CN110256479A - A kind of chiral pyrrolidine derivative and preparation method thereof of siliceous acyl group skeleton - Google Patents
A kind of chiral pyrrolidine derivative and preparation method thereof of siliceous acyl group skeleton Download PDFInfo
- Publication number
- CN110256479A CN110256479A CN201910339842.2A CN201910339842A CN110256479A CN 110256479 A CN110256479 A CN 110256479A CN 201910339842 A CN201910339842 A CN 201910339842A CN 110256479 A CN110256479 A CN 110256479A
- Authority
- CN
- China
- Prior art keywords
- siliceous
- acyl group
- pyrrolidine derivative
- preparation
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 125000002252 acyl group Chemical group 0.000 title claims abstract description 28
- FKCMADOPPWWGNZ-YUMQZZPRSA-N [(2r)-1-[(2s)-2-amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O FKCMADOPPWWGNZ-YUMQZZPRSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 84
- -1 acylated silane compound Chemical class 0.000 claims abstract description 46
- 239000003446 ligand Substances 0.000 claims abstract description 44
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 42
- 239000003863 metallic catalyst Substances 0.000 claims abstract description 15
- 239000000654 additive Substances 0.000 claims abstract description 9
- 230000000996 additive effect Effects 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 claims abstract description 5
- 239000012429 reaction media Substances 0.000 claims abstract description 5
- 239000011261 inert gas Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 102
- 239000002904 solvent Substances 0.000 claims description 60
- 238000006243 chemical reaction Methods 0.000 claims description 47
- 239000010949 copper Substances 0.000 claims description 37
- 239000012043 crude product Substances 0.000 claims description 35
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 35
- 238000000746 purification Methods 0.000 claims description 34
- 238000010898 silica gel chromatography Methods 0.000 claims description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 239000012074 organic phase Substances 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 8
- 229910052802 copper Inorganic materials 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- FGOSNANIQLJNSZ-UHFFFAOYSA-N acetonitrile copper Chemical compound [Cu].CC#N.CC#N.CC#N.CC#N FGOSNANIQLJNSZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000012805 post-processing Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical group Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910000077 silane Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910003978 SiClx Inorganic materials 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 abstract description 40
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 125000000524 functional group Chemical group 0.000 abstract description 4
- 239000012847 fine chemical Substances 0.000 abstract description 3
- 238000006053 organic reaction Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 128
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 66
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 64
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 55
- 239000000047 product Substances 0.000 description 42
- 239000000126 substance Substances 0.000 description 35
- 239000001913 cellulose Substances 0.000 description 33
- 229920002678 cellulose Polymers 0.000 description 33
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 32
- 239000004471 Glycine Substances 0.000 description 32
- 239000002262 Schiff base Substances 0.000 description 32
- 239000003513 alkali Substances 0.000 description 32
- WIKQEUJFZPCFNJ-UHFFFAOYSA-N carbonic acid;silver Chemical compound [Ag].[Ag].OC(O)=O WIKQEUJFZPCFNJ-UHFFFAOYSA-N 0.000 description 32
- 238000012544 monitoring process Methods 0.000 description 32
- 239000012299 nitrogen atmosphere Substances 0.000 description 32
- KQTXIZHBFFWWFW-UHFFFAOYSA-L silver(I) carbonate Inorganic materials [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 0.000 description 32
- 238000003756 stirring Methods 0.000 description 32
- 238000012360 testing method Methods 0.000 description 32
- 239000012071 phase Substances 0.000 description 31
- 239000007787 solid Substances 0.000 description 31
- 239000003795 chemical substances by application Substances 0.000 description 30
- 238000001819 mass spectrum Methods 0.000 description 30
- 229910052751 metal Inorganic materials 0.000 description 30
- 239000002184 metal Substances 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 29
- 150000004756 silanes Chemical class 0.000 description 29
- 229960004592 isopropanol Drugs 0.000 description 27
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 12
- 238000005259 measurement Methods 0.000 description 10
- ASQOQJYHIYYTEJ-GBESFXJTSA-N (1r,7s,9as)-7-decyl-2,3,4,6,7,8,9,9a-octahydro-1h-quinolizin-1-ol Chemical compound O[C@@H]1CCCN2C[C@@H](CCCCCCCCCC)CC[C@H]21 ASQOQJYHIYYTEJ-GBESFXJTSA-N 0.000 description 6
- 229910052710 silicon Inorganic materials 0.000 description 5
- 239000010703 silicon Substances 0.000 description 5
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 235000010338 boric acid Nutrition 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 230000000855 fungicidal effect Effects 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- QJBZDBLBQWFTPZ-UHFFFAOYSA-N pyrrolnitrin Chemical compound [O-][N+](=O)C1=C(Cl)C=CC=C1C1=CNC=C1Cl QJBZDBLBQWFTPZ-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- QGHDLJAZIIFENW-UHFFFAOYSA-N 4-[1,1,1,3,3,3-hexafluoro-2-(4-hydroxy-3-prop-2-enylphenyl)propan-2-yl]-2-prop-2-enylphenol Chemical group C1=C(CC=C)C(O)=CC=C1C(C(F)(F)F)(C(F)(F)F)C1=CC=C(O)C(CC=C)=C1 QGHDLJAZIIFENW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010003130 Arrhythmia supraventricular Diseases 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000221198 Basidiomycota Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 235000004237 Crocus Nutrition 0.000 description 1
- 241000596148 Crocus Species 0.000 description 1
- 206010015856 Extrasystoles Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 235000015511 Liquidambar orientalis Nutrition 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000000418 Premature Cardiac Complexes Diseases 0.000 description 1
- 102000008847 Serpin Human genes 0.000 description 1
- 108050000761 Serpin Proteins 0.000 description 1
- 239000004870 Styrax Substances 0.000 description 1
- 244000028419 Styrax benzoin Species 0.000 description 1
- 235000000126 Styrax benzoin Nutrition 0.000 description 1
- 206010042600 Supraventricular arrhythmias Diseases 0.000 description 1
- NGBFQHCMQULJNZ-UHFFFAOYSA-N Torsemide Chemical compound CC(C)NC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 NGBFQHCMQULJNZ-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229910052789 astatine Inorganic materials 0.000 description 1
- RYXHOMYVWAEKHL-UHFFFAOYSA-N astatine atom Chemical group [At] RYXHOMYVWAEKHL-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- UVTNFZQICZKOEM-UHFFFAOYSA-N disopyramide Chemical compound C=1C=CC=NC=1C(C(N)=O)(CCN(C(C)C)C(C)C)C1=CC=CC=C1 UVTNFZQICZKOEM-UHFFFAOYSA-N 0.000 description 1
- 229960001066 disopyramide Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000006362 organocatalysis Methods 0.000 description 1
- 230000001314 paroxysmal effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229960002132 pyrrolnitrin Drugs 0.000 description 1
- 102000003702 retinoic acid receptors Human genes 0.000 description 1
- 108090000064 retinoic acid receptors Proteins 0.000 description 1
- 239000003001 serine protease inhibitor Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003587 threonine derivatives Chemical class 0.000 description 1
- 229960005461 torasemide Drugs 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 230000010148 water-pollination Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/12—Organo silicon halides
- C07F7/121—Preparation or treatment not provided for in C07F7/14, C07F7/16 or C07F7/20
- C07F7/127—Preparation or treatment not provided for in C07F7/14, C07F7/16 or C07F7/20 by reactions not affecting the linkages to the silicon atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
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Abstract
The present invention relates to field of catalytic chemistry, specifically disclose a kind of chiral pyrrolidine derivative and preparation method thereof of siliceous acyl group skeleton, the compound has the structure as shown in formula (I), preparation method includes: under inert gas protection, by Phosphine ligands, metallic catalyst and reaction medium are mixed, sequentially add acylated silane compound, additive and azomethine ylide, by 1, 3- dipole [3+2] cycloaddition reaction obtains the chiral pyrrolidine derivative of siliceous acyl group skeleton, the preparation method is easy to operate, mild condition, with preferable yield and high enantioselectivity, obtained derivative contains multiple functional groups and multiple chiral centers, with potential bioactivity, it can be used as fine-chemical intermediate to be widely used in various organic reactions and pharmaceutical synthesis, with considerable application value.
Description
Technical field
The present invention relates to field of catalytic chemistry, and in particular to a kind of chiral pyrrolidine derivative of siliceous acyl group skeleton and its
Preparation method.
Technical background
Pyrroles's ring structure is widely present in many natural products and drug molecule, is that extremely important organic synthesis is built
Block, and also effect is significant in organocatalysis for pyrrolidines and auxiliary threonine derivative, in many asymmetric catalysis
All show very efficient catalytic activity and stereoselectivity.
Compound containing chiral pyrrolidine unit is applied especially extensively in medicine, such as: treatment cardiovascular and cerebrovascular disease
Disopyramide is often alleviated and overruns for atrial premature beats, the paroxysmal atrial rhythm of the heart, has good curative effect to supraventricular arrhythmias；
The Torasemide for treating cardiovascular and cerebrovascular disease, edema diseases various for heart failure, chronic heart failure and liver ascites etc.
There is all well and good curative effect；Anticarcinogen Gefitinib is a kind of selective tyrosine kinase inhibitor.
In terms of pesticide, pyridine insecticides can with disease caused by effectively preventing basidiomycetes, sac fungus and Fungi Imperfecti,
It is the eighties in last century, and people extract pyroles antibiotic pyrrolnitrin from the false unicellular bacterium in ocean, and then to it
It is transformed and has developed novel fungicide seed treatment summary, and further have developed fluorine and omit bacterium eyeball, it is a series of so as to form this
Fungicide.
Therefore many countries have all put into a large amount of fund research heterocyclic compound, and the design and synthesis of heterocyclic compound are early
One of the research hotspot of organic synthesis field is had become, especially designs the heterocyclic compound that there is physiological activity with synthesis, such as
Following figure a, the analog have synthesized and have tested in vitro its ability for inhibiting ACE (Angiotensin-Converting) enzymatic activity, and
Show effect identical with captopril；Such as following figure b, the inhibiting effect of Angiotensin-Converting (ACE)；Such as following figure c, depending on
The Orally active agonist TAC101 of the α and β hypotype of retinoic acid receptor, has been advanced in growth and metastasis of tumours animal model,
Promising result will do it the Phase I clinical trial of lung cancer therapy；The serpin as shown in following figure d.
Currently, many methods have been developed to construct this nitrogen-containing heterocycle in researcher, wherein azomethine ylide is in alkene
1,3- Dipolar Cycloaddition due to it efficiently, the characteristics such as high atom utilization and Green Chemistry are widely used.The reaction
Asymmetry catalysis synthetic method in 2002 by thread is solemn and the seminar of Jorgensen professor respectively independently reports, hereafter state
Each research group follows up in succession on border, Zhou Yonggui, king including Carrerreo, Fukuzawa, Schreiber and the country
Chun Jiangdeng seminar has successively developed many efficient catalyst systems and reaction model.Many configurations are not only used
The type of ligand, metallic catalyst is also a lot of, including Zn, Ag, Cu, Au, Ni etc..
Summary of the invention
The object of the present invention is to provide a kind of chiral pyrrolidine derivative of siliceous acyl group skeleton, which contains
Multiple functional groups and multiple chiral centers, have potential bioactivity, can be used as fine-chemical intermediate be widely used in it is various
In organic reaction and pharmaceutical synthesis, there is considerable application value.
Pass through transition metal-catalyzed asymmetric 1,3- dipole [3+2] ring another object of the present invention is to provide a kind of
Addition reaction synthesizes the preparation method of the chiral pyrrolidine derivative of siliceous acyl group skeleton, and the preparation method is easy to operate, condition
Mildly, there is preferable yield and high enantioselectivity.
The invention is realized by the following technical scheme:
A kind of chiral pyrrolidine derivative of siliceous acyl group skeleton has the structure as shown in formula (I):
In formula, substituent R1It for alkyl or is phenyl that is unsubstituted or being replaced by alkyl, halogenated alkyl or halogen atom；It takes
For base R2It for alkyl, naphthalene or is phenyl that is unsubstituted or being replaced by alkyl, alkoxy or halogen atom.
Further, the substituent R1For C1~C6Alkyl is unsubstituted or by C1~C3Alkyl, C1~C3It is halogenated
The phenyl that alkyl or halogen atom replace；Substituent R2For C1~C3Alkyl, naphthalene are unsubstituted or by C1~C3Alkyl, C1~
C3The phenyl that alkoxy or halogen atom replace.
Wherein, " C1~C6Alkyl " refers to the alkyl with 1~6 carbon atom of linear chain or branched chain；" halogenated alkyl " refers to
The alkyl that hydrogen atom is replaced by halogen atom；" halogen atom " refers to fluorine atom, chlorine atom, bromine atom, iodine atom and astatine atom.
There is compound prepared by the present invention groups, the peculiar properties of silicyl such as silicon substrate, ester group, silicon acyl group to make its tool
There is good lipophilicity, can effectively promote the stability of own metabolism；Ester group makes it have good hydrophily.In addition silicon substrate can
A variety of functional groups are converted to by reaction, when silicon substrate is converted to hydrogen, aldehyde radical pyrroles's cycle compound can be formed, when silicon substrate is converted
At hydroxyl, auxiliary propylhomoserin similar structural compound can be formed；The pyrroles of siliceous acyl group can desiliconization be converted to styrax pyrrole ring chemical combination
Object.
The preparation method of the chiral pyrrolidine derivative of above-mentioned siliceous acyl group skeleton, comprising: under inert gas protection, will
Phosphine ligands, metallic catalyst and reaction medium are mixed, and sequentially add acylated silane compound shown in formula (II), add
Add azomethine ylide shown in agent and formula (III), obtains siliceous acyl group bone by 1,3- dipole [3+2] cycloaddition reaction
The chiral pyrrolidine derivative of frame, reaction equation are as follows:
R in formula (II)1With R in formula (III)2Definition it is identical with formula (I).
The method of the present invention is using the azomethine ylide being readily synthesized and acylated silane compound as raw material, first passage mistake
Asymmetric 1,3- dipole [3+2] cycloaddition reaction for crossing metal catalytic efficiently synthesizes the chiral pyrrolidine of the siliceous acyl group skeleton of series
Derivative.Wherein, for the complex compound that metallic catalyst and Phosphine ligands are formed in situ as catalytic precursor, catalytic precursor participates in catalysis
In circulating system, the target product of higher yields is can be obtained in high catalytic efficiency；The three-dimensional structure of product is controlled by additive again
High enantioselectivity target product can be obtained in type.
Azomethine ylide and acylated silane compound are as raw material, and reaction is readily synthesized, easy to operate, post-processing side
Just, preferable yield and enantioselectivity product are obtained.
The Phosphine ligands are any one in following formula L1~L4 compound represented:
Preferably, the Phosphine ligands are L2, L3 or L4, the present invention is former by specific metallic catalyst and Phosphine ligands
The complex compound that position is formed is as catalytic precursor, and easy to operate, catalytic precursor participates in catalytic cycle system, and catalytic efficiency
The target product of higher yields and enantioselectivity can be obtained in height.
The metallic catalyst is the mixture of silver carbonate and copper catalyst, and copper catalyst is selected from cuprous bromide, hexafluoro
Any one in four acetonitrile copper of phosphoric acid, four acetonitrile copper of tetrafluoro boric acid, copper acetate or copper trifluoromethanesulfcomposite.
Preferably, the metallic catalyst is the mixture of silver carbonate and four acetonitrile copper of hexafluorophosphoric acid, this is because
The combination of both metallic catalysts preferably and ligand binding can improve yield and enantioselectivity.
The additive is selected from potassium phosphate, potassium dihydrogen phosphate, potassium carbonate, saleratus, sodium carbonate, four aryl boric acids
Sodium, cesium carbonate, triethylamine, N, 11 carbon -7- alkene of N- diisopropylethylamine (DIPEA) or 1,8- diazabicyclo [5.4.0]
(DBU) any one in.
Preferably, the additive is potassium carbonate, this is because preferred additive not only can control product
Spatial configuration can also improve the yield of target product to which the enantioselectivity of target product can be improved.
The molar ratio of the acylation silane compound and azomethine ylide, Phosphine ligands, metallic catalyst, additive
For 1:(1.2~1.5): (0.02~0.2): (0.03~0.06): (0.1~0.15).
Any one of the reaction medium in toluene, tetrahydrofuran, methylene chloride or ether.
The reaction temperature is 0~30 DEG C, and the reaction time is 20~30h, and reaction condition is mild, stirs at room temperature
Reaction can be completed, it is easy to operate, it is suitble to large-scale production and application.
The chiral pyrrolidine derivative for obtaining siliceous acyl group skeleton after post treatment after reaction, post-processing packet
It includes: first being extracted with ethyl acetate, solvent is evaporated off in the dry back spin of organic phase, and crude product passes through silica gel column chromatography separating purification.
Compared with prior art, the beneficial effects of the present invention are:
(1) the method for the present invention is easy to operate, and reaction can be completed in stirring at room temperature, and crude product is removed by rapid column chromatography
Sterling can be obtained by being concentrated under reduced pressure after miscellaneous, convenient post-treatment, obtain serial polyfunctional group multichiral center high yield, high mapping choosing
The chiral pyrrolidine derivative of selecting property.
(2) what the method for the present invention obtained contains polyfunctional group multichiral center pyrrole ring product system pyroles antibiotic, can
As broad-spectrum antifungal drug.Since the derivative contains multiple functional groups and multiple chiral centers, have potential biology living
Property, it can be widely applied to various organic syntheses, medicine, materials chemistry and field of fine chemical, there is considerable application value；
Detailed description of the invention
Fig. 1 is the nucleus magnetic hydrogen spectrum figure of the chiral pyrrolidine derivative 6a of siliceous acyl group skeleton made from embodiment 1；
Fig. 2 is the nuclear-magnetism carbon spectrogram of the chiral pyrrolidine derivative 6a of siliceous acyl group skeleton made from embodiment 1.
Specific embodiment
Below with reference to embodiment, invention is further described in detail, raw materials used commercially available in embodiment or use
Conventional method preparation.
Embodiment 1:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5a (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4a (0.20mmol), is stirred to react for 24 hours, after reaction by TLC monitoring, is extracted with ethyl acetate at room temperature, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 62.6mg pale yellow solid 6a by silica gel column chromatography separating purification crude product, yield is
82%, 98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.53 (d, J=6.0Hz, 2H), 7.36 (s, 2H),
7.32-7.07 (m, 6H), 4.35 (d, J=9.6Hz, 1H), 4.28 (d, J=9.6Hz, 1H), 4.18 (t, J=9.6Hz, 1H),
3.92 (t, J=9.6Hz, 1H), 3.24 (s, 3H), 2.58 (s, 1H), -0.31 (s, 9H)13C NMR(101MHz,CDCl3)δ
251.0,173.4,140.7,138.8,128.8,128.3,128.1,127.4,127.0,68.6,66.9,65.2,53.4,
51.5,-4.2.
High resolution mass spectrum (ESI, m/z): C22H28NO3Si[M+H]+Calculated value: 82.1833, find value: 382.1830.Than
Optical activity:(c=3.66, CHCl3).Fusing point: 88-90 DEG C.Phase chromatography-use Phenomenex Lux 5u
Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 98%ee) measures enantiomeric excess；It is main right
Reflect isomers tr=5.96 minutes, secondary enantiomter tr=32.18 minutes.
HRMS(ESI,m/z)calculated for C22H28NO3Si[M+H]+Calculated value 82.1833, found:
382.1830.(c=3.66, CHCl3).Mp 88-90℃.Enantiomeric excess was
determined by HPLC with a Phenomenex Lux 5u Cellulose column(hexanes:2-
Propanol=80:20,1.0mL/min, 210nm, 98%ee)；major enantiomer tr=5.96min, minor
enantiomer tr=32.18min.
Embodiment 2:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5a (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4b (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 45.0mg white solid 6b by silica gel column chromatography separating purification crude product, yield is
50%, 92%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.54 (t, J=8.8,4H), 7.39 (t, J=
7.6Hz, 4H), 7.33 (d, J=6.8Hz, 1H), 4.33 (t, J=8.1Hz, 1H), 4.13 (t, J=9.2Hz, 1H), 3.98 (t,
J=9.2Hz, 1H), 3.27 (s, 1H), 2.80 (s, 1H), -0.30 (s, 2H)13C NMR(101MHz,CDCl3)δ250.5,
(172.9,143.6,140.4,129.7 d, J=32.3Hz), 129.0,128.6,128.4,127.1,125.4 (q, J=
4.0Hz), 124.1 (d, J=272.7Hz), 68.7,66.9,65.1,52.4,51.7, -4.1. high resolution mass spectrum (ESI, m/z):
C23H27F3NO3Si [M+H]+calculated value: 450.1707, find value: 450.1703.Specific rotatory power:(c=
1.12,CHCl3).Fusing point: 110-112 DEG C.Phase chromatography-use Phenomenex Lux 5u Cellulose column (n-hexane: different
Propyl alcohol=80:20,1.0mL/min, 210nm, 92%ee) measurement enantiomeric excess；Main enantiomter tr=5.18 minutes,
Secondary enantiomter tr=22.60 minutes.
Embodiment 3:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5a (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4c (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 59.1mg white solid 6b by silica gel column chromatography separating purification crude product, yield is
71%, 94%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.51 (d, J=7.6Hz, 2H), 7.36 (t, J=
7.6Hz, 2H), 7.30 (d, J=7.6Hz, 1H), 7.22 (dd, J=20.0,8.4Hz, 4H), 4.32 (d, J=7.6Hz, 1H),
4.27 (d, J=7.6Hz, 1H), 4.09 (t, J=9.6Hz, 1H), 3.88 (t, J=9.6Hz, 1H), 3.29 (s, 3H), 2.73
(s,1H),-0.30(s,9H).13C NMR(101MHz,CDCl3)δ250.4,173.0,140.7,137.8,133.1,129.5,
128.8,128.4,128.1,126.9,68.7,66.6,65.0,52.2,51.5, -4.2. high resolution mass spectrum (ESI, m/z):
C22H27ClNO3Si [M+H]+calculated value: 416.1443, find value: 416.1436.Specific rotatory power:(c=
1.33,CHCl3).Fusing point: 117-119 DEG C.Phase chromatography-use Phenomenex Lux 5u Cellulose column (n-hexane: different
Propyl alcohol=85:15,0.8mL/min, 210nm, 94%ee) measurement enantiomeric excess；Main enantiomter tr=7.74 minutes,
Secondary enantiomter tr=39.76 minutes.
Embodiment 4:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5a (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4d (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 39.6mg white solid 6d by silica gel column chromatography separating purification crude product, yield is
83%, 98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.52 (d, J=7.6Hz, 2H), 7.35 (t, J=
7.2Hz, 2H), 7.29 (d, J=7.2Hz, 1H), 7.09 (dd, J=22.4,8.0Hz, 4H), 4.35 (d, J=8.8Hz, 1H),
4.25 (d, J=8.8Hz, 1H), 4.17 (t, J=9.6Hz, 1H), 3.88 (t, J=9.6Hz, 1H), 3.26 (s, 3H), 2.72
(s,1H),2.28(s,3H),-0.30(s,9H).13C NMR(101MHz,CDCl3)δ251.0,173.4,140.9,136.8,
135.6,128.9,128.8,128.0,127.0,68.7,66.7,65.2,53.1,51.4,2 1.0, -4.2. high resolution mass spectrum
(ESI, m/z): C23H30NO3Si [M+H]+calculated value: 396.1989, find value: 396.1986.Specific rotatory power:(c=1.20, CHCl3).Fusing point: 108-110 DEG C.Phase chromatography-use Phenomenex Lux 5u
Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 98%ee) measures enantiomeric excess；It is main right
Reflect isomers tr=5.59 minutes, secondary enantiomter tr=31.33 minutes.
Embodiment 5:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5a (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4e (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 55.3mg white solid 6e by silica gel column chromatography separating purification crude product, yield is
60%, 98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.49 (d, J=7.6Hz, 2H), 7.39 (d, J=
8.4Hz, 2H), 7.35 (t, J=8.0Hz, 2H), 7.29 (t, J=7.2Hz, 1H), 7.13 (d, J=8.0Hz, 2H), 4.31 (d,
J=6.4Hz, 1H), 4.26 (d, J=7.6Hz, 1H), 4.07 (t, J=9.2Hz, 1H), 3.85 (t, J=9.2Hz, 1H), 3.30
(s,3H),2.50(s,1H),-0.30(s,9H).13C NMR(101MHz,CDCl3)δ250.73,173.14,140.68,
138.41,131.54,129.93,128.95,128.27,127.01,121.31,68.83,66.78,65.08,52.35,
51.73, -4.06. high resolution mass spectrum (ESI, m/z): C22H27BrNO3Si [M+H]+calculated value: 460.0938, find value:
460.0926.Specific rotatory power:(c=1.23, CHCl3).Fusing point: 113-115 DEG C.Phase chromatography-use
Phenomenex Lux 5u Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 98%ee) is surveyed
Determine enantiomeric excess；Main enantiomter tr=6.29 minutes, secondary enantiomter tr=32.15 minutes.
Embodiment 6:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5a (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4f (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 59.1mg pale yellow solid 6f by silica gel column chromatography separating purification crude product, yield is
74%, 96%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.52 (d, J=7.6Hz, 2H), 7.36 (t, J=
7.2Hz, 2H), 7.29 (dd, J=9.6,6.8Hz, 2H), 7.20 (dd, J=14.0,7.2Hz, 1H), 7.06 (t, J=7.2Hz,
1H), 7.00 (t, J=10,1H), 4.38-4.25 (m, 3H), 4.21 (t, J=9.2Hz, 1H), 3.26 (s, 3H), 2.60 (s,
1H),-0.26(s,9H).13C NMR(101MHz,CDCl3) δ 250.5,173.4,160.0 (d, J=248.5Hz), 140.8,
129.1,129.0,128.8 (d, J=4.0Hz), 128.3,127.4,125.9 (d, J=19.2), 124.1 (d, J=4.0Hz),
115.4 (d, J=23.2Hz), 67.1,66.9,64.2,51.6,45.6, -4.0. high resolution mass spectrum (ESI, m/z):
C22H27FNO3Si [M+H]+calculated value: 400.1739, find value: 460.1754.Specific rotatory power:(c=
1.58,CHCl3).Fusing point: 123-125 DEG C.Phase chromatography-use Phenomenex Lux 5u Cellulose column (n-hexane: different
Propyl alcohol=85:15,0.8mL/min, 210nm, 96%ee) measurement enantiomeric excess；Main enantiomter tr=7.86 minutes,
Secondary enantiomter tr=36.53 minutes.
Embodiment 7:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5a (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4g (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 55.7mg pale yellow solid 6g by silica gel column chromatography separating purification crude product, yield is
67%, 96%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.42 (d, J=7.2Hz, 2H), 7.28-7.12 (m,
5H), 7.06 (t, J=7.2Hz, 1H), 7.02 (t, J=7.2Hz, 1H), 4.44 (t, J=9.6Hz, 1H), 4.32 (d, J=
9.2Hz, 1H), 4.21 (d, J=9.2Hz, 1H), 4.08 (t, J=9.6Hz, 1H), 3.08 (s, 3H), 2.58 (s, 1H), -0.38
(s,9H).13C NMR(101MHz,CDCl3)δ250.1,173.5,140.9,136.5,134.8,129.5,128.8,128.4,
128.2,127.8,127.1,126.7,67.0,66.9,63.2,51.4,48.4, -3.9. high resolution mass spectrum (ESI, m/z):
C22H27ClNO3Si [M+H]+calculated value: 416.1443, find value: 416.1442.Specific rotatory power:(c=
1.26,CHCl3).Fusing point: 126-128 DEG C.Phase chromatography-use Phenomenex Lux 5u Cellulose column (n-hexane: different
Propyl alcohol=80:20,1.0mL/min, 210nm, 96%ee) measurement enantiomeric excess；Main enantiomter tr=6.31 minutes,
Secondary enantiomter tr=13.01 minutes.
Embodiment 8:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5a (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4h (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 70.9mg white solid 6h by silica gel column chromatography separating purification crude product, yield is
77%, 96%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.54 (t, J=7.2Hz, 3H), 7.37 (dd, J=
14.0,7.2Hz 3H), 7.31 (d, J=7.2Hz, 1H), 7.24 (t, J=7.2Hz, 1H), 7.07 (t, J=7.6Hz, 1H),
4.56 (t, J=9.2Hz, 1H), 4.47 (d, J=9.6Hz, 1H), 4.34 (d, J=9.2Hz, 1H), 4.20 (t, J=9.6Hz,
1H),3.22(s,3H),2.72(s,1H),-0.25(s,9H).13C NMR(101MHz,CDCl3)δ250.1,173.5,140.8,
138.3,132.9,128.8,128.7,128.2,127.9,127.3,127.1,125.7,67.4,66.9,63.3,51.4,
51.1, -3.9. high resolution mass spectrum (ESI, m/z): C22H27BrNO3Si [M+H]+calculated value: 460.0938, find value:
460.0917.Specific rotatory power:(c=1.02, CHCl3).Fusing point: 116-118 DEG C.Phase chromatography-use
Phenomenex Lux 5u Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 96%ee) is surveyed
Determine enantiomeric excess；Main enantiomter tr=6.68 minutes, secondary enantiomter tr=10.82 minutes.
Embodiment 9:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5a (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4i (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 47.7mg crocus oily 6i by silica gel column chromatography separating purification crude product, yield is
53%, 92%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.74 (d, J=7.6Hz, 1H), 7.62 (d, J=
7.6Hz, 1H), 7.58-7.48 (m, 3H), 7.42-7.29 (m, 4H), 4.43-4.32 (m, 2H), 4.30 (d, J=8.8Hz,
1H), 4.14 (t, J=9.2Hz, 1H), 3.19 (s, 3H), 2.39 (s, 1H), -0.36 (s, 9H)13C NMR(101MHz,
CDCl3) δ 250.3,173.0,140.3,139.1,131.8,129.1 (d, J=29.3Hz), 128.8,128.4,128.3,
127.1,127.1,125.8 (q, J=6.1Hz), 124.1 (d, J=274.7Hz), 69.5,67.3,65.2,51.4,47.6 ,-
4.4. high resolution mass spectrum (ESI, m/z): C22H27BrNO3Si [M+H]+calculated value: 450.1707, find value: 450.1685.Than rotation
Luminosity:(c=2.18, CHCl3).Phase chromatography-use Phenomenex Lux 5u Cellulose column (just oneself
Alkane: isopropanol=80:20,1.0mL/min, 210nm, 92%ee) measurement enantiomeric excess；Main enantiomter tr=6.03
Minute, secondary enantiomter tr=7.47 minutes.
Embodiment 10:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5a (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4j (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 43.3mg white solid 6j by silica gel column chromatography separating purification crude product, yield is
52%, 98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.52 (d, J=7.2Hz, 2H), 7.37 (t, J=
7.2Hz 2H), 7.30 (t, J=7.2Hz, 1H), 7.24-7.19 (m, 3H), 7.17-7.12 (m, 1H), 4.28 (t, J=
9.6Hz, 2H), 4.12 (t, J=9.6Hz, 1H), 3.89 (t, J=9.2Hz, 1H), 3.32 (s, 3H), 2.21 (s, 1H), -0.30
(s,9H).13C NMR(101MHz,CDCl3)δ250.7,173.2,140.9,140.5,134.2,129.6,128.9,128.2,
127.5,127.0,126.3,68.2,66.9,65.0,52.7,51.6, -4.2. high resolution mass spectrum (ESI, m/z):
C22H27ClNO3Si [M+H]+calculated value: 416.1443, find value: 416.1432.Specific rotatory power:(c=
0.35,CHCl3).Fusing point: 104-106 DEG C.Phase chromatography-use Phenomenex Lux 5u Cellulose column (n-hexane: different
Propyl alcohol=80:20,1.0mL/min, 210nm, 98%ee) measurement enantiomeric excess；Main enantiomter tr=6.74 minutes,
Secondary enantiomter tr=57.74 minutes.
Embodiment 11:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5a (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4k (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 32.8mg pale yellow solid 6k by silica gel column chromatography separating purification crude product, yield is
40%, 98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.53 (d, J=7.2Hz, 2H), 7.37 (t, J=
7.2Hz, 2H), 7.31 (d, J=7.2Hz, 1H), 7.11 (dd, J=19.2,8.0Hz, 4H), 4.35 (d, J=9.6Hz, 1H),
4.26 (d, J=9.2Hz, 1H), 4.17 (t, J=9.6Hz, 1H), 3.90 (t, J=9.6Hz, 1H), 3.26 (s, 3H), 2.59
(q, J=7.6Hz, 2H), 2.01 (s, 1H), 1.18 (t, J=7.6Hz, 3H), -0.31 (s, 9H)13C NMR(101MHz,
CDCl3)δ251.3,173.7,143.6,141.0,135.9,128.9,128.5,127.8,127.1,68.7,66.9,65.4,
53.4,51.6,28.6,15.8, -4.1. high resolution mass spectrum (ESI, m/z): C24H32NO3Si [M+H]+calculated value: 410.2146,
Find value: 410.2137.Specific rotatory power:(c=0.43, CHCl3).Fusing point: 73-75 DEG C.Liquid chromatogram
With Phenomenex Lux 5u Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 98%ee)
Measure enantiomeric excess；Main enantiomter tr=4.80 minutes, secondary enantiomter tr=22.57 minutes.
Embodiment 12:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5l (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4a (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 51.9mg white solid 6l by silica gel column chromatography separating purification crude product, yield is
65%, 94%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.53 (t, J=7.6Hz2H), 7.25 (m, 3H),
7.07 (t, J=8.4Hz, 2H), 4.37 (d, J=5.5Hz, 1H), 4.28 (d, J=6.7Hz, 1H), 4.15 (t, J=9.4Hz,
1H), 3.90 (t, J=9.5Hz, 1H), 3.26 (s, 2H), 2.60 (s, 1H), -0.29 (s, 5H)13C NMR(101MHz,
CDCl3) δ 251.0,173.4,162.5 (d, J=247.5Hz), 138.5,136.7 (d, J=2.0Hz), 128.6 (d, J=
8.1Hz), 128.4,128.1,127.4,115.6 (d, J=21.2Hz), 68.4,65.8,65.0,53.3,51.5, -4.2. are high
Resolution Mass Spectrometry (ESI, m/z): C22H27FNO3Si [M+H]+calculated value: 400.1724, find value: 400.1739.Specific rotatory power:(c=0.83, CHCl3).Fusing point: 110-112 DEG C.Phase chromatography-use Phenomenex Lux 5u
Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 94%ee) measures enantiomeric excess；It is main right
Reflect isomers tr=5.16 minutes, secondary enantiomter tr=10.51 minutes.
Embodiment 13:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5m (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4a (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 54.1mg white solid 6m by silica gel column chromatography separating purification crude product, yield is
65%, 94%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.49 (d, J=8.4Hz, 2H), 7.35 (d, J=
8.4Hz, 2H), 7.31-7.19 (m, 5H), 4.40 (d, J=9.3Hz, 1H), 4.28 (d, J=9.3Hz, 1H), 4.13 (t, J=
9.6Hz, 1H), 3.87 (t, J=9.6Hz, 1H), 3.26 (s, 2H), 2.67 (s, 1H), -0.28 (s, 9H)13C NMR
(101MHz,CDCl3)δ250.7,173.2,139.6,138.5,133.7,128.9,128.4,128.4,128.1,127.5,
68.3,65.5,65.0,53.2,51.5, -4.1. high resolution mass spectrum (ESI, m/z): C22H27FNO3Si [M+H]+calculated value:
416.1443 finding value: 416.1440.Specific rotatory power:(c=0.63, CHCl3).Fusing point: 108-110 DEG C.
Phase chromatography-use Phenomenex Lux 5u Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm,
94%ee) measure enantiomeric excess；Main enantiomter tr=6.04 minutes, secondary enantiomter tr=10.0 minutes.
Embodiment 14:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5n (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4a (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 70.0mg white solid 6b by silica gel column chromatography separating purification crude product, yield is
76%, 94%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.50 (d, J=8.0Hz, 2H), 7.43 (d, J=
8.0Hz, 2H), 7.33-7.17 (m, 5H), 4.39 (s, 1H), 4.28 (s, 1H), 4.11 (t, J=8.0Hz, 1H), 3.87 (t, J
=8.0Hz, 1H), 3.26 (s, 3H), 2.69 (s, 1H), -0.27 (s, 9H)13C NMR(101MHz,CDCl3)δ250.8,
172.7,140.2,138.6,132.0,128.8,128.5,128.2,127.6,121.8,68.5,67.0,65.5,53.5,
51.62, -4.00. high resolution mass spectrum (ESI, m/z): C22H27FNO3Si [M+H]+calculated value: 460.0938, find value:
460.0932.Specific rotatory power:(c=4.40, CHCl3).Fusing point: 92-94 DEG C.Phase chromatography-use
Phenomenex Lux 5u Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 94%ee) is surveyed
Determine enantiomeric excess；Main enantiomter tr=6.14 minutes, secondary enantiomter tr=9.83 minutes.
Embodiment 15:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5o (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4a (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 57.0mg pale yellow solid 6b by silica gel column chromatography separating purification crude product, yield is
72%, 98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.41 (d, J=7.6Hz, 2H), 7.31-7.21 (m,
5H), 7.19 (t, J=8.4Hz, 3H), 4.31 (d, J=8.4Hz, 1H), 4.28 (d, J=8.4Hz, 1H), 4.17 (t, J=
9.2Hz, 1H), 3.92 (t, J=9.6Hz, 1H), 3.25 (s, 3H), 2.71 (s, 1H), 2.35 (s, 3H), -0.30 (s, 9H)13C
NMR(101MHz,CDCl3)δ251.1,173.4,138.8,137.8,137.4,129.4,128.3,128.1,127.3,
), 126.8,68.6,66.7,65.2 53.4,51.5,21.2, -4.2. high resolution mass spectrum (ESI, m/z): C23H30NO3Si[M+H]+
Calculated value: 396.1989, find value: 396.1956.Specific rotatory power:(c=0.56, CHCl3).Fusing point: 72-
74℃.Phase chromatography-use Phenomenex Lux 5u Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min,
210nm, 98%ee) measurement enantiomeric excess；Main enantiomter tr=6.10 minutes, secondary enantiomter tr=
35.44 minutes.
Embodiment 16:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5p (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4a (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 51.0mg white solid 6p by silica gel column chromatography separating purification crude product, yield is
62%, 96%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.46 (d, J=8.4Hz, 2H), 7.30-7.19 (m,
5H), 6.90 (d, J=8.4Hz, 2H), 4.29 (d, J=9.6Hz, 1H), 4.25 (d, J=9.6Hz, 1H), 4.17 (t, J=
10.0Hz, 1H), 3.92 (t, J=9.6Hz, 1H), 3.81 (s, 3H), 3.24 (s, 3H), 2.50 (s, 1H), -0.29 (s, 9H)
.13C NMR(101MHz,CDCl3)δ251.4,173.6,159.6,139.0,128.4,128.2,128.2,127.4,114.2,
68.7,66.6,65.3,55.4,53.5,51.6, -4.0. high resolution mass spectrum (ESI, m/z): C23H30NO4Si [M+H]+calculated value:
412.1939 finding value: 412.1930.Specific rotatory power:(c=5.88, CHCl3).Fusing point: 75-77 DEG C.
Phase chromatography-use Phenomenex Lux 5u Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm,
96%ee) measure enantiomeric excess；Main enantiomter tr=7.92 minutes, secondary enantiomter tr=28.61 minutes.
Embodiment 17:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5q (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4a (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 44.3mg white solid 6q by silica gel column chromatography separating purification crude product, yield is
56%, 92%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.98 (d, J=8.0Hz, 1H), 7.33 (t, J=
7.6Hz, 1H), 7.31-7.16 (m, 7H), 7.11 (d, J=7.6Hz, 1H), 4.61 (d, J=9.2Hz, 1H), 4.30 (d, J=
9.6Hz, 1H), 4.25 (t, J=9.6Hz, 1H), 3.97 (t, J=10.0Hz, 1H), 3.24 (s, 3H), 2.24 (s, 3H) ,-
0.32(s,9H).13C NMR(101MHz,CDCl3)δ251.4,173.7,138.9,138.7,136.0,130.7,128.5,
128.2,127.8,127.5,126.9,126.5,68.4,65.5,62.6,54.0,51.6,1 9.7, -4.2. high resolution mass spectrum
(ESI, m/z): C23H30NO4Si [M+H]+calculated value: 396.1989, find value: 396.1978.Specific rotatory power:(c=1.09, CHCl3).Fusing point: 106-108 DEG C.Phase chromatography-use Phenomenex Lux 5u
Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 92%ee) measures enantiomeric excess；It is main right
Reflect isomers tr=6.22 minutes, secondary enantiomter tr=25.45 minutes.
Embodiment 18:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5r (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4a (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 62.2mg white solid 6r by silica gel column chromatography separating purification crude product, yield is
72%, 92%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.89 (d, J=8.8Hz, 2H), 7.84 (dd, J=
5.6,3.6Hz, 2H), 7.75 (d, J=8.4Hz, 1H), 7.48 (p, J=6.6Hz, 2H), 7.27 (t, J=4.4Hz, 4H),
7.22 (td, J=8.4,4.0Hz, 1H), 4.58 (d, J=9.2Hz, 1H), 4.34 (d, J=9.2Hz, 1H), 4.28 (t, J=
9.6Hz, 1H), 3.94 (t, J=9.6Hz, 1H), 3.28 (s, 3H), 2.75 (s, 1H), -0.34 (s, 9H)13C NMR
(101MHz,CDCl3)δ251.2,173.4,139.0,138.3,133.5,133.3,128.9,128.5,128.3,128.0,
), 127.8,127.5 126.4,126.1,125.8), 124.9,68.6,66.7,65.4,53.5,51.6, -4.0. high-resolution matter
Compose (ESI, m/z): C26H30NO3Si [M+H]+calculated value: 432.1989, find value: 432.1978.Specific rotatory power:(c=1.28, CHCl3).Fusing point: 120-122 DEG C.Phase chromatography-use Phenomenex Lux 5u
Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 92%ee) measures enantiomeric excess；It is main right
Reflect isomers tr=7.31 minutes, secondary enantiomter tr=12.09 minutes.
Embodiment 19:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5s (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4a (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 50.6mg white solid 6s by silica gel column chromatography separating purification crude product, yield is
64%, 98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.35-7.19 (m, 8H), 7.11 (d, J=7.2Hz,
1H), 4.31 (d, J=9.6Hz, 1H), 4.27 (d, J=9.6Hz, 1H), 4.17 (t, J=9.6Hz, 1H), 3.92 (t, J=
9.6Hz,1H),3.24(s,3H),2.56(s,1H),2.37(s,3H),-0.30(s,9H).13C NMR(101MHz,CDCl3)δ
251.2,173.4,140.5,138.9,138.4,128.8,128.7,128.3,128.1,127.6,127.3,123.9),
), 68.7,66.9,65.3 53.5,51.5,21.4, -4.2. high resolution mass spectrum (ESI, m/z): C23H30NO3Si [M+H]+calculating
Value: 396.1989, find value: 396.1973.Specific rotatory power:(c=0.86, CHCl3).Fusing point: 116-
120℃.Phase chromatography-use Phenomenex Lux 5u Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min,
210nm, 98%ee) measurement enantiomeric excess；Main enantiomter tr=6.21 minutes, secondary enantiomter tr=
50.94 minutes.
Embodiment 20:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(CH3CN)4PF6(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, in room
Glycine Schiff base 5t (0.30mmol), alkali K are sequentially added after stirring 30min under temperature in advance2CO3(0.02mmol), acylated silanes
It closes object 4a (0.20mmol), is stirred to react at room temperature for 24 hours.After reaction by TLC monitoring, it is extracted with ethyl acetate, it is organic
Mutually solvent is evaporated off in dry back spin, obtains 49.7mg pale yellow solid 6t by silica gel column chromatography separating purification crude product, yield is
54%, 94%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.67 (s, 1H), 7.48 (d, J=7.6Hz, 1H),
7.44 (d, J=7.6Hz, 1H), 7.34-7.17 (m, 6H), 4.39 (d, J=8.8Hz, 1H), 4.28 (d, J=8.8Hz, 1H),
4.12 (t, J=9.6Hz, 1H), 3.85 (t, J=9.6Hz, 1H), 3.27 (s, 3H), 2.43 (s, 1H), -0.26 (s, 9H)13C
NMR(101MHz,CDCl3)δ251.0,173.2,143.6,138.6,131.2,130.5,130.1,128.5,128.2,
127.6,125.6,122.9,68.4,65.7,65.1,53.3,51.6, -4.1. high resolution mass spectrum (ESI, m/z):
C22H27BrNO3Si [M+H]+calculated value: 460.0938, find value: 462.0988.Specific rotatory power:(c=
0.82,CHCl3).Fusing point: 120-121 DEG C.Phase chromatography-use Phenomenex Lux 5u Cellulose column (n-hexane: different
Propyl alcohol=80:20,1.0mL/min, 210nm, 94%ee) measurement enantiomeric excess；Main enantiomter tr=5.30 minutes,
Secondary enantiomter tr=11.16 minutes.
Embodiment 21:
Under nitrogen atmosphere, Phosphine ligands PPh is added into test tube3(1.0mg, 0.004mmol), metallic catalyst Ag2CO3
(0.6mg,0.002mmol),Cu(CH3CN)4BF4(0.6mg, 0.002mmol), 0.2mL solvent toluene, is stirred in advance at room temperature
Glycine Schiff base 5a (0.24mmol), alkali KHCO are sequentially added after 30min3(0.026mmol), acylated silane compound 4a
(0.20mmol) is stirred to react 20h at 0 DEG C.After reaction by TLC monitoring, it is extracted with ethyl acetate, after organic phase is dry
Revolving removes solvent, obtains 53.3mg white solid 6a, yield 70%, racemic by silica gel column chromatography separating purification crude product
Product.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.53 (d, J=6.0Hz, 2H), 7.36 (s, 2H),
7.32-7.07 (m, 6H), 4.35 (d, J=9.6Hz, 1H), 4.28 (d, J=9.6Hz, 1H), 4.18 (t, J=9.6Hz, 1H),
3.92 (t, J=9.6Hz, 1H), 3.24 (s, 3H), 2.58 (s, 1H), -0.31 (s, 9H)13C NMR(101MHz,CDCl3)δ
251.0,173.4,140.7,138.8,128.8,128.3,128.1,127.4,127.0,68.6,66.9,65.2,53.4,
51.5, -4.2. high resolution mass spectrum (ESI, m/z): C22H28NO3Si [M+H]+calculated value: 382.1833, find value: 382.1830.
Specific rotatory power:(c=3.66, CHCl3).Fusing point: 88-90 DEG C.Phase chromatography-use Phenomenex Lux 5u
Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 0ee) measures enantiomeric excess；Main mapping
Isomers tr=5.96 minutes, secondary enantiomter tr=32.18 minutes.
Embodiment 22:
Under nitrogen atmosphere, Phosphine ligands (R)-Segphos (13.4mg, 0.022mmol), metal catalytic are added into test tube
Agent Ag2CO3(5.5mg,0.02mmol),Cu(CH3CN)4PF6(7.5mg, 0.02mmol), 0.4mL methylene chloride, in room temperature
Glycine Schiff base 5a (0.26mmol), alkali Na are sequentially added after stirring 30min in advance down2CO3(0.03mmol), acylated silanes
It closes object 4a (0.20mmol), 30 DEG C are stirred to react 30h, after reaction by TLC monitoring, are extracted with ethyl acetate, organic phase
Solvent is evaporated off in dry back spin, obtains 57.1mg pale yellow solid 6a by silica gel column chromatography separating purification crude product, yield is
75%, 98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.53 (d, J=6.0Hz, 2H), 7.36 (s, 2H),
7.32-7.07 (m, 6H), 4.35 (d, J=9.6Hz, 1H), 4.28 (d, J=9.6Hz, 1H), 4.18 (t, J=9.6Hz, 1H),
3.92 (t, J=9.6Hz, 1H), 3.24 (s, 3H), 2.58 (s, 1H), -0.31 (s, 9H)13C NMR(101MHz,CDCl3)δ
251.0,173.4,140.7,138.8,128.8,128.3,128.1,127.4,127.0,68.6,66.9,65.2,53.4,
51.5, -4.2. high resolution mass spectrum (ESI, m/z): C22H28NO3Si[M+H]+Calculated value: 382.1833, find value: 382.1830.
Specific rotatory power:(c=3.66, CHCl3).Fusing point: 88-90 DEG C.Phase chromatography-use Phenomenex Lux 5u
Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 98%ee) measures enantiomeric excess；It is main right
Reflect isomers tr=5.96 minutes, secondary enantiomter tr=32.18 minutes.
Embodiment 23:
Under nitrogen atmosphere, Phosphine ligands (R)-BINAP (13.7mg, 0.022mmol), metallic catalyst are added into test tube
Ag2CO3(5.5mg,0.02mmol),Cu(CH3CN)4PF6(7.5mg, 0.02mmol), 2mL solvents tetrahydrofurane, at room temperature in advance
Glycine Schiff base 5a (0.3mmol), alkali Cs are sequentially added after stirring 30min2CO3(0.02mmol), acylated silane compound 4a
Reaction is stirred at room temperature for 24 hours in (0.20mmol), after reaction by TLC monitoring, is extracted with ethyl acetate, after organic phase is dry
Revolving removes solvent, obtains 60.9mg pale yellow solid 6a by silica gel column chromatography separating purification crude product, yield 80%, and 98%
ee。
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.53 (d, J=6.0Hz, 2H), 7.36 (s, 2H),
7.32-7.07 (m, 6H), 4.35 (d, J=9.6Hz, 1H), 4.28 (d, J=9.6Hz, 1H), 4.18 (t, J=9.6Hz, 1H),
3.92 (t, J=9.6Hz, 1H), 3.24 (s, 3H), 2.58 (s, 1H), -0.31 (s, 9H)13C NMR(101MHz,CDCl3)δ
251.0,173.4,140.7,138.8,128.8,128.3,128.1,127.4,127.0,68.6,66.9,65.2,53.4,
51.5, -4.2. high resolution mass spectrum (ESI, m/z): C22H28NO3Si[M+H]+Calculated value: 382.1833, find value: 382.1830.
Specific rotatory power:(c=3.66, CHCl3).Fusing point: 88-90 DEG C.Phase chromatography-use Phenomenex Lux 5u
Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 98%ee) measures enantiomeric excess；It is main right
Reflect isomers tr=5.96 minutes, secondary enantiomter tr=32.18 minutes.
Embodiment 24:
Under nitrogen atmosphere, Phosphine ligands (R)-BINAP (13.7mg, 0.022mmol), metallic catalyst are added into test tube
Ag2CO3(5.5mg,0.02mmol),Cu(CH3CN)4PF6(7.5mg, 0.02mmol), 2mL solvents tetrahydrofurane, at room temperature in advance
Glycine Schiff base 5a (0.3mmol), alkali Et are sequentially added after stirring 30min3N (0.02mmol), acylated silane compound 4a
Reaction is stirred at room temperature for 24 hours in (0.20mmol), after reaction by TLC monitoring, is extracted with ethyl acetate, after organic phase is dry
Revolving removes solvent, obtains 55.6mg pale yellow solid 6a by silica gel column chromatography separating purification crude product, yield 73%, and 98%
ee。
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.53 (d, J=6.0Hz, 2H), 7.36 (s, 2H),
7.32-7.07 (m, 6H), 4.35 (d, J=9.6Hz, 1H), 4.28 (d, J=9.6Hz, 1H), 4.18 (t, J=9.6Hz, 1H),
3.92 (t, J=9.6Hz, 1H), 3.24 (s, 3H), 2.58 (s, 1H), -0.31 (s, 9H)13C NMR(101MHz,CDCl3)δ
251.0,173.4,140.7,138.8,128.8,128.3,128.1,127.4,127.0,68.6,66.9,65.2,53.4,
51.5, -4.2. high resolution mass spectrum (ESI, m/z): C22H28NO3Si[M+H]+Calculated value: 382.1833, find value: 382.1830.
Specific rotatory power:(c=3.66, CHCl3).Fusing point: 88-90 DEG C.Phase chromatography-use Phenomenex Lux 5u
Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 98%ee) measures enantiomeric excess；It is main right
Reflect isomers tr=5.96 minutes, secondary enantiomter tr=32.18 minutes.
Embodiment 25:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg, 0.006mmol), CuBr (0.8 0.006mmol), 2.0mL solvents tetrahydrofurane are stirred in advance at room temperature
Glycine Schiff base 5a (0.30mmol), alkali K are sequentially added after 30min3PO4(0.02mmol), acylated silane compound 4a
(0.20mmol) is stirred to react for 24 hours at room temperature, after reaction by TLC monitoring, is extracted with ethyl acetate, organic phase is dry
Solvent is evaporated off in back spin, obtains 49.6mg pale yellow solid 6a by silica gel column chromatography separating purification crude product, yield 65%,
98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.53 (d, J=6.0Hz, 2H), 7.36 (s, 2H),
7.32-7.07 (m, 6H), 4.35 (d, J=9.6Hz, 1H), 4.28 (d, J=9.6Hz, 1H), 4.18 (t, J=9.6Hz, 1H),
3.92 (t, J=9.6Hz, 1H), 3.24 (s, 3H), 2.58 (s, 1H), -0.31 (s, 9H)13C NMR(101MHz,CDCl3)δ
251.0,173.4,140.7,138.8,128.8,128.3,128.1,127.4,127.0,68.6,66.9,65.2,53.4,
51.5, -4.2. high resolution mass spectrum (ESI, m/z): C22H28NO3Si[M+H]+Calculated value: 382.1833, find value: 382.1830.
Specific rotatory power:(c=3.66, CHCl3).Fusing point: 88-90 DEG C.Phase chromatography-use Phenomenex Lux 5u
Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 98%ee) measures enantiomeric excess；It is main right
Reflect isomers tr=5.96 minutes, secondary enantiomter tr=32.18 minutes.
Embodiment 26:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(OAc)2(1.1mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, at room temperature
Glycine Schiff base 5a (0.30mmol), alkali KH are sequentially added after stirring 30min in advance2PO4(0.02mmol), acylated silanes chemical combination
Object 4a (0.20mmol) is stirred to react for 24 hours at room temperature, after reaction by TLC monitoring, is extracted with ethyl acetate, organic phase
Solvent is evaporated off in dry back spin, obtains 55.0mg pale yellow solid 6a by silica gel column chromatography separating purification crude product, yield is
72%, 98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.53 (d, J=6.0Hz, 2H), 7.36 (s, 2H),
7.32-7.07 (m, 6H), 4.35 (d, J=9.6Hz, 1H), 4.28 (d, J=9.6Hz, 1H), 4.18 (t, J=9.6Hz, 1H),
3.92 (t, J=9.6Hz, 1H), 3.24 (s, 3H), 2.58 (s, 1H), -0.31 (s, 9H)13C NMR(101MHz,CDCl3)δ
251.0,173.4,140.7,138.8,128.8,128.3,128.1,127.4,127.0,68.6,66.9,65.2,53.4,
51.5, -4.2. high resolution mass spectrum (ESI, m/z): C22H28NO3Si[M+H]+Calculated value: 382.1833, find value: 382.1830.
Specific rotatory power:(c=3.66, CHCl3).Fusing point: 88-90 DEG C.Phase chromatography-use Phenomenex Lux 5u
Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 98%ee) measures enantiomeric excess；It is main right
Reflect isomers tr=5.96 minutes, secondary enantiomter tr=32.18 minutes.
Embodiment 27:
Under nitrogen atmosphere, Phosphine ligands (R)-XylBINAP (7.3mg, 0.01mmol), metal catalytic are added into test tube
Agent Ag2CO3(1.7mg,0.006mmol),Cu(OTf)2(2.2mg, 0.006mmol), 2.0mL solvents tetrahydrofurane, at room temperature
Glycine Schiff base 5a (0.30mmol), alkali NaBPh are sequentially added after stirring 30min in advance4(0.02mmol), acylated silanes chemical combination
Object 4a (0.20mmol) is stirred to react for 24 hours at room temperature, after reaction by TLC monitoring, is extracted with ethyl acetate, organic phase
Solvent is evaporated off in dry back spin, obtains 56.5mg pale yellow solid 6a by silica gel column chromatography separating purification crude product, yield is
74%, 98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.53 (d, J=6.0Hz, 2H), 7.36 (s, 2H),
7.32-7.07 (m, 6H), 4.35 (d, J=9.6Hz, 1H), 4.28 (d, J=9.6Hz, 1H), 4.18 (t, J=9.6Hz, 1H),
(3.92 t, J=9.6Hz, 1H), 3.24 (s, 3H), 2.58 (s, 1H), -0.31 (s, 9H)13C NMR(101MHz,CDCl3)δ
251.0,173.4,140.7,138.8,128.8,128.3,128.1,127.4,127.0,68.6,66.9,65.2,53.4,
51.5, -4.2. high resolution mass spectrum (ESI, m/z): C22H28NO3Si[M+H]+Calculated value: 382.1833, find value: 382.1830.
Specific rotatory power:(c=3.66, CHCl3).Fusing point: 88-90 DEG C.Phase chromatography-use Phenomenex Lux 5u
Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 98%ee) measures enantiomeric excess；It is main right
Reflect isomers tr=5.96 minutes, secondary enantiomter tr=32.18 minutes.
Embodiment 28:
Under nitrogen atmosphere, Phosphine ligands (R)-Segphos (13.4mg, 0.022mmol), metal catalytic are added into test tube
Agent Ag2CO3(5.5mg,0.02mmol),Cu(CH3CN)4PF6(7.5mg, 0.02mmol), 2.0mL solvent ether, at room temperature in advance
It is sequentially added glycine Schiff base 5a (0.30mmol) after stirring 30min, alkali DIPEA (0.02mmol), acylated silane compound
4a (0.20mmol) is stirred to react for 24 hours at room temperature, after reaction by TLC monitoring, is extracted with ethyl acetate, organic relevant
Solvent is evaporated off in dry back spin, obtains 63.4mg pale yellow solid 6a by silica gel column chromatography separating purification crude product, yield 83%,
98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.53 (d, J=6.0Hz, 2H), 7.36 (s, 2H),
7.32-7.07 (m, 6H), 4.35 (d, J=9.6Hz, 1H), 4.28 (d, J=9.6Hz, 1H), 4.18 (t, J=9.6Hz, 1H),
3.92 (t, J=9.6Hz, 1H), 3.24 (s, 3H), 2.58 (s, 1H), -0.31 (s, 9H)13C NMR(101MHz,CDCl3)δ
251.0,173.4,140.7,138.8,128.8,128.3,128.1,127.4,127.0,68.6,66.9,65.2,53.4,
51.5, -4.2. high resolution mass spectrum (ESI, m/z): C22H28NO3Si[M+H]+Calculated value: 382.1833, find value: 382.1830.
Specific rotatory power:(c=3.66, CHCl3).Fusing point: 88-90 DEG C.Phase chromatography-use Phenomenex Lux 5u
Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 98%ee) measures enantiomeric excess；It is main right
Reflect isomers tr=5.96 minutes, secondary enantiomter tr=32.18 minutes.
Embodiment 29:
Under nitrogen atmosphere, Phosphine ligands (R)-Segphos (13.4mg, 0.022mmol), metal catalytic are added into test tube
Agent Ag2CO3(5.5mg,0.02mmol),Cu(CH3CN)4PF6(7.5mg, 0.02mmol), 2.0mL solvent ether, at room temperature in advance
It is sequentially added glycine Schiff base 5a (0.30mmol) after stirring 30min, alkali DBU (0.02mmol), acylated silane compound 4a
(0.20mmol) is stirred to react for 24 hours at room temperature, after reaction by TLC monitoring, is extracted with ethyl acetate, organic phase is dry
Solvent is evaporated off in back spin, obtains 61.1mg pale yellow solid 6a by silica gel column chromatography separating purification crude product, yield 80%,
98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) δ 7.53 (d, J=6.0Hz, 2H), 7.36 (s, 2H),
7.32-7.07 (m, 6H), 4.35 (d, J=9.6Hz, 1H), 4.28 (d, J=9.6Hz, 1H), 4.18 (t, J=9.6Hz, 1H),
3.92 (t, J=9.6Hz, 1H), 3.24 (s, 3H), 2.58 (s, 1H), -0.31 (s, 9H)13C NMR(101MHz,CDCl3)δ
251.0,173.4,140.7,138.8,128.8,128.3,128.1,127.4,127.0,68.6,66.9,65.2,53.4,
51.5, -4.2. high resolution mass spectrum (ESI, m/z): C22H28NO3Si[M+H]+Calculated value: 382.1833, find value: 382.1830.
Specific rotatory power:(c=3.66, CHCl3).Fusing point: 88-90 DEG C.Phase chromatography-use Phenomenex Lux 5u
Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 98%ee) measures enantiomeric excess；It is main right
Reflect isomers tr=5.96 minutes, secondary enantiomter tr=32.18 minutes.
Embodiment 30:
Under nitrogen atmosphere, Phosphine ligands (R)-Segphos (13.4mg, 0.022mmol), metal catalytic are added into test tube
Agent Ag2CO3(5.5mg,0.02mmol),Cu(CH3CN)4PF6(7.5mg, 0.02mmol), 2.0mL solvent ether, at room temperature in advance
It is sequentially added glycine Schiff base 5u (0.30mmol) after stirring 30min, alkali DBU (0.02mmol), acylated silane compound 4l
(0.20mmol) is stirred to react for 24 hours at room temperature, after reaction by TLC monitoring, is extracted with ethyl acetate, organic phase is dry
Solvent is evaporated off in back spin, obtains 61.1mg pale yellow solid 6l by silica gel column chromatography separating purification crude product, yield 80%,
98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) 4.35 (d, J=9.6Hz, 1H), 4.28 (d, J=
9.6Hz, 1H), 4.18 (t, J=9.6Hz, 1H), 3.92 (t, J=9.6Hz, 1H), 3.24 (s, 3H), 2.58 (s, 1H), 1.06
(d, J=9.6Hz, 3H), 0.93 (d, J=9.6Hz, 3H), -0.31 (s, 9H)13C NMR(101MHz,CDCl3)δ251.0,
173.4,68.6,66.9,65.2,53.4,51.5,22.1,18.4-4.2. high resolution mass spectrum (ESI, m/z): C12H23NO3Si[M
+H]+Calculated value: 257.4050, find value: 257.4044.Specific rotatory power:(c=3.66, CHCl3).It is molten
Point: 120-122 DEG C.Phase chromatography-use Phenomenex Lux 5u Cellulose column (n-hexane: isopropanol=80:20,
1.0mL/min, 210nm, 98%ee) measurement enantiomeric excess；Main enantiomter tr=5.84 minutes, secondary enantiomerism
Body tr=17.66 minutes.
Embodiment 31:
Under nitrogen atmosphere, Phosphine ligands (R)-Segphos (13.4mg, 0.022mmol), metal catalytic are added into test tube
Agent Ag2CO3(5.5mg,0.02mmol),Cu(CH3CN)4PF6(7.5mg, 0.02mmol), 2.0mL solvent ether, at room temperature in advance
It is sequentially added glycine Schiff base 5u (0.30mmol) after stirring 30min, alkali DBU (0.02mmol), acylated silane compound 4m
(0.20mmol) is stirred to react for 24 hours at room temperature, after reaction by TLC monitoring, is extracted with ethyl acetate, organic phase is dry
Solvent is evaporated off in back spin, obtains 61.1mg pale yellow solid 6m by silica gel column chromatography separating purification crude product, yield 80%,
98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) 4.35 (d, J=9.6Hz, 1H), 4.28 (d, J=
9.6Hz, 1H), 4.18 (t, J=9.6Hz, 1H), 3.92 (t, J=9.6Hz, 1H), 3.24 (s, 3H), 2.58 (s, 1H), 1.31
(s, 2H), 1.25 (s, 2H), 1.19 (s, 2H), 1.06 (d, J=9.6Hz, 3H), 0.88 (d, J=9.6Hz, 3H), -0.31 (s,
9H).13C NMR(101MHz,CDCl3)δ251.0,173.4,63.7,51.9,48.1,40.0,29.7,29.3,26.4,23.0,
14.1-4.2. high resolution mass spectrum (ESI, m/z): C12H23NO3Si[M+H]+Calculated value: 299.4860, find value: 299.4844.
Specific rotatory power:(c=3.66, CHCl3).Fusing point: 99-102 DEG C.Phase chromatography-use Phenomenex Lux
5u Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm, 98%ee) measures enantiomeric excess；It is main
Want enantiomter tr=5.66 minutes, secondary enantiomter tr=19.22 minutes.
Embodiment 32:
Under nitrogen atmosphere, Phosphine ligands (R)-Segphos (13.4mg, 0.022mmol), metal catalytic are added into test tube
Agent Ag2CO3(5.5mg,0.02mmol),Cu(CH3CN)4PF6(7.5mg, 0.02mmol), 2.0mL solvent ether, at room temperature in advance
It is sequentially added glycine Schiff base 5u (0.30mmol) after stirring 30min, alkali DBU (0.02mmol), acylated silane compound 4n
(0.20mmol) is stirred to react for 24 hours at room temperature, after reaction by TLC monitoring, is extracted with ethyl acetate, organic phase is dry
Solvent is evaporated off in back spin, obtains 61.1mg pale yellow solid 6n by silica gel column chromatography separating purification crude product, yield 80%,
98%ee.
The physical and chemical index of the product:1H NMR(400MHz,CDCl3) 4.35 (d, J=9.6Hz, 1H), 4.28 (d, J=
9.6Hz, 1H), 4.18 (t, J=9.6Hz, 1H), 3.92 (t, J=9.6Hz, 1H), 3.24 (s, 3H), 2.58 (s, 1H), 1.26
(s, 4H), 1.25 (s, 4H), 1.19 (s, 2H), 1.06 (d, J=9.6Hz, 3H), 0.88 (d, J=9.6Hz, 3H), -0.31 (s,
9H).13C NMR(101MHz,CDCl3)δ251.0,173.4,68.6,66.9,65.2,53.4,51.5,31.8,29.7,29.6,
27.1,26.7,22.7,22.1,18.4,14.1-4.2. high resolution mass spectrum (ESI, m/z): C12H23NO3Si[M+H]+Calculated value:
327.5400 finding value: 327.5500.Specific rotatory power:(c=3.66, CHCl3).Fusing point: 105-106 DEG C.
Phase chromatography-use Phenomenex Lux 5u Cellulose column (n-hexane: isopropanol=80:20,1.0mL/min, 210nm,
98%ee) measure enantiomeric excess；Main enantiomter tr=5.11 minutes, secondary enantiomter tr=20.87 minutes.
The foregoing is merely presently preferred embodiments of the present invention, it is all according to equivalent change made by scope of the present invention patent with
Modification, shall all be covered by the patent of the invention.
Claims (10)
1. a kind of chiral pyrrolidine derivative of siliceous acyl group skeleton, which is characterized in that have the structure as shown in formula (I):
In formula, substituent R1It for alkyl or is phenyl that is unsubstituted or being replaced by alkyl, halogenated alkyl or halogen atom；Substituent group
R2It for alkyl, naphthalene or is phenyl that is unsubstituted or being replaced by alkyl, alkoxy or halogen atom.
2. the chiral pyrrolidine derivative of siliceous acyl group skeleton according to claim 1, which is characterized in that the substituent group
R1For C1~C6Alkyl is unsubstituted or by C1~C3Alkyl, C1~C3The phenyl that halogenated alkyl or halogen atom replace；Replace
Base R2For C1~C3Alkyl, naphthalene are unsubstituted or by C1~C3Alkyl, C1~C3The phenyl that alkoxy or halogen atom replace.
3. the preparation method of the chiral pyrrolidine derivative of siliceous acyl group skeleton according to claim 1 or 2, comprising:
Under inert gas shielding, Phosphine ligands, metallic catalyst and reaction medium are mixed, acyl shown in formula (II) is sequentially added
Azomethine ylide shown in SiClx alkyl compound, additive and formula (III), by 1,3- dipole [3+2] cycloaddition reaction
The chiral pyrrolidine derivative of siliceous acyl group skeleton is obtained, reaction equation is as follows:
R in formula (II)1With R in formula (III)2Definition it is identical with formula (I).
4. the preparation method of the chiral pyrrolidine derivative of siliceous acyl group skeleton according to claim 3, which is characterized in that
The Phosphine ligands are any one in following formula L1~L4 compound represented:
5. the preparation method of the chiral pyrrolidine derivative of siliceous acyl group skeleton according to claim 3, which is characterized in that
The metallic catalyst is the mixture of silver carbonate and copper catalyst, and copper catalyst is selected from cuprous bromide, hexafluorophosphoric acid tetrem
Any one in nitrile copper, four acetonitrile copper of tetrafluoro boric acid, copper acetate or copper trifluoromethanesulfcomposite.
6. the preparation method of the chiral pyrrolidine derivative of siliceous acyl group skeleton according to claim 3, which is characterized in that
The additive be selected from potassium phosphate, potassium dihydrogen phosphate, potassium carbonate, saleratus, sodium carbonate, four aryl boric acid sodium, cesium carbonate,
Triethylamine, N, any one in 11 carbon -7- alkene of N- diisopropylethylamine or 1,8- diazabicyclo [5.4.0].
7. the preparation method of the chiral pyrrolidine derivative of siliceous acyl group skeleton according to claim 3, which is characterized in that
The molar ratio of the acylation silane compound and azomethine ylide, Phosphine ligands, metallic catalyst, additive is 1:(1.2
~1.5): (0.02~0.2): (0.03~0.06): (0.1~0.15).
8. the preparation method of the chiral pyrrolidine derivative of siliceous acyl group skeleton according to claim 3, which is characterized in that
Any one of the reaction medium in toluene, tetrahydrofuran, methylene chloride or ether.
9. the preparation method of the chiral pyrrolidine derivative of siliceous acyl group skeleton according to claim 3, which is characterized in that
The reaction temperature is 0~30 DEG C, and the reaction time is 20~30h.
10. the preparation method of the chiral pyrrolidine derivative of siliceous acyl group skeleton according to claim 3, feature exist
In the chiral pyrrolidine derivative for obtaining siliceous acyl group skeleton after post treatment after reaction, post-processing includes: elder generation
It is extracted with ethyl acetate, solvent is evaporated off in the dry back spin of organic phase, and crude product passes through silica gel column chromatography separating purification.
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| CN1203586A (en) * | 1995-11-30 | 1998-12-30 | 曾尼卡有限公司 | Preparation of chiral 3-hydroxy-2-pyrrolidinone derivatives |
| WO2001058588A1 (en) * | 2000-02-10 | 2001-08-16 | The Penn State Research Foundation | Chiral ferrocene phosphines and their use in asymmetric catalytic reactions |
| CN103570691A (en) * | 2013-11-01 | 2014-02-12 | 山西大学 | Chiral pyrrolidine functionalized imidazolium salt, and preparation method and application thereof |
| CN108101820A (en) * | 2018-02-10 | 2018-06-01 | 上海鑫凯化学科技有限公司 | The synthesis technology and intermediate of a kind of chiral pyrrolidine |
| CN109096167A (en) * | 2018-07-03 | 2018-12-28 | 杭州师范大学 | A kind of more carbonyl official substituted chiral pyrrolidin derivatives and preparation method thereof |
| CN109111391A (en) * | 2018-07-03 | 2019-01-01 | 杭州师范大学 | The chiral pyrrolidine derivative and its synthetic method of a kind of ring skeleton containing ternary and application |
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