ 206.1,159.8,159.2,147.0,135.6,132.5 (q, J=
32.7Hz), 129.4,129.0,123.2 (q, J=271.0Hz), 114.7,112.8,111.3,63.1,59.9,55.3.
19F NMR(376.5MHz,CDCl3)δ-63.3.
4th, infrared spectrum：IR(thin film)3621,3364,2928,2845,1711,1618,1516,1473,1394,
1279,1176,1130,1034,945,864,812,691,543cm-1.
5th, high resolution mass spectrum：HRMS m/z(CI)calcd.for C20H15F6NO2(M)+415.1007,
found415.0998.
It can be seen that its Theoretical Mass is 415.1007 from the result, and the observation that peak is found in actual mass spectrum is
415.0998；Specific rotatory power in conjunction with nuclear magnetic resonance and infrared elementary analysis, and standard can determine product structure such as
Under：
For the product of the present embodiment.
Embodiment 8
Using Ar1=4-SMeC6H42- furan alcohols and Ar2=3,5- (CF3)2C6H3Arylamine be used as reaction raw materials, use
10% chiral phosphoric acid catalyst is reacted, according to same steps described in examples detailed above 1, is reacted 10 hours, is obtained colorless oil
Shape product liquid 114mg, it is 88% to calculate yield.
Equally, after the step prepares completion, resulting oil product is analyzed, the means of analysis are using survey
Determine specific rotatory power, efficient liquid phase chromatographic analysis and determine ee values, nuclear magnetic resonance, infrared and high resolution mass spectrum.Wherein, test analysis
Data are as follows：
1st, the specific rotatory power [α] that D lines are determined at 23 DEG CD 23:- 69.3 (c=0.4, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelAD-H posts；5%i-PrOH in
hexanes；1.0mL/min；Retention time:9.6min(major),15.9min(minor).Result of calculation is 90%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum, fluorine spectrum：
1H NMR(400MHz,CDCl3) δ 7.69 (dd, J=2.0Hz, 5.6Hz, 1H), 7.24 (d, J=8.4Hz, 2H),
7.17 (s, 1H), 7.01 (d, J=8.4Hz, 2H), 6.80 (s, 2H), 6.46 (dd, J=1.6Hz, 6.0Hz, 1H), 4.73 (dd,
J=2.0Hz, 8.4Hz, 1H), 4.67 (d, J=8.0Hz, 1H), 3.30 (d, J=2.4Hz, 1H), 2.46 (s, 3H)
13C NMR(100MHz,CDCl3) δ 205.6,160.0,146.9,138.3,135.5,134.1,132.5 (q, J=
32.8Hz), 128.3,127.5,123.2 (q, J=271.1), 112.8 (d, J=3.3Hz), 111.4 (t, J=4.0Hz),
62.9,60.0,15.9.
19F NMR(376.5MHz,CDCl3)δ-63.3.
4th, infrared spectrum：IR(thin film)3369,2923,1710,1619,1532,1480,1438,1393,1349,
1277,1175,1128,989,947,862,804,759,691,547cm-1.
5th, high resolution mass spectrum：HRMS m/z(CI)calcd.for C20H15F6NOS(M)+431.0779,
found431.0782.
It can be seen that its Theoretical Mass is 431.0779 from the result, and the observation that peak is found in actual mass spectrum is
431.0782；Specific rotatory power in conjunction with nuclear magnetic resonance and infrared elementary analysis, and standard can determine product structure such as
Under：
For the product of the present embodiment.
Embodiment 9
Using Ar1=2-naphthyl 2- furan alcohols and Ar2=3,5- (CF3)2C6H3Arylamine be used as reaction raw materials, use
10% chiral phosphoric acid catalyst is reacted, according to same steps described in examples detailed above 1, is reacted 32 hours, is obtained yellow oil
Shape product liquid 114mg, it is 72% to calculate yield.
Equally, after the step prepares completion, resulting oil product is analyzed, the means of analysis are using survey
Determine specific rotatory power, efficient liquid phase chromatographic analysis and determine ee values, nuclear magnetic resonance, infrared and high resolution mass spectrum.Wherein, test analysis
Data are as follows：
1st, the specific rotatory power [α] that D lines are determined at 23 DEG CD 23:- 69.4 (c=0.5, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelAD-H posts；5%i-PrOH in
hexanes；1.0mL/min；Retention time:8.8min(major),11.8min(minor).Result of calculation is 88%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum, fluorine spectrum：
1H NMR(400MHz,CDCl3) δ 7.85-7.82 (m, 2H), 7.74 (dd, J=3.6Hz, 6.0Hz, 1H), 7.68
(dd, J=2.4Hz, 5.6Hz, 1H), 7.57 (s, 1H), 7.51-7.47 (m, 2H), 7.15-7.13 (m, 2H), 6.80 (s, 2H),
(d, J=2.4Hz, the 1H) of 6.49 (dd, J=1.6Hz, 6.0Hz, 1H), 4.80 (s, 1H), 4.65 (s, 1H), 3.46
13C NMR(100MHz,CDCl3)δ206.1,160.4,146.9,135.4,134.7,133.4,132.7,132.4
(q, J=32.8Hz), 129.2,127.7,127.6,127.4,126.5,126.2,124.9,123.2 (q, J=271.2Hz),
(112.8,111.2 q, J=3.8Hz), 62.8,60.4.
19F NMR(376.5MHz,CDCl3)δ-63.3.
4th, infrared spectrum：IR(thin film)3370,3061,2923,2856,2359,1709,1619,1524,1473,
1438,1391,1277,1175,1128,991,949,860,814,746,690,477cm-1.
5th, high resolution mass spectrum：HRMS m/z(CI)calcd.for C23H15F6NO(M)+435.1058,
found435.1051.
It can be seen that its Theoretical Mass is 435.1058 from the result, and the observation that peak is found in actual mass spectrum is
435.1051；Specific rotatory power in conjunction with nuclear magnetic resonance and infrared elementary analysis, and standard can determine product structure such as
Under：
For the product of the present embodiment.
Embodiment 10
Using Ar1=2-thiophenyl 2- furan alcohols and Ar2=3,5- (CF3)2C6H3Arylamine as reaction raw materials,
Reacted with 10% chiral phosphoric acid catalyst, according to same steps described in examples detailed above 1, react 16 hours, obtain yellow
Oily liquids product 163mg, it is 97% to calculate yield.
Equally, after the step prepares completion, resulting oil product is analyzed, the means of analysis are using survey
Determine specific rotatory power, efficient liquid phase chromatographic analysis and determine ee values, nuclear magnetic resonance, infrared and high resolution mass spectrum.Wherein, test analysis
Data are as follows：
1st, the specific rotatory power [α] that D lines are determined at 23 DEG CD 23:- 31.2 (c=0.6, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelIC posts；5%i-PrOHin
hexanes；1.0mL/min；Retention time:8.0min(major),11.3min(minor).Result of calculation is 88%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum, fluorine spectrum：
1H NMR(400MHz,CDCl3) δ 7.67 (dd, J=1.2Hz, 4.4Hz, 1H), 7.26 (d, J=4.4Hz, 1H),
7.20 (s, 1H), 7.00 (t, J=3.6Hz, 1H), 6.93-6.92 (m, 3H), 6.43 (d, J=6.0Hz, 1H), 4.87 (d, J=
8.0Hz, 1H), 4.75 (d, J=8.4Hz, 1H), 3.68 (d, J=2.4Hz, 1H)
13C NMR(100MHz,CDCl3) δ 203.7,159.6,146.8,137.9,134.5,132.7 (q, J=
32.9Hz), 127.3,126.3,125.2,123.2 (q, J=271.2Hz), 112.8,111.5,63.1,55.2.
19F NMR(376.5MHz,CDCl3)δ-63.3.
4th, infrared spectrum：IR(thin film)3371,3083,2962,2924,2859,2359,1715,1620,1530,
1474,1438,1392,1350,1277,1176,1130,1028,946,864,803,761,696,598,524cm-1.
5th, high resolution mass spectrum：HRMS m/z(CI)calcd.for C17H12F6NOS(M+H)+392.0544,found
392.0542.
It can be seen that its Theoretical Mass is 392.0544 from the result, and the observation that peak is found in actual mass spectrum is
392.0542；Specific rotatory power in conjunction with nuclear magnetic resonance and infrared elementary analysis, and standard can determine product structure such as
Under：
For the product of the present embodiment.
Embodiment 11
Using Ar1=2-furanyl 2- furan alcohols and Ar2=3,5- (CF3)2C6H3Arylamine be used as reaction raw materials, use
10% chiral phosphoric acid catalyst is reacted, according to same steps described in examples detailed above 1, is reacted 43 hours, is obtained yellow oil
Shape product liquid 115mg, it is 62% to calculate yield.
Equally, after the step prepares completion, resulting oil product is analyzed, the means of analysis are using survey
Determine specific rotatory power, efficient liquid phase chromatographic analysis and determine ee values, nuclear magnetic resonance, infrared and high resolution mass spectrum.Wherein, test analysis
Data are as follows：
1st, the specific rotatory power [α] that D lines are determined at 23 DEG CD 23:- 35.7 (c=1.1, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelIC posts；2%i-PrOHin
hexanes；1.0mL/min；Retention time:13.0min(major),19.6min(minor).Result of calculation is 90%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum, fluorine spectrum：
1H NMR(400MHz,CDCl3) δ 7.68 (dd, J=2.4Hz, 5.6Hz, 1H), 7.39 (d, J=1.2Hz, 1H),
7.20 (s, 1H), 6.94 (s, 2H), 6.43 (dd, J=2.0Hz, 6.0Hz, 1H), 6.37 (dd, J=2.0Hz, 3.2Hz, 1H),
(d, J=2.8Hz, the 1H) of 6.26 (d, J=3.2Hz, 1H), 5.02-4.99 (m, 1H), 4.65 (d, J=8.4Hz, 1H), 3.52
13C NMR(100MHz,CDCl3) δ 202.8,159.9,149.1,146.9,142.6,134.8,132.6 (q, J=
32.6Hz), 123.3 (q, J=271Hz), 112.7,111.5 (t, J=3.9Hz), 110.8,108.8,59.6,54.0.
19F NMR(376.5MHz,CDCl3)δ-63.3.
4th, infrared spectrum：IR(thin film)3369,1717,1619,1534,1475,1439,1393,1280,1177,
1131,1005,944,865,738,690cm-1.
5th, high resolution mass spectrum：HRMS m/z(CI)calcd.for C17H11F6NO2(M)+375.0694,
found375.0691.
It can be seen that its Theoretical Mass is 375.0694 from the result, and the observation that peak is found in actual mass spectrum is
375.0691；Specific rotatory power in conjunction with nuclear magnetic resonance and infrared elementary analysis, and standard can determine product structure such as
Under：
For the product of the present embodiment.
Embodiment 12
α benzylated products are prepared according to following reaction equation:
Implementation steps：Reaction raw materials (100mg, 0.258mmol, 89%ee) are dissolved in dry DMF (4mL), then
Sequentially add K2CO3(144mg, 1.03mmol), KI (4.30mg, 25.8 μm of ol) and BnBr (0.10mL, 0.774mmol) it
Afterwards, in stirring at normal temperature 30h, add water (5mL) and be quenched.It is extracted with ethyl acetate (20mL × 3), washes (5mL × 3), food
Salt is washed and (5mL) and then uses anhydrous sodium sulfate drying, obtained after concentration with silica gel column chromatography yellow oily liquid product (110mg,
90%yield)
Equally, after the step prepares completion, resulting oil product is analyzed, the means of analysis are using survey
Determine specific rotatory power, efficient liquid phase chromatographic analysis and determine ee values, nuclear magnetic resonance, infrared and high resolution mass spectrum.Wherein, test analysis
Data are as follows：
1st, the specific rotatory power [α] that D lines are determined at 23 DEG CD 23:- 119 (c=1.0, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelOD-H posts；3%i-PrOH in
hexanes；1.0mL/min；Retention time:10.5min(major),14.8min(minor).Result of calculation is 88%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum, fluorine spectrum：
1H NMR(400MHz,CDCl3)δ7.39-7.29(m,7H),7.21-7.15(m,5H),6.74(s,2H),6.41
(dd, J=2.0Hz, 5.6Hz, 1H), 4.91 (d, J=10.8Hz, 1H), 3.73 (d, J=13.6Hz, 1H), 3.63 (d, J=
10.4Hz, 1H), 3.32 (d, J=13.6Hz, 1H)
13C NMR(100MHz,CDCl3) δ 209.4,162.1,147.3,139.1,136.1,136.0,132.5 (q, J=
32.7Hz), 130.6,128.7 (2C), 127.9 (2C), 127.4,123.3 (q, J=271.1Hz), 112.9,111.4,61.1,
60.0,40.8.
19F NMR(376.5MHz,CDCl3)δ-63.3.
4th, infrared spectrum：IR(thin film)3692,3378,3063,3031,2926,1708,1619,1523,1499,
1475,1439,1391,1344,1316,1277,1177,1131,1107,1033,996,942,863,820,790,762,
732,700,682cm-1.
5th, high resolution mass spectrum：HRMS m/z(CI)calcd.for C26H20F6NO(M+H)+476.1449,found
476.1457.
It can be seen that its Theoretical Mass is 476.1449 from the result, and the observation that peak is found in actual mass spectrum is
476.1457；Specific rotatory power in conjunction with nuclear magnetic resonance and infrared elementary analysis, and standard can determine product structure such as
Under：
For the product of the present embodiment.
Embodiment 13
RMgBr attack product is prepared according to following equation：
Implementation steps：At subzero 788 DEG C, reaction raw materials (60.0mg, 0.156mmol, 89%ee) are dissolved in THF (2mL)
In, allylic bromination magnesium solution (0.47mL, 0.47mmol, 1.0M in2- is then slowly added dropwise
Methyltetrahydrofuran) after .20 minutes, saturation NH is added4Reaction is quenched in Cl solution (1mL).Temperature is raised to often
Temperature, is extracted, anhydrous sodium sulfate drying with ethyl acetate (10mL × 3), and concentration, silica gel column chromatography obtains colourless oil liquid product
(58mg, 88%yield).
Equally, after the step prepares completion, resulting oil product is analyzed, the means of analysis are using survey
Determine specific rotatory power, efficient liquid phase chromatographic analysis and determine ee values, nuclear magnetic resonance, infrared and high resolution mass spectrum.Wherein, test analysis
Data are as follows：
1st, the specific rotatory power [α] that D lines are determined at 25 DEG CD 25:- 76.4 (c=1.0, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelOD-H posts；5%i-PrOH in
hexanes；1.0mL/min；Retention time:8.4min(major),16.3min(minor).Result of calculation is 88%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum, fluorine spectrum：
1H NMR(400MHz,CDCl3) δ 7.41-7.37 (m, 5H), 7.08 (s, 1H), 6.80 (s, 2H), 6.17 (dd, J=
1.6Hz, 5.6Hz, 1H), 6.08 (dd, J=1.6Hz, 5.6Hz, 1H), 5.88-5.82 (m, 1H), 5.21-5.15 (m, 2H),
4.95-4.90 (m, 1H), 4.25 (d, J=7.6Hz, 1H), 3.10 (d, J=6.4Hz, 1H), 2.50 (dd, J=6.8Hz,
14.4Hz, 1H), 2.38 (dd, J=8.0Hz, 13.2Hz, 1H)
13C NMR(100MHz,CDCl3) δ 147.8,137.9,136.8,134.9,133.2,132.3 (q, J=
32.5Hz), 129.5,128.9,127.8,123.4 (q, J=271.0Hz), 119.5,112.5,110.4 (q, J=3.9Hz),
83.2,64.7,60.4,45.3.
19F NMR(376.5MHz,CDCl3)δ-63.3.
4th, infrared spectrum：IR(thin film)3678,3548,3358,3064,2926,1736,1621,1519,1496,
1475,1454,1435,1394,1277,1176,1129,1033,995,949,924,863,846,776,745,732,701,
682,606cm-1.
5th, high resolution mass spectrum：HRMS m/z(CI)calcd.for C22H19F6NO(M)+427.1371,
found427.1365.
It can be seen that its Theoretical Mass is 427.1371 from the result, and the observation that peak is found in actual mass spectrum is
427.1365；Specific rotatory power in conjunction with nuclear magnetic resonance and infrared elementary analysis, and standard can determine product structure such as
Under：
For the product of the present embodiment.
Embodiment 14：
The product of hydrogenation and Baeyer-Villiger oxidations is prepared according to following equation：
Implementation steps：Under normal temperature, reaction raw materials (100mg, 0.258mmol, 89%ee) are dissolved in ethyl acetate (4mL)
In, add PtO2After (10mg, 44.1 μm of ol) solid, it is hydrogen by gas displacement in bottle, 30 is then stirred under an atmosphere of hydrogen
Minute.Then suction filtered through kieselguhr is used, is washed with ethyl acetate after (20mL × 3), concentrate eluant and is obtained yellow oily liquid and be
The product of hydrogenation.The product is dissolved in dichloromethane (5mL), NaHCO is then added3(86.7mg,1.03mmol,
4.0equiv) with mCPBA (119mg, 0.516mmol, 75%purity).Reactant mixture is stirred at normal temperatures 3 hours, used
Saturated sodium thiosulfate solution (5mL) is quenched, ethyl acetate extraction (10mL × 3), anhydrous Na2SO4Dry, concentration, silica gel column layer
Yellow oily liquid product (75.8mg, 73%yield) is obtained after analysis.
Equally, after the step prepares completion, resulting oil product is analyzed, the means of analysis are using survey
Determine specific rotatory power, efficient liquid phase chromatographic analysis and determine ee values, nuclear magnetic resonance, infrared and high resolution mass spectrum.Wherein, test analysis
Data are as follows：
1st, the specific rotatory power [α] that D lines are determined at 23 DEG CD 23:- 41.8 (c=1.0, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelOD-H posts；10%i-PrOH in
hexanes；1.0mL/min；Retention time:9.6min(major),22.6min(minor).Result of calculation is 90%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum, fluorine spectrum：
1H NMR(400MHz,CDCl3) δ 7.35-7.30 (m, 5H), 7.11 (s, 1H), 6.76 (s, 2H), 5.32 (d, J=
6.8Hz, 1H), 4.51 (d, J=7.6Hz, 1H), 3.93-3.86 (m, 1H), 2.90-2.81 (m, 1H), 2.79-2.71 (m,
1H),2.28-2.20(m,1H),2.05-1.98(m,1H).
13C NMR(100MHz,CDCl3) δ 170.4,146.8,136.9,132.4 (q, J=32.7Hz), 129.0,
(128.9,126.1,123.3 q, J=271.0Hz), 112.4,111.1,84.4,52.3,27.3,23.8.
19F NMR(376.5MHz,CDCl3)δ-63.2.
4th, infrared spectrum：IR(thin film)3692,3348,2929,1726,1619,1546,1476,1439,1394,
1277,1172,1128,1042,997,956,914,862,845,756,733,700,682,526cm-1.
5th, high resolution mass spectrum：HRMS m/z(CI)calcd.for C19H16F6NO2(M+H)+404.1085,found
404.1083.
It can be seen that its Theoretical Mass is 404.1085 from the result, and the observation that peak is found in actual mass spectrum is
404.1083；Specific rotatory power in conjunction with nuclear magnetic resonance and infrared elementary analysis, and standard can determine product structure such as
Under：
For the product of the present embodiment.
Embodiment 15
By the product of the gained of embodiment 4 after the Benzylation steps of the α described in embodiment 12, corresponding benzyl can be obtained
Base product, then can prepare the product of hydrogenation by following equation：
Implementation steps：Reaction raw materials (156mg, 0.345mmol, 88%ee) are dissolved in ethyl acetate (6mL), added
Pd/C (50mg, 10wt%), is then hydrogen by gas displacement in bottle, and stir 19 hours under an atmosphere of hydrogen.Diatomite is taken out
Filter, ethyl acetate is washed (10mL × 3), is concentrated, and silica gel column chromatography obtains yellow oily liquid product (106mg, 73%yield).
Equally, after the step prepares completion, resulting oil product is analyzed, the means of analysis are using survey
Determine specific rotatory power, efficient liquid phase chromatographic analysis and determine ee values, nuclear magnetic resonance, infrared and high resolution mass spectrum.Wherein, test analysis
Data are as follows：
1st, the specific rotatory power [α] that D lines are determined at 25 DEG CD 25:- 51.2 (c=1.0, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelIC posts；5%i-PrOHin
hexanes；1.0mL/min；Retention time:16.0min(major),21.6min(minor).Result of calculation is 89%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum, fluorine spectrum：
1H NMR(400MHz,CDCl3)δ7.46-7.36(m,3H),7.34-7.27(m,5H),7.13-7.10(m,2H),
6.68-6.64 (m, 2H), 6.56 (dd, J=2.4Hz, 8.8Hz, 1H), 4.06 (d, J=5.6Hz, 1H), 3.80 (br s, 2H),
3.42 (d, J=13.6Hz, 1H), 3.29 (d, J=13.2Hz, 1H), 2.96 (d, J=8.0Hz, 1H), 2.59-2.52 (m,
1H),2.25-2.18(m,1H),2.09-2.00(m,1H),1.64-1.50(m,1H).
13C NMR(100MHz,CDCl3)δ219.3,138.8,138.0,136.7,136.4,131.0,128.6,128.3
(2C), 127.6,126.8,124.8 (q, J=270.9Hz), 119.7,119.1,115.1 (q, J=29.4Hz), 111.7 (q, J
=5.2Hz), 61.9,57.0,40.7,38.2,25.7.
19F NMR(376.5MHz,CDCl3)δ-62.4.
4th, infrared spectrum：IR(thin film)3700,2928,1737,1514,1430,1332,1288,1235,1140,
1107,1045,821,735,703,540cm-1.
5th, high resolution mass spectrum：HRMS m/z(CI)calcd.for C25H23F3N2O(M)+424.1762,
found424.1767.
It can be seen that its Theoretical Mass is 424.1762 from the result, and the observation that peak is found in actual mass spectrum is
424.1767；Specific rotatory power in conjunction with nuclear magnetic resonance and infrared elementary analysis, and standard can determine product structure such as
Under：
For the product of the present embodiment.
Embodiment 16
By the product of the gained of embodiment 15, the chiral 4- amidos cyclopentanone that can prepare removing aryl by following equation is produced
Thing.
Implementation steps：Raw material (65mg, 0.153mmol, 89%ee) is dissolved in acetonitrile (6mL), and is cooled to 0 DEG C.
It is then slowly added into sulfuric acid solution (3mL, 1M) and ceric ammonium nitrate solution (2mL, 0.912mmol, 0.25g/mL
concentration).Kept for 0 DEG C react 2 hours, extracted with dichloromethane (20mL × 3), merged organic phase, use saturation
Na2SO3Solution washes (5mL) and saturation K2CO3Solution is washed (5mL), anhydrous sodium sulfate drying, and concentration, silica gel column chromatography obtains Huang
Color oily liquids product (30.0mg, 74%yield).
Equally, after the step prepares completion, resulting oil product is analyzed, the means of analysis are using survey
Determine specific rotatory power, efficient liquid phase chromatographic analysis and determine ee values, nuclear magnetic resonance, infrared and high resolution mass spectrum.Wherein, test analysis
Data are as follows：
1st, the specific rotatory power [α] that D lines are determined at 25 DEG CD 25:- 25.8 (c=1.0, CHCl3)。
2nd, efficient liquid phase chromatographic analysis determines ee values：Chiral column DaicelAS-H posts；10%i-PrOH
in hexanes；1.0mL/min；Retention time:9.5min(major),12.6min(minor).Result of calculation is 90%ee.
3rd, the hydrogen spectrum of nuclear magnetic resonance spectroscopy, carbon spectrum：
1H NMR(400MHz,CDCl3) δ 7.36-7.19 (m, 8H), 7.08-7.07 (m, 2H), 3.55 (dd, J=5.6Hz,
8.8Hz, 1H), 3.32 (d, J=13.6Hz, 1H), 3.20 (d, J=13.6Hz, 1H), 2.54-2.46 (m, 1H), 2.07-1.97
(m,2H),1.56-1.47(m,1H),1.16(br s,2H).
13C NMR(100MHz,CDCl3)δ219.9,138.4,137.0,130.9,128.3(2C),128.1,127.0,
126.6,62.6,55.4,40.8,38.0,28.7.
3, infrared spectrum：IR(thin film)3671,3076,2930,1736,1585,1498,1451,1400,1322,
1129,774,702cm-1.
5th, high resolution mass spectrum：HRMS m/z(CI)calcd.for C18H19NO(M)+265.1467,found265.1471.
It can be seen that its Theoretical Mass is 265.1467 from the result, and the observation that peak is found in actual mass spectrum is
265.1471；Specific rotatory power in conjunction with nuclear magnetic resonance and infrared elementary analysis, and standard can determine product structure such as
Under：
For the product of the present embodiment.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
Any modifications, equivalent substitutions and improvements made within refreshing and principle etc., should be included in the scope of the protection.
Claims (10)
1. a kind of preparation method of chiral 4- amidos cyclopentenone, comprises the following steps：
Aromatic amine and catalyst CPA shown in offer 2- furan alcohols as shown in Equation 1, formula 2, wherein, the CPA is that 1- pyrenyls take
The phosphoric acid of the chiral spiro skeleton in generation,
The aromatic amine and the CPA are dissolved in after the first organic solvent, 0-5 DEG C is cooled to, the 2- furans is then added
The solution of first organic solvent of alcohol, azepine Piancatelli is reset instead between asymmetric molecult is carried out under the conditions of being stirred at room temperature
Should, the chiral 4- amidos cyclopentenone shown in formula 3 is obtained,
2. the preparation method of chirality 4- amido cyclopentenones as claimed in claim 1, it is characterised in that the 2- furan alcohols
In the structure of formula 1, the Ar1For one kind in phenyl ring or substituted benzene ring, condensed ring or substitution condensed ring, heterocycle.
3. the preparation method of chirality 4- amido cyclopentenones as claimed in claim 2, it is characterised in that the substituted benzene ring,
In the substitution condensed ring, substituted radical is one kind in halogen, methyl, methoxyl group, sulfydryl, and the heterocycle includes furans, thiophene
In one kind.
4. the preparation method of chirality 4- amido cyclopentenones as claimed in claim 1, it is characterised in that the formula of the aromatic amine
In 2 structures, the Ar2 is in phenyl ring or substituted benzene ring, and the substituted benzene ring, substituted radical is trifluoromethyl, itrile group, nitre
One kind in base, halogen, methyl, methoxyl group.
5. the preparation method of the chiral 4- amidos cyclopentenone as described in claim 1-4 is any, it is characterised in that the CPA
Addition be the 2- furan alcohols mole dosage 5-20mol%.
6. the preparation method of the chiral 4- amidos cyclopentenone as described in claim 1-4 is any, it is characterised in that described first
Organic solvent is one kind in 1,2- dichloroethanes, dichloromethane, chloroform, toluene.
7. the application of chiral 4- amidos cyclopentenone prepared by a kind of any methods describeds of such as claim 1-6, it is characterised in that
Comprise the following steps：
Chiral 4- amidos cyclopentenone shown in offer formula 3, the second organic solvent is dissolved in by the chiral 4- amidos cyclopentenone
Afterwards, K is sequentially added2CO3, iodide and BnBr, reaction obtains the α benzylated products shown in formula 4 under the conditions of being stirred at room temperature,
8. the application of chiral 4- amidos cyclopentenone prepared by a kind of any methods describeds of such as claim 1-6, it is characterised in that
Comprise the following steps：
Chiral 4- amidos cyclopentenone shown in offer formula 3, the 3rd organic solvent is dissolved in by the chiral 4- amidos cyclopentenone
Afterwards, allylic bromination magnesium is added dropwise, stirring reaction obtains product shown in formula 5 under the conditions of -75 DEG C to -78 DEG C,
9. the application of chiral 4- amidos cyclopentenone prepared by a kind of any methods describeds of such as claim 1-6, it is characterised in that
Comprise the following steps：
Chiral 4- amidos cyclopentenone shown in offer formula 3, the 4th organic solvent is dissolved in by the chiral 4- amidos cyclopentenone
In, add hydrogen activity catalyst, under an atmosphere of hydrogen stirring reaction；
Product is dissolved in the 5th organic solvent, mCPBA is then added, stirring reaction obtains product shown in formula 6 at normal temperatures,
10. the application of chiral 4- amidos cyclopentenone prepared by a kind of any methods describeds of such as claim 1-6, its feature exists
In comprising the following steps：
Chiral 4- amidos cyclopentenone shown in offer formula 7, the 6th organic solvent is dissolved in by the chiral 4- amidos cyclopentenone
In, hydrogen activity catalyst, under an atmosphere of hydrogen stirring reaction are added, intermediate shown in formula 8 is obtained；
Intermediate shown in formula 8 is dissolved in the 7th organic solvent, 0-5 DEG C is cooled to, then added after sulfuric acid and ammonium ceric nitrate, it is permanent
Temperature reaction, obtains product shown in formula 9,
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| CN110078652A (en) * | 2019-04-12 | 2019-08-02 | 香港科技大学深圳研究院 | Chiral four aryl replace methane and preparation method thereof |
| CN116024083A (en) * | 2023-02-22 | 2023-04-28 | 凯莱英生命科学技术(天津)有限公司 | Device and method for preparing chiral amine compound by continuous flow reaction |
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| CN105330608A (en) * | 2015-10-27 | 2016-02-17 | 南方科技大学 | Urazole chiral axis compound and catalytic asymmetric synthesis method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110078652A (en) * | 2019-04-12 | 2019-08-02 | 香港科技大学深圳研究院 | Chiral four aryl replace methane and preparation method thereof |
| CN110078652B (en) * | 2019-04-12 | 2021-02-12 | 香港科技大学深圳研究院 | Chiral tetraaryl substituted methane and preparation method thereof |
| CN116024083A (en) * | 2023-02-22 | 2023-04-28 | 凯莱英生命科学技术(天津)有限公司 | Device and method for preparing chiral amine compound by continuous flow reaction |
| CN116024083B (en) * | 2023-02-22 | 2023-06-13 | 凯莱英生命科学技术(天津)有限公司 | Device and method for preparing chiral amine compound by continuous flow reaction |
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