CN110407844A - 一种Toddacoumalone类化合物或其药学上可接受的盐及其制备方法和应用 - Google Patents
一种Toddacoumalone类化合物或其药学上可接受的盐及其制备方法和应用 Download PDFInfo
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- CN110407844A CN110407844A CN201910779476.2A CN201910779476A CN110407844A CN 110407844 A CN110407844 A CN 110407844A CN 201910779476 A CN201910779476 A CN 201910779476A CN 110407844 A CN110407844 A CN 110407844A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 256
- -1 Toddacoumalone class compound Chemical class 0.000 title claims abstract description 44
- 150000003839 salts Chemical class 0.000 title claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 59
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 229930185107 quinolinone Natural products 0.000 claims abstract description 37
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000013067 intermediate product Substances 0.000 claims description 223
- 238000000034 method Methods 0.000 claims description 113
- 239000002904 solvent Substances 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 33
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 32
- 150000003053 piperidines Chemical class 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- 239000003513 alkali Substances 0.000 claims description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 239000000654 additive Substances 0.000 claims description 12
- 230000000996 additive effect Effects 0.000 claims description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 10
- 150000003346 selenoethers Chemical class 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 claims description 7
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 claims description 7
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- PQMOXTJVIYEOQL-UHFFFAOYSA-N Cumarin Natural products CC(C)=CCC1=C(O)C(C(=O)C(C)CC)=C(O)C2=C1OC(=O)C=C2CCC PQMOXTJVIYEOQL-UHFFFAOYSA-N 0.000 claims description 6
- 238000006000 Knoevenagel condensation reaction Methods 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- FSOGIJPGPZWNGO-UHFFFAOYSA-N Meomammein Natural products CCC(C)C(=O)C1=C(O)C(CC=C(C)C)=C(O)C2=C1OC(=O)C=C2CCC FSOGIJPGPZWNGO-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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 239000005711 Benzoic acid Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 235000010233 benzoic acid Nutrition 0.000 claims description 5
- 235000019441 ethanol Nutrition 0.000 claims description 5
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 229940126062 Compound A Drugs 0.000 claims description 4
- 238000005698 Diels-Alder reaction Methods 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 4
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims description 4
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- XOCXFEZJQVXXFX-UHFFFAOYSA-N [Se](OC#N)OC#N.[N+](=O)([O-])C1=C(C(=O)C2=CC=CC=C2)C=CC=C1 Chemical compound [Se](OC#N)OC#N.[N+](=O)([O-])C1=C(C(=O)C2=CC=CC=C2)C=CC=C1 XOCXFEZJQVXXFX-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 229950002366 nafoxidine Drugs 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- 238000007341 Heck reaction Methods 0.000 claims description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 3
- 239000000470 constituent Substances 0.000 claims description 3
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- WHNPOQXWAMXPTA-UHFFFAOYSA-N 3-methylbut-2-enamide Chemical compound CC(C)=CC(N)=O WHNPOQXWAMXPTA-UHFFFAOYSA-N 0.000 claims description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical class CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 238000006689 Grieco elimination reaction Methods 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000000908 ammonium hydroxide Substances 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Chemical group 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- IWZKICVEHNUQTL-UHFFFAOYSA-M potassium hydrogen phthalate Chemical compound [K+].OC(=O)C1=CC=CC=C1C([O-])=O IWZKICVEHNUQTL-UHFFFAOYSA-M 0.000 claims description 2
- 150000003233 pyrroles Chemical class 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 230000017260 vegetative to reproductive phase transition of meristem Effects 0.000 claims description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 238000003484 Grieco reaction Methods 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 235000019253 formic acid Nutrition 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 36
- 230000000694 effects Effects 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 320
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 81
- 238000005160 1H NMR spectroscopy Methods 0.000 description 81
- 239000000047 product Substances 0.000 description 55
- 235000002639 sodium chloride Nutrition 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- IOVBMEHJQSKXAU-CSLHTZHMSA-N (2r,4s)-2-[(e)-2-(5,7-dimethoxy-2-oxochromen-8-yl)ethenyl]-2,6-dimethyl-4-(2-methylprop-1-enyl)-3,4-dihydropyrano[3,2-c]quinolin-5-one Chemical compound C12=CC=CC=C2N(C)C(=O)C([C@H](C=C(C)C)C2)=C1O[C@@]2(C)/C=C/C1=C2OC(=O)C=CC2=C(OC)C=C1OC IOVBMEHJQSKXAU-CSLHTZHMSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- IOVBMEHJQSKXAU-UHFFFAOYSA-N Toddacoumalone Natural products COc1cc(OC)c2C=CC(=O)Oc2c1C=CC3(C)CC(C=C(C)C)C4=C(O3)c5ccccc5N(C)C4=O IOVBMEHJQSKXAU-UHFFFAOYSA-N 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 3
- 229950005741 rolipram Drugs 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000012925 biological evaluation Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
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- QDRXRBUXLFRISD-UHFFFAOYSA-N (2-nitrophenyl)selanyl cyanate Chemical compound [O-][N+](=O)C1=CC=CC=C1[Se]OC#N QDRXRBUXLFRISD-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
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- VIOFYLQVVYLKOM-UHFFFAOYSA-N C(C)[N+](CC1=CC=CC=C1)(CC)CC.[Cl+] Chemical compound C(C)[N+](CC1=CC=CC=C1)(CC)CC.[Cl+] VIOFYLQVVYLKOM-UHFFFAOYSA-N 0.000 description 1
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- 208000012902 Nervous system disease Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
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- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 241001093501 Rutaceae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000059156 Toddalia Species 0.000 description 1
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- 239000007983 Tris buffer Substances 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
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- 238000004458 analytical method Methods 0.000 description 1
- IMOZEMNVLZVGJZ-QGZVFWFLSA-N apremilast Chemical compound C1=C(OC)C(OCC)=CC([C@@H](CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-QGZVFWFLSA-N 0.000 description 1
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- 201000008937 atopic dermatitis Diseases 0.000 description 1
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- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Abstract
本发明属于药物化学技术领域，公开了一种Toddacoumalone类化合物或其药学上可接受的盐及其制备方法和应用。所述Toddacoumalone类化合物的分子结构通式为如下式I、式II或式II所示。本发明提供的Toddacoumalone类化合物具有较好的抗磷酸二酯酶4活性，并且所提供的Toddacoumalone类化合物的制备方法，采用简单易得的喹啉酮类底物和醛类化合物为原料，反应步骤简短，收率较高。该制备方法具有反应底物易得，催化体系简单，操作简便，官能团耐受性好，经济有效，产物结构多样化等优点，具有十分重要的学术价值和进一步应用和推广意义。
Description
技术领域
本发明属于药物化学技术领域，特别涉及一种Toddacoumalone类化合物或其药学上可接受的盐及其制备方法和应用。
背景技术
磷酸二酯酶(PDEs)共由11种各具特性的同工酶家族(PDE1-PDE11)组成，能调节二级信号信使环磷酸腺苷(cAMP)和环磷酸鸟苷(cGMP)的细胞水平(Pharmacol.Rev.2006,58,488-520)。磷酸二酯酶-4可以特异性的的水解环磷酸腺苷，是一个多种肺部、皮肤病学和严重神经系统疾病的重要靶标。最近，磷酸二酯酶-4抑制剂Roflumilast，Apremilast，Crisaborole分别被FDA批准用于治疗慢性阻塞性肺病，银屑病性关节炎和过敏性皮炎。然而，包括临床应用的大多数PDE4抑制剂，都存在限制剂量的副作用，如恶心、呕吐和胃肠道反应(Front.Pharmacol.2018,9,1048)。因此，对新型PDE4抑制剂的研究依然有增无减。
天然产物在新药开发过程中能提供特殊的价值和启示，它们经常作为重要的探针分子和引物来识别新的药物靶标。Toddacoumalone是一种含有香豆素和喹诺酮骨架的二聚物，是1991年首次从芸香科植物飞龙掌血(Toddalia asiatica(L.)Lam.(Rutaceae))中首次分离得到的天然产物(Tetrahedron Lett.1991,32,6907-6910)，具有很好的抗磷酸二酯酶-4活性(IC50＝0.14μM)，远远大于阳性对照药Rolipram(IC50＝0.59μM)(J.Nat.Prod.2014,77,955-962)。Toddacoumalone在自然界中的含量较少且提取困难不易获到。目前，尚未有文献报道该类化合物的合成。因此，发明一种简捷、实用的方法来制备Toddacoumalone类化合物或其药学上可接受的盐具有重要意义。
发明内容
为了克服上述现有技术的缺点与不足，本发明的首要目的在于提供一种Toddacoumalone类化合物或其药学上可接受的盐。
本发明另一目的在于提供上述Toddacoumalone类化合物或其药学上可接受的盐的制备方法。
本发明再一目的在于提供上述Toddacoumalone类化合物或其药学上可接受的盐在制备抗磷酸二酯酶4药物中的应用。
本发明再一目的在于提供一种抗磷酸二酯酶4的组合物，其活性成分包括有上述的Toddacoumalone类化合物或其药学上可接受的盐。
本发明的目的通过下述方案实现：
一种Toddacoumalone类化合物或其药学上可接受的盐，所述Toddacoumalone类化合物的分子结构通式为式I、式II、式III或式I、式II、式III各自结构通式的4种对映体，所示如下：
其中，R1选自氢，甲基(Me)，苯基(Ph)或苄基(Bn)；R2选自氢或烷基；R3选自氢，卤素，三氟甲基，烷基，芳基或取代芳基；R4和R5独立地选自氢或烷基；所述烷基优选为甲基，乙基或丁基；M选自碳或氮；n＝0或1。
优选地，所述式I具有F1-F27所示的如下结构或如下结构式各自的4种对映体：
一种上述Toddacoumalone类化合物或其药学上可接受的盐的制备方法，采用以下线路合成：
其中：R1，R2，R3，R4，R5，R6，M与前述一致；
上述合成方法的步骤为：
(1)由喹啉酮类化合物A和不饱和醛G为起始原料，在碱1催化下，通过Knoevenagel缩合反应制备中间产物B；
(2)将溶剂2、催化剂1、添加剂1、步骤(1)所得中间产物B与异戊烯醛混合均匀，然后通过Diels-Alder反应制备乙醛类中间产物C；
(3)将步骤(2)所得中间产物C与还原剂1、溶剂3混合后，通过还原反应制备乙醇类中间产物D；
(4)将步骤(3)所得中间产物D和2-硝基苯基硒基氰酸酯溶于溶剂4后，加入催化剂2进行催化反应，得到硒化物，然后将硒化物溶于溶剂5中，与氧化剂1混合后，通过Grieco消除反应制备中间产物E；
(5)将步骤(4)所得中间产物E、碘代香豆素H、催化剂3、碱2与溶剂6混合均匀，通过Heck反应制备得到目标化合物F。
优选地，步骤(1)所述Knoevenagel缩合反应在溶剂1中进行；所述溶剂1包括但不限定为吡啶、甲苯、二氯甲烷、四氢呋喃、乙醇和甲醇中的至少一种；优选为吡啶。
步骤(1)所述碱1包括但不限定为哌啶、四氢吡咯、吡啶、1,6-二甲基吡啶和吡咯中的至少一种，优选为吡啶。
步骤(1)所述喹啉酮类化合物A与不饱和醛G的摩尔比为5:5～5:10；优选为5：6。
步骤(1)所述碱1的用量满足每1mmol喹啉酮类化合物对应加入0.1～3mL的碱1；优选为加入1.0mL的碱1。
步骤(1)所述溶剂1的用量满足每1mmol喹啉酮类化合物对应加入1～5mL的溶剂1；优选为加入2mL的溶剂1。
更优选地，当步骤(1)所述碱1与溶剂1同为吡啶时，每1mmol喹啉酮类化合物对应加入2mL的吡啶。
步骤(1)所述Knoevenagel缩合反应为在60～130℃下回流反应0.5～5h；优选为在100℃下回流反应3h。
步骤(2)所述的溶剂2包括但不限定为二氧六环、氯仿、乙腈、二氯甲烷和四氢呋喃中的至少一种，优选为四氢呋喃。
步骤(2)所述添加剂1包括但不限定为苯甲酸、水杨酸、乙酸、氯乙酸、邻硝基苯甲酸以及其他取代的苯甲酸中的至少一种，优选为苯甲酸。
步骤(2)所述的催化剂1包括但不限定为手性催化剂和非手性催化剂；其中非手性催化剂为哌啶、四氢吡咯和脯氨酸中的至少一种，选为哌啶；手性催化剂为脯氨酸衍生的二级胺手性催化剂；优选为1a和1b中的至少一种，1a和1b的结构式如下所述：
需要特别说明的是非手性催化剂可用于外消旋体的Toddacoumalone类化合物的制备，手性催化剂可用于对映体过量的手性Toddacoumalone类化合物的制备。
步骤(2)所述溶剂2的用量满足每1mmol的中间产物B对应加入250～2000μL溶剂2，优选为加入1000μL溶剂2。
步骤(2)所述中间产物B、异戊烯醛、添加剂1和催化剂1的摩尔比为1～3：1～6：0.1～0.5：0.1～0.5；优选为0.25：0.375：0.05：0.05。
步骤(2)所述Diels-Alder反应的时间为12～72h，优选为在室温下反应48h。
步骤(3)所述溶剂3包括但不限定为乙醇、氯仿、甲醇、二氯甲烷和四氢呋喃中的至少一种，优选为甲醇和二氯甲烷的混合溶剂；所述溶剂3的用量满足每0.25mmol的中间产物B1对应加入250～2000μL溶剂3，优选为加入1000μL溶剂3。
步骤(3)所述还原剂1包括但不限定为硼氢化钠、氰基硼氢化钠和四氢铝锂的至少一种；优选为硼氢化钠。
步骤(3)所述反应物C与还原剂1的摩尔比为1：1.5～1：4，优选为1：2。
步骤(3)所述还原反应为在冰浴下反应0.1～2h，优选为反应0.5h。
步骤(4)所述的溶剂4和溶剂5独立地包括但不限定为二氧六环、氯仿、乙醚、二氯甲烷和四氢呋喃中的至少一种；优选为四氢呋喃。
步骤(4)所述溶剂4的用量满足每0.1mmol的中间产物D对应加入5～20mL有机溶剂4；
步骤(4)所述溶剂5的用量满足每1mg硒化物对应加入20～60μL溶剂5；
步骤(4)所述催化剂2为三正丁基磷；
步骤(4)所述中间产物D、2-硝基苯基硒基氰酸酯和催化剂2的摩尔比为0.1～0.3：0.2～0.6：0.2～0.6，优选为0.2：0.4：0.4。
步骤(4)所述氧化剂1包括但不限定于过氧化氢和间氯过氧苯甲酸中的至少一种，优选为30％(v/v)过氧化氢；所述氧化剂1的用量满足每1g硒化物对应加入500～650μL过氧化氢水溶液；优选为加入570μL过氧化氢水溶液。
步骤(4)所述催化反应的时间为0.5～5h，优选为在室温下反应3h。
步骤(4)所述Grieco消除反应为在-40～10℃下反应5～48h；优选为在0℃下反应12h。
步骤(5)所述溶剂6包括但不限定为二甲基甲酰胺、二甲基丙烯酰胺和二甲基亚砜中的至少一种，优选为二甲基甲酰胺。
步骤(5)所述催化剂3为乙酸钯、氯化钯、四三苯基膦钯和二氯二三苯基膦钯中的至少一种，优选的催化剂3是乙酸钯。
步骤(5)所述碱2为氢氧化锂、氢氧化镁、氢氧化铵、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾和三乙胺中的至少一种；优选为碳酸氢钠。
步骤(5)所述中间产物E、碘代香豆素H、催化剂3和碱2的摩尔比为0.1～0.5：0.1～0.5：0.04～0.1：0.1～1；0.2：0.2：0.08：0.8。
优选地，步骤(5)还加入了添加剂2，所述添加剂2为四丁基溴化铵、苄基三乙基氯化铵和四丁基氯化铵中的至少一种；优选为四丁基溴化铵。
步骤(5)所述添加剂2和碱2的摩尔比为0.1～0.5：0.1～1；优选为0.2：0.8。
步骤(5)所述Heck反应为在60～120℃下反应10～36h；优选为在90℃下反应24h。
上述Toddacoumalone类化合物或其药学上可接受的盐在制备抗磷酸二酯酶4药物中的应用。
本发明还提供一种抗磷酸二酯酶4的组合物，其活性成分包括有上述的Toddacoumalone类化合物或其药学上可接受的盐。
本发明相对于现有技术，具有如下的优点及有益效果：
1、本发明提供了天然产物Toddacoumalone的首次全合成方法。
2、本发明提供的Toddacoumalone类化合物的制备方法，采用简单易得的喹啉酮类底物和醛类化合物为原料，反应步骤简短，收率较高。该制备方法具有反应底物易得，催化体系简单，操作简便，官能团耐受性好，经济有效，产物结构多样化等优点，具有十分重要的学术价值和进一步应用和推广意义。
3、本发明提供的Toddacoumalone类化合物具有很好的抗磷酸二酯酶4活性。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实施例中所用试剂如无特殊说明均可从市场常规购得。
实施例1化合物F1的制备
1、中间产物(B1)的制备:以喹啉酮A1(5mmol,1eq)和醛G1(6mmol,1.2eq)为底物(底物的具体结构见表1)，以吡啶为碱和溶剂(10mL)，在100℃下回流3小时，冷却，浓缩，然后用稀盐酸洗去残留吡啶，再用饱和食盐水洗涤有机相两次，合并有机相侯，经无水硫酸钠干燥，浓缩，将剩余物通过柱层析分离即得到中间产物(B1)，收率为79％。上述中间产物(B1)的表征数据为：
1H NMR(400MHz,CDCl3)δ＝10.76(s,1H),7.89(dd,J＝8.0,0.8Hz,1H),7.50-7.44(m,1H),7.28(s,1H),7.23–7.16(m,1H),6.75(d,J＝10.0Hz,1H),5.55(d,J＝10.0Hz,1H),1.63(s,6H).13C NMR(100MHz,CDCl3)δ＝162.80,157.23,138.02,130.77,126.15,122.51,122.07,117.21,116.06,115.27,105.70,79.05,28.34。
2、中间产物(D1)的制备：将中间产物(B1)(0.25mmol,1.0equiv)，异戊烯醛(0.375mmol,1.5equiv)和苯甲酸(0.05mmol,0.2equiv)，溶解在四氢呋喃(250μL)中，加入哌啶(0.05mmol,0.2equiv)，在室温下反应48小时得到中间产物(C1)，然后将所得中间产物(C1)(1.25mmol,5equiv)与甲醇(500μL)和二氯甲烷(500μL)混合后，冰浴下，加入硼氢化钠(2.5mmol,10equiv)，继续搅拌0.5小时，然后用冰水淬灭，再使用二氯甲烷(5mL)提取反应物三次，合并有机相后，经无水硫酸钠干燥，过滤，浓缩后，将剩余物通过柱层析分离即得到非手性的中间产物(D1)，收率为56％。上述中间产物(D1)的表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.91(dd,J＝8.0,1.2Hz,1H),7.57-7.52(m,1H),7.33(d,J＝8.4Hz,1H),7.26–7.19(m,1H),5.09–5.01(m,1H),3.98(t,J＝6.4Hz,2H),3.74(dd,J＝16.4,8.8Hz,1H),2.11-2.05(m,2H),2.02-1.97(m,1H),1.85-1.83(m,1H),1.83(s,3H),1.77(s,3H),1.40(s,3H).13C NMR(100MHz,CDCl3)δ162.61,154.97,138.86,131.41,130.32,127.19,122.78,121.48,116.51,113.80,109.51,78.39,58.80,43.42,39.15,28.95,25.90,22.96,17.97.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D1)。
3、中间产物(E1)的制备：氩气保护下，将中间产物D1(0.2mmol，1.0equiv)，2-硝基苯基硒基氰酸酯(0.4mmol，2.0equiv)，溶于无水四氢呋喃(2.0mL)中，然后在搅拌下滴入三正丁基磷(0.4mmol，2.0equiv)。在室温下反应3小时，反应完成后用乙醇淬灭反应，再使用硅胶直接吸附，通过柱层析分离即得到黄色油状的硒化物。将102mg该硒化物溶于四氢呋喃(4.0mL)中。置于零摄氏度下，滴入60μL的30(v/v)％的过氧化氢水溶液，在此温度下继续反应12小时，加水淬灭反应，用乙酸乙酯(5.0mL)提取3次，合并有机相后，依次进行水洗，干燥，过滤，浓缩，经柱层析分离即得到中间产物(E1)，收率为85％。
4、产物(F1)的制备：氩气保护下，将中间产物E1(0.2mmol，1.0equiv)，碘代香豆素H(0.2mmol，1.0equiv)，乙酸钯(0.08mmol，0.4equiv)，四丁基溴化铵(0.2mmol，1.0equiv)，碳酸氢钠(0.8mmol，4.0equiv)溶于无水二甲基甲酰胺(2.0mL)中。90摄氏度下反应24小时，冷却后，加入乙酸乙酯(10.0mL)稀释，然后水洗有机相，再依次经过无水硫酸钠干燥，过滤，浓缩，最后通过柱层析分离即得到化合物F1，收率为61％。
上述化合物F1的表征数据为：1H NMR(400MHz,CDCl3)δ＝8.23(d,J＝8.0Hz,1H),7.96(d,J＝9.6Hz,1H),7.55(t,J＝7.2Hz,1H),7.34–7.27(m,2H),6.94(s,2H),6.27(s,1H),6.13(d,J＝9.6Hz,1H),5.12(d,J＝8.8Hz,1H),3.92(s,3H),3.82(s,3H),3.81-3.75(m,1H),2.21-2.06(m,2H),1.84(s,3H),1.64(s,3H),1.61(s,3H).13C NMR(100MHz,CDCl3)δ＝162.87,161.17,160.82,155.81,155.29,153.66,138.81,138.59,137.41,131.07,130.10,127.66,123.28,121.47,116.66,115.59,113.57,111.02,109.81,106.29,103.75,90.27,78.65,56.00,55.90,40.25,29.18,26.77,25.86,17.93。
实施例2化合物F2的制备
1、中间产物(B2)的制备
按照实施例1制备中间产物B1的方法制备，不同之处在于底物为喹啉酮A2和醛G1(底物的具体结构见表1)，收率为87％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.97(d,J＝8.0Hz,1H),7.59–7.51(m,1H),7.32(d,J＝8.4Hz,1H),7.23(t,J＝7.6Hz,1H),6.76(d,J＝10.0Hz,1H),5.54(d,J＝10.0Hz,1H),3.70(s,3H),1.52(s,6H).13C NMR(100MHz,CDCl3)δ＝161.01,155.18,139.37,130.84,126.33,123.13,121.69,117.99,116.11,114.00,105.88,78.74,29.26,28.23.
2、中间产物(D2)的制备
按照实施例1制备中间产物D1的方法进行制备，收率为65％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.91(dd,J＝8.0,1.2Hz,1H),7.57-7.52(m,1H),7.33(d,J＝8.4Hz,1H),7.26–7.19(m,1H),5.09–5.01(m,1H),3.98(t,J＝6.4Hz,2H),3.74(dd,J＝16.4,8.8Hz,1H),3.69(s,3H),2.11-2.05(m,2H),2.02-1.97(m,1H),1.85-1.83(m,1H),1.83(s,3H),1.77(s,3H),1.40(s,3H).13C NMR(100MHz,CDCl3)δ162.61,154.97,138.86,131.41,130.32,127.19,122.78,121.48,116.51,113.80,109.51,78.39,58.80,43.42,39.15,29.22,28.95,25.90,22.96,17.97.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D2)。
3、中间产物(E2)的制备
按照实施例1制备中间产物E1的方法制备，收率为86％。
4、产物(F2)的制备
按照实施例1制备产物F1的方法制备，收率为60％。其表征数据为：
1H NMR(400MHz,CDCl3)δ8.23(d,J＝8.0Hz,1H),7.96(d,J＝9.6Hz,1H),7.55(t,J＝7.2Hz,1H),7.34–7.27(m,2H),6.94(s,2H),6.27(s,1H),6.13(d,J＝9.6Hz,1H),5.12(d,J＝8.8Hz,1H),3.92(s,3H),3.82(d,J＝5.1Hz,3H),3.81-3.75(m,1H),3.67(s,3H),2.21-2.06(m,2H),1.84(s,3H),1.64(s,3H),1.61(s,3H).13C NMR(100MHz,CDCl3)δ162.87,161.17,160.82,155.81,155.29,153.66,138.81,138.59,137.41,131.07,130.10,127.66,123.28,121.47,116.66,115.59,113.57,111.02,109.81,106.29,103.75,90.27,78.65,56.00,55.90,40.25,29.41,29.18,26.77,25.86,17.93.
实施例3化合物F3的制备
1、中间产物(B3)的制备:
按照实施例1制备中间产物B1的方法制备，不同之处在于底物为喹啉酮A3和醛G1(底物的具体结构见表1)，收率为75％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.97(d,J＝8.0Hz,1H),7.59–7.51(m,1H),7.23(t,J＝7.6Hz,1H),6.76(d,J＝10.0Hz,1H),5.54(d,J＝10.0Hz,1H),3.70(s,3H),1.52(s,6H).13CNMR(100MHz,CDCl3)δ＝161.01,155.18,130.84,126.33,123.13,121.69,117.99,116.11,114.00,105.88,78.74,29.26,28.23.
2、中间产物(D3)的制备：
按照实施例1制备中间产物D1的方法制备，收率为62％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.91(dd,J＝8.0,1.2Hz,1H),7.57-7.52(m,1H),7.26–7.19(m,1H),5.09–5.01(m,1H),3.98(t,J＝6.4Hz,2H),3.74(dd,J＝16.4,8.8Hz,1H),3.69(s,3H),2.11-2.05(m,2H),2.02-1.97(m,1H),1.85-1.83(m,1H),1.83(s,3H),1.77(s,3H),1.40(s,3H).13C NMR(100MHz,CDCl3)δ＝162.61,154.97,131.41,130.32,127.19,122.78,121.48,116.51,113.80,109.51,78.39,58.80,43.42,39.15,29.22,28.95,25.90,22.96,17.97.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D3)。
3、中间产物(E3)的制备：
按照实施例1制备中间产物E1的方法制备，收率为88％。
4、产物(F3)的制备：
按照实施例1制备产物F1的方法制备，收率为65％。其表征数据为：
1H NMR(400MHz,CDCl3)δ8.23(d,J＝8.0Hz,1H),7.96(d,J＝9.6Hz,1H),7.55(t,J＝7.2Hz,1H),7.32–7.28(m,1H),6.94(s,2H),6.27(s,1H),6.13(d,J＝9.6Hz,1H),5.12(d,J＝8.8Hz,1H),3.92(s,3H),3.82(d,J＝5.1Hz,3H),3.81-3.75(m,1H),3.67(s,3H),2.21-2.06(m,2H),1.84(s,3H),1.64(s,3H),1.61(s,3H).13C NMR(100MHz,CDCl3)δ162.87,161.17,160.82,155.81,155.29,153.66,138.59,137.41,131.07,130.10,127.66,123.28,121.47,116.66,115.59,113.57,111.02,109.81,106.29,103.75,90.27,78.65,56.00,55.90,40.25,29.41,29.18,26.77,25.86,17.93.
实施例4化合物F4的制备
1、中间产物(B4)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A4和醛G1(底物的具体结构见表1)，收率为77％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.99(dd,J＝8.0,1.4Hz,1H),7.61–7.53(m,2H),7.53–7.46(m,1H),7.33–7.26(m,3H),7.22–7.15(m,1H),6.74(d,J＝10.0Hz,1H),6.62(d,J＝8.4Hz,1H),5.56(d,J＝10.0Hz,1H),1.57(s,6H).13C NMR(100MHz,CDCl3)δ＝161.19,155.93,140.38,137.89,130.45,130.08,129.18,128.75,126.37,122.83,121.98,117.75,115.90,115.85,105.95,79.11,28.41.
2、中间产物(D4)的制备：
按照实施例1制备中间产物D1的方法制备，收率为68％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.90(d,J＝8.0Hz,1H),7.60–7.49(m,2H),7.47–7.43(m,1H),7.32–7.20(m,4H),7.16(t,J＝7.6Hz,1H),6.61(d,J＝8.4Hz,1H),5.08(d,J＝8.4Hz,1H),3.97(t,J＝6.8Hz,2H),3.75(dd,J＝16.4,8.4Hz,1H),2.16–2.06(m,2H),2.02–1.97(m,1H),1.82–1.87(m,1H),1.74(s,3H),1.69(s,3H),1.44(s,3H).13C NMR(100MHz,CDCl3)δ＝162.61,155.60,139.92,138.09,131.24,130.07,129.93,129.83,129.39,129.28,128.50,127.05,122.49,121.65,116.21,115.57,109.68,78.57,58.79,43.44,39.20,28.84,25.87,23.25,17.85.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D4)。
3、中间产物(E4)的制备：
按照实施例1制备中间产物E1的方法制备，收率为85％。
4、产物(F4)的制备：
按照实施例1制备产物F1的方法制备，收率为60％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝8.23(d,J＝8.0Hz,1H),7.96(d,J＝9.6Hz,1H),7.55(t,J＝7.2Hz,1H),7.34–7.27(m,7H),6.94(s,2H),6.27(s,1H),6.13(d,J＝9.6Hz,1H),5.12(d,J＝8.8Hz,1H),3.92(s,3H),3.82(s,3H),3.81-3.75(m,1H),2.21-2.06(m,2H),1.84(s,3H),1.64(s,3H),1.61(s,3H).13C NMR(125MHz,CDCl3)δ＝167.18,161.54,158.17,157.21,153.94,152.41,141.44,141.27,138.41,136.87,133.33,133.29,130.62,129.64,127.42,126.38,124.51,124.08,122.95,122.87,120.38,117.47,110.12,109.31,104.84,95.41,80.75,56.83,40.85,37.01,28.66,25.63,18.93.
实施例5化合物F5的制备
1、中间产物(B5)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A5和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.97(dd,J＝8.0,1.4Hz,1H),7.42–7.36(m,1H),7.31–7.25(m,3H),7.24–7.14(m,4H),6.81(d,J＝10.0Hz,1H),5.60–5.50(m,3H),1.55(s,6H).13CNMR(100MHz,CDCl3)δ＝161.20,155.59,138.86,136.85,130.89,128.75,127.15,126.59,126.38,123.22,121.83,117.98,116.34,114.92,105.60,78.99,45.80,28.38.
2、中间产物(D5)的制备：
按照实施例1制备中间产物D1的方法制备,收率为62％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.82(dd,J＝8.0,1.6Hz,1H),7.33–7.26(m,1H),7.23–7.16(m,2H),7.15–7.05(m,5H),5.44(s,2H),5.02(d,J＝8.4Hz,1H),3.89(t,J＝6.8Hz,2H),3.72(dd,J＝16.0,8.4Hz,1H),2.04–2.00(m,2H),1.97–1.91(m,1H),1.82–1.76(m,1H),1.73(s,3H),1.68(s,3H),1.35(s,3H).13C NMR(100MHz,CDCl3)δ＝162.67,155.28,138.32,137.00,131.46,130.28,128.66,127.26,126.99,126.51,122.84,121.54,116.70,114.68,109.33,78.49,58.81,45.63,43.43,39.13,28.97,25.87,23.20,18.00.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D5)。
3、中间产物(E5)的制备：
按照实施例1制备中间产物E1的方法制备,收率为86％。
4、产物(F5)的制备：
按照实施例1制备产物F1的方法制备,收率为60％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝8.23(d,J＝8.0Hz,1H),7.96(d,J＝9.6Hz,1H),7.55(t,J＝7.2Hz,1H),7.34–7.27(m,7H),6.94(s,2H),6.27(s,1H),6.13(d,J＝9.6Hz,1H),5.44(s,2H),5.12(d,J＝8.8Hz,1H),3.92(s,3H),3.82(s,3H),3.81-3.75(m,1H),2.21-2.06(m,2H),1.84(s,3H),1.64(s,3H),1.61(s,3H).13C NMR(125MHz,CDCl3)δ＝162.71,161.54,158.17,157.21,154.16,153.94,139.31,138.41,137.14,136.87,133.33,131.43,128.64,128.48,128.14,126.38,124.35,123.56,123.18,122.87,117.08,113.01,110.12,109.31,104.84,95.41,80.75,56.83,48.59,40.85,37.01,28.66,25.63,18.93
实施例6化合物F6的制备
1、中间产物(B6)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A6和醛G1(底物的具体结构见表1)，收率为76％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.75(d,J＝0.8Hz,1H),7.31–7.25(m,2H),7.24–7.15(m,4H),7.10(d,J＝8.8Hz,1H),6.81(d,J＝10.0Hz,1H),5.56(d,J＝10.0Hz,1H),5.52(s,2H),2.38(s,3H),1.55(s,6H).13C NMR(100MHz,CDCl3)δ＝161.08,155.45,136.97,136.90,132.16,131.43,128.72,127.09,126.57,126.25,122.80,118.10,116.21,114.89,105.61,78.89,45.75,28.34,20.71.
2、中间产物(D6)的制备：
按照实施例1制备中间产物D1的方法制备，收率为59％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.66(s,1H),7.28–7.23(m,4H),7.21–7.14(m,4H),7.08(d,J＝8.4Hz,1H),5.51(dd,J＝30.8,16.8Hz,2H),5.10(d,J＝8.4Hz,1H),3.98(t,J＝6.8Hz,2H),3.79(dd,J＝16.0,8.4Hz,1H),2.37(s,3H),2.10(t,J＝6.4Hz,2H),2.01(dd,J＝14.0,6.8Hz,1H),1.89–1.82(m,1H),1.80(s,3H),1.75(s,3H),1.43(s,3H).
13C NMR(100MHz,CDCl3)δ＝161.52,154.09,136.10,135.30,130.46,130.33,130.07,127.60,126.36,125.91,125.46,121.45,115.55,113.64,108.28,77.39,57.83,44.56,42.37,38.05,27.97,24.84,22.22,19.77,16.97.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D6)。
3、中间产物(E6)的制备：
按照实施例1制备中间产物E1的方法制备，收率为88％。
4、产物(F6)的制备：
按照实施例1制备产物F1的方法制备，收率为61％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.96(d,J＝9.6Hz,1H),7.55(t,J＝7.2Hz,1H),7.34–7.27(m,7H),6.94(s,2H),6.27(s,1H),6.13(d,J＝9.6Hz,1H),5.44(s,2H),5.12(d,J＝8.8Hz,1H),3.92(s,3H),3.82(s,3H),3.81-3.75(m,1H),2.42(s,3H),2.21-2.06(m,2H),1.84(s,3H),1.64(s,3H),1.61(s,3H).13C NMR(125MHz,CDCl3)δ＝162.71,161.54,158.17,157.21,154.71,153.94,138.41,137.14,137.02,136.87,133.33,131.40,129.62,128.64,128.48,128.14,126.38,124.27,123.36,122.87,122.04,116.09,110.12,109.31,104.84,95.41,80.75,56.83,48.59,40.85,37.01,28.66,25.63,21.20,18.93.
实施例7化合物F7的制备
1、中间产物(B7)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A7和醛G1(底物的具体结构见表1)，收率为76％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.38(d,J＝3.2Hz,1H),7.32–7.25(m,2H),7.21(t,J＝5.2Hz,3H),7.13(d,J＝9.2Hz,1H),7.01(dd,J＝9.2,3.2Hz,1H),6.81(d,J＝10.0Hz,1H),5.57(d,J＝10.0Hz,1H),5.52(s,2H),3.85(s,3H),1.55(s,6H).13C NMR(100MHz,CDCl3)δ＝160.75,155.04,154.65,136.95,133.47,128.74,127.13,126.56,126.47,119.57,118.12,117.02,116.36,106.00,104.92,79.00,55.72,45.87,28.36.
2、中间产物(D7)的制备：
按照实施例1制备中间产物D1的方法制备,收率为66％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.34(d,J＝3.2Hz,1H),7.30–7.22(m,2H),7.22–7.08(m,4H),7.00–6.97(m,1H),5.55(d,J＝16.4Hz,1H),5.46(d,J＝16.4Hz,1H),5.10(d,J＝8.4Hz,1H),3.96(t,J＝6.8Hz,2H),3.82(s,3H),3.81–3.76(m,1H),2.11–2.07(m,2H),2.04–1.99(m,1H),1.88–1.83(m,1H),1.80(s,3H),1.75(s,3H),1.42(s,3H).13C NMR(100MHz,CDCl3)δ＝162.24,154.74,154.45,137.11,132.84,131.41,128.66,127.30,126.97,126.47,118.62,117.40,116.09,109.78,105.09,78.47,58.82,55.66,45.69,43.41,39.15,29.04,25.86,23.19,18.00.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D7)。
3、中间产物(E7)的制备：
按照实施例1制备中间产物E1的方法制备,收率为85％。
4、产物(F7)的制备：
按照实施例1制备产物F1的方法制备,收率为56％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝8.53(d,J＝14.9Hz,1H),7.97(d,J＝21.8Hz,1H),7.57(dd,J＝15.0,2.9Hz,1H),7.34–7.25(m,5H),7.23(d,J＝2.9Hz,1H),6.92(d,J＝30.2Hz,1H),6.57(s,1H),6.43(d,J＝30.2Hz,1H),6.25(d,J＝21.8Hz,1H),5.69–5.61(m,1H),4.94(s,2H),4.56(dt,J＝12.5,8.1Hz,1H),3.92(s,6H),3.77(s,3H),1.92(dd,J＝24.7,8.1Hz,1H),1.82(d,J＝2.0Hz,3H),1.70(d,J＝2.0Hz,3H),1.64(dd,J＝24.9,8.1Hz,1H),1.34(s,3H).13C NMR(125MHz,CDCl3)δ＝161.90,161.30,157.95,155.84,155.81,155.56,153.71,139.23,136.93,136.87,135.63,133.33,128.53,128.41,128.04,123.26,122.44,122.07,119.34,118.14,111.57,111.02,109.10,106.00,104.69,95.44,83.72,56.83,56.08,49.04,41.18,34.13,26.36,25.63,18.93.
实施例8化合物F8的制备
1、中间产物(B8)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A8和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.61(dd,J＝8.8,2.8Hz,1H),7.32–7.10(m,7H),6.79(d,J＝10.0Hz,1H),5.59(d,J＝10.0Hz,1H),5.52(s,2H),1.55(s,6H).13C NMR(100MHz,CDCl3)δ＝160.86,157.89(d,JC,F＝240.6Hz),154.65(d,JC,F＝3.1Hz),136.58,135.32,128.83,127.29,127.02,126.52,118.27(d,JC,F＝23.9Hz),117.77,117.35(d,JC,F＝8.3Hz),116.58(d,JC,F＝7.9Hz),108.52(d,JC,F＝23.9Hz),106.37,79.31,46.02,28.38.
2、中间产物(D8)的制备：
按照实施例1制备中间产物D1的方法制备,收率为62％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.56(dd,J＝8.8,2.4Hz,1H),7.29–7.25(m,2H),7.22–7.18(m,1H),7.17–7.05(m,4H),5.54(d,J＝16.4Hz,1H),5.46(d,J＝16.4Hz,1H),5.09(d,J＝8.0Hz,1H),3.95(t,J＝6.8Hz,2H),3.79(dd,J＝16.0,8.4Hz,1H),2.11–2.06(m,2H),2.05–1.99(m,1H),1.89–1.83(m,1H),1.81(s,3H),1.75(s,3H),1.42(s,3H).13C NMR(100MHz,CDCl3)δ＝162.35,157.73(d,JC,F＝239.9Hz),154.52(d,JC,F＝2.7Hz),136.74,134.77,131.73,128.75,127.13,126.94,126.45,117.94(d,JC,F＝23.9Hz),116.28(d,JC,F＝7.9Hz),110.30,108.46(d,JC,F＝24Hz),78.62,58.68,45.84,43.38,39.04,29.02,25.86,23.30,18.01.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D8)。
3、中间产物(E8)的制备：
按照实施例1制备中间产物E1的方法制备,收率为86％。
4、产物(F8)的制备：
按照实施例1制备产物F1的方法制备,收率为63％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝7.97(d,J＝21.8Hz,1H),7.83–7.75(m,1H),7.38–7.24(m,7H),6.92(d,J＝30.2Hz,1H),6.57(s,1H),6.44(d,J＝30.2Hz,1H),6.25(d,J＝21.8Hz,1H),5.64–5.56(m,1H),4.94(s,2H),4.60(dt,J＝12.5,8.1Hz,1H),3.92(s,6H),1.92(dd,J＝24.7,8.1Hz,1H),1.82(d,J＝2.0Hz,3H),1.74–1.60(m,4H),1.34(s,3H).13C NMR(125MHz,CDCl3)δ＝161.90,161.30,157.73(d,JC,F＝78.6Hz),155.81,153.71,139.23,136.94,135.63(d,JC,F＝2.8Hz),133.33,128.53,128.41,128.03,123.26,122.44,121.69(d,JC,F＝7.6Hz),117.49(d,JC,F＝20.1Hz),116.94(d,JC,F＝7.5Hz),112.92(d,JC,F＝20Hz),111.57,111.03,106.00,104.69,95.43,83.72,56.83,49.04,41.18,34.12,26.36,25.63,18.93.
实施例9化合物F9的制备
1、中间产物(B9)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A9和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.91(s,1H),7.34–7.10(m,7H),6.78(d,J＝10.0Hz,1H),5.59(d,J＝10.0Hz,1H),5.50(s,2H),1.55(s,6H).13C NMR(100MHz,CDCl3)δ＝160.86,154.43,137.28,136.42,130.78,128.84,127.63,127.33,127.05,126.51,122.55,117.69,117.47,116.40,106.36,79.41,45.90,28.39.
2、中间产物(D9)的制备：
按照实施例1制备中间产物D1的方法制备,收率为62％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.85(d,J＝2.4Hz,1H),7.34–7.23(m,3H),7.22–7.18(m,1H),7.14–7.09(m,3H),5.49(dd,J＝39.6,15.2Hz,2H),5.07(d,J＝8.4Hz,1H),3.95(t,J＝6.8Hz,2H),3.78(dd,J＝16.0,8.4Hz,1H),2.13–2.05(m,2H),2.05–1.98(m,1H),1.89–1.82(m,1H),1.80(s,3H),1.75(s,3H),1.42(s,3H).13C NMR(100MHz,CDCl3)δ＝162.33,154.34,136.78,136.57,131.80,130.22,128.74,127.24,127.16,126.84,126.42,122.40,117.89,116.13,110.27,78.67,58.68,45.72,43.38,38.94,29.02,25.84,23.33,18.00.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D9)。
3、中间产物(E9)的制备：
按照实施例1制备中间产物E1的方法制备,收率为88％。
4、产物(F9)的制备：
按照实施例1制备产物F1的方法制备,收率为62％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝7.97(d,J＝21.8Hz,1H),7.75(d,J＝15.0Hz,1H),7.68(d,J＝2.9Hz,1H),7.53(dd,J＝14.9,3.0Hz,1H),7.35–7.23(m,5H),6.92(d,J＝30.2Hz,1H),6.57(s,1H),6.44(d,J＝30.2Hz,1H),6.25(d,J＝21.8Hz,1H),5.64–5.56(m,1H),4.94(s,2H),4.59(dt,J＝12.3,8.0Hz,1H),3.92(s,6H),1.92(dd,J＝24.8,8.0Hz,1H),1.82(d,J＝2.0Hz,3H),1.70(d,J＝2.0Hz,3H),1.65(dd,J＝24.7,8.1Hz,1H),1.34(s,3H).13C NMR(125MHz,CDCl3)δ＝161.90,161.30,157.95,155.84,155.81,153.71,139.23,136.94,136.88,136.50,133.33,130.69,128.87,128.53,128.41,128.03,123.62,123.26,122.44,120.89,119.06,111.57,111.03,106.00,104.69,95.43,83.72,56.83,49.04,41.18,34.12,26.36,25.63,18.93.
实施例10化合物F10的制备
1、中间产物(B10)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A10和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝8.05(d,J＝2.0Hz,1H),7.45(dd,J＝9.2,2.4Hz,1H),7.32–7.16(m,5H),7.07(d,J＝8.8Hz,1H),6.78(d,J＝10.0Hz,1H),5.59(d,J＝10.0Hz,1H),5.50(s,2H),1.55(s,6H).13C NMR(100MHz,CDCl3)δ＝160.85,154.36,137.66,136.37,133.53,128.85,127.35,127.09,126.50,125.60,117.89,117.66,116.69,115.01,106.34,79.45,45.87,28.40.
2、中间产物(D10)的制备：
按照实施例1制备中间产物D1的方法制备,收率为62％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.99(d,J＝2.4Hz,1H),7.43(dd,J＝9.2,2.4Hz,1H),7.28–7.25(m,2H),7.22–7.18(m,1H),7.13(d,J＝7.2Hz,2H),7.04(d,J＝8.8Hz,1H),5.53(d,J＝15.2Hz,1H),5.43(d,J＝15.2Hz,1H),5.07(d,J＝8.4Hz,1H),3.95(t,J＝6.8Hz,2H),3.78(dd,J＝15.6,8.0Hz,1H),2.09(t,J＝6.4Hz,2H),2.02(dd,J＝14.0,7.0Hz,1H),1.89–1.83(m,1H),1.80(s,3H),1.75(s,3H),1.42(s,3H).13C NMR(100MHz,CDCl3)δ＝162.30,154.27,137.17,136.53,132.97,131.81,128.74,127.17,126.82,126.41,125.42,118.31,116.41,114.61,110.25,78.68,58.66,45.68,43.38,38.92,29.01,25.84,23.33,18.00.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D10)。
3、中间产物(E10)的制备：
按照实施例1制备中间产物E1的方法制备,收率为89％。
4、产物(F10)的制备：
按照实施例1制备产物F1的方法制备,收率为60％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝7.97(d,J＝21.8Hz,1H),7.91(d,J＝2.7Hz,1H),7.70(d,J＝15.0Hz,1H),7.65(dd,J＝15.0,2.7Hz,1H),7.34–7.24(m,5H),6.92(d,J＝30.2Hz,1H),6.57(s,1H),6.44(d,J＝30.2Hz,1H),6.25(d,J＝21.8Hz,1H),5.62–5.56(m,1H),4.94(s,2H),4.58(dt,J＝12.5,8.1Hz,1H),3.92(s,6H),1.92(dd,J＝24.8,8.0Hz,1H),1.82(d,J＝2.0Hz,3H),1.70(d,J＝2.0Hz,3H),1.65(dd,J＝24.8,8.0Hz,1H),1.34(s,3H).13C NMR(125MHz,CDCl3)δ＝161.90,161.30,157.95,155.84,155.81,153.71,139.23,136.93,136.87,136.84,134.77,133.33,128.53,128.41,128.04,125.25,123.26,122.44,119.72,115.40,113.85,111.57,111.02,106.00,104.69,95.44,83.72,56.83,49.04,41.18,34.13,26.36,25.63,18.93.
实施例11化合物F11的制备
1、中间产物(B11)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A11和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝8.20(s,1H),7.60(d,J＝8.8Hz,1H),7.35–7.17(m,6H),6.79(d,J＝10.0Hz,1H),5.62(d,J＝10.0Hz,1H),5.55(s,2H),1.58(s,6H).13C NMR(100MHz,CDCl3)δ161.09,154.94,140.68,136.17,128.91,127.45,127.29,127.07(q,JC,F＝6.3Hz),126.52,124.05(q,JC,F＝147.1Hz),120.82(q,JC,F＝4.1Hz),117.47,116.12,115.37,106.46,79.71,46.00,28.43.
2、中间产物(D11)的制备：
按照实施例1制备中间产物D1的方法制备,收率为65％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝8.15(d,J＝1.2Hz,1H),7.58(dd,J＝8.8,2.0Hz,1H),7.31–7.13(m,6H),5.53(dd,J＝40.4,14.8Hz,2H),5.07(d,J＝8.4Hz,1H),3.96(t,J＝6.8Hz,2H),3.79(dd,J＝16.0,8.4Hz,1H),2.14–2.08(m,2H),2.05(dd,J＝14.0,7.0Hz,1H),1.89–1.84(m,1H),1.82(s,3H),1.76(s,3H),1.44(s,3H).13C NMR(100MHz,CDCl3)δ＝162.57,154.92,140.29,136.34,132.02,128.83,127.30,126.60(q,JC,F＝6.7Hz),126.45,125.49,123.71(q,JC,F＝66.2Hz),120.63(q,JC,F＝8.0Hz),116.56,115.08,110.41,78.89,58.62,45.81,43.43,38.94,29.00,25.85,23.30,18.01.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D11)。
3、中间产物(E11)的制备：
按照实施例1制备中间产物E1的方法制备,收率为88％。
4、产物(F11)的制备：
按照实施例1制备产物F1的方法制备,收率为66％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝7.95(d,J＝21.8Hz,1H),7.84(d,J＝2.1Hz,1H),7.75–7.71(m,2H),7.33–7.22(m,5H),6.89(d,J＝4.9Hz,2H),6.55(s,1H),6.23(d,J＝21.8Hz,1H),5.62–5.54(m,1H),4.93(s,2H),4.58(dt,J＝12.3,8.2Hz,1H),3.91(s,6H),1.91(dd,J＝24.8,8.1Hz,1H),1.82(d,J＝2.0Hz,3H),1.71–1.60(m,4H),1.34(s,3H).13C NMR(125MHz,CDCl3)δ＝161.90,161.30,157.95,155.84,155.81,153.71,142.06,139.23,136.93,136.87,133.33,128.53,128.41,128.04,127.59(q,JC,F＝8.5Hz),126.12(q,JC,F＝63.8Hz),122.88(q,JC,F＝155Hz),119.80(q,JC,F＝8.8Hz),119.47,114.78,111.57,111.02,106.00,104.69,95.44,83.72,56.83,49.04,41.18,34.13,26.36,25.63,18.93.
实施例12化合物F12的制备
1、中间产物(B12)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A12和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.60(dd,J＝8.0,1.6Hz,1H),7.13(t,J＝7.6Hz,1H),7.04(dd,J＝8.0,1.2Hz,1H),6.75(d,J＝10.0Hz,1H),5.53(d,J＝10.0Hz,1H),3.92(s,3H),3.88(s,3H),1.50(s,6H).13C NMR(100MHz,CDCl3)δ＝162.15,154.97,148.58,131.06,126.56,122.26,118.33,118.03,115.61,114.27,106.01,78.68,56.69,35.11,28.18.
2、中间产物(D12)的制备：
按照实施例1制备中间产物D1的方法制备,收率为64％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.50(dd,J＝8.0,1.2Hz,1H),7.12(t,J＝8.0Hz,1H),7.04(dd,J＝8.0,1.2Hz,1H),5.01–4.94(m,1H),3.95(t,J＝6.8Hz,2H),3.88(d,J＝1.6Hz,6H),3.71(dd,J＝17.2,8.0Hz,1H),2.06(t,J＝6.8Hz,2H),1.95(dd,J＝14.0,8.0Hz,2H),1.81(d,J＝1.2Hz,3H),1.74(s,3H),1.36(s,3H).13C NMR(100MHz,CDCl3)δ＝163.68,154.71,148.48,131.42,130.62,127.01,122.08,118.93,115.11,113.65,109.66,78.41,58.73,56.66,43.61,39.01,34.93,28.93,25.87,22.68,17.96.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D12)。
3、中间产物(E12)的制备：
按照实施例1制备中间产物E1的方法制备,收率为89％。
4、产物(F12)的制备：
按照实施例1制备产物F1的方法制备,收率为61％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝8.04(dd,J＝14.9,3.0Hz,1H),7.93(d,J＝21.8Hz,1H),7.50(t,J＝15.0Hz,1H),7.18(dd,J＝14.9,3.0Hz,1H),6.89(d,J＝30.2Hz,1H),6.54(s,1H),6.33(d,J＝30.0Hz,1H),6.22(d,J＝21.8Hz,1H),5.88–5.81(m,1H),4.42(dt,J＝12.5,7.8Hz,1H),3.90(s,6H),3.84(s,3H),3.44(s,3H),1.91(dd,J＝24.7,7.9Hz,1H),1.81(d,J＝2.0Hz,3H),1.69(d,J＝1.8Hz,3H),1.63(dd,J＝24.7,7.9Hz,1H),1.33(s,3H).13C NMR(125MHz,CDCl3)δ＝161.36,161.30,158.59,157.95,155.81,153.71,148.78,139.23,136.87,133.33,129.50,124.69,123.26,122.44,117.83,117.27,116.42,111.52,111.02,106.00,104.69,95.44,83.72,56.83,41.18,34.13,34.02,26.36,25.63,18.93.
实施例13化合物F13的制备
1、中间产物(B13)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A13和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.31–7.21(m,6H),6.81(d,J＝10.0Hz,1H),6.67(s,1H),5.54–5.50(m,3H),3.93(s,3H),3.74(s,3H),1.55(s,6H).13C NMR(100MHz,CDCl3)δ＝161.13,155.50,152.23,145.05,137.14,134.67,128.82,127.26,126.70,125.32,118.28,109.12,104.00,103.79,98.48,78.95,56.24,55.92,46.20,28.36.
2、中间产物(D13)的制备：
按照实施例1制备中间产物D1的方法制备,收率为61％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.31–7.16(m,7H),6.65(s,1H),5.58(d,J＝16.0Hz,1H),5.46(d,J＝16.0Hz,1H),5.11(d,J＝8.4Hz,1H),3.96(t,J＝6.0Hz,2H),3.90(s,3H),3.79(dd,J＝16.4,8.4Hz,1H),3.72(s,3H),2.09(dd,J＝12.8,6.8Hz,2H),2.01(dd,J＝14.0,7.2Hz,1H),1.87–1.83(m,1H),1.81(s,3H),1.76(s,3H),1.43(s,3H).13C NMR(100MHz,CDCl3)δ＝162.69,155.06,151.54,144.74,137.27,133.79,131.23,128.74,127.64,127.13,126.64,109.43,107.42,103.78,98.28,78.49,58.89,56.17,55.89,46.02,43.40,39.22,28.91,25.90,23.18,18.01.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D13)。
3、中间产物(E13)的制备：
按照实施例1制备中间产物E1的方法制备,收率为87％。
4、产物(F13)的制备：
按照实施例1制备产物F1的方法制备,收率为64％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝7.93(d,J＝21.8Hz,1H),7.41(s,1H),7.32–7.21(m,5H),7.19(s,1H),6.89(d,J＝30.0Hz,1H),6.54(s,1H),6.39(d,J＝30.0Hz,1H),6.22(d,J＝21.8Hz,1H),5.65–5.58(m,1H),4.92(s,2H),4.51(dt,J＝12.5,8.1Hz,1H),3.90(s,6H),3.83(s,3H),3.74(s,3H),1.91(dd,J＝24.7,8.1Hz,1H),1.81(d,J＝1.8Hz,3H),1.69(d,J＝2.0Hz,3H),1.64(dd,J＝24.8,8.0Hz,1H),1.33(s,3H).13C NMR(125MHz,CDCl3)δ＝161.90,161.30,157.95,155.84,155.81,153.71,152.72,149.52,139.23,136.93,136.87,133.33,128.53,128.41,128.04,126.04,123.26,122.44,113.18,113.11,111.57,111.02,106.00,104.69,99.75,95.44,83.72,56.83,49.04,41.18,34.13,26.36,25.63,18.93.
实施例14化合物F14的制备
1、中间产物(B14)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A14和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝8.82(d,J＝2.4Hz,1H),8.21(dd,J＝9.2,2.4Hz,1H),7.34–7.27(m,3H),7.20(d,J＝7.2Hz,3H),6.77(d,J＝10.0Hz,1H),5.66(d,J＝10.0Hz,1H),5.56(s,2H),1.60(s,6H).13C NMR(100MHz,CDCl3)δ＝160.96,154.80,142.47,142.14,135.70,129.01,127.86,127.65,126.47,125.25,119.62,117.09,116.18,115.56,106.82,80.20,46.28,28.51.
2、中间产物(D14)的制备：
按照实施例1制备中间产物D1的方法制备,收率为66％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝8.77(d,J＝2.8Hz,1H),8.19(dd,J＝9.6,2.8Hz,1H),7.33–7.20(m,4H),7.16(d,J＝7.2Hz,2H),5.59(d,J＝15.2Hz,1H),5.48(d,J＝15.2Hz,1H),5.06(d,J＝8.4Hz,1H),3.97(t,J＝6.8Hz,2H),3.79(dd,J＝16.0,8.4Hz,1H),2.16–2.04(m,3H),1.90–1.80(m,1H),1.82(s,3H),1.76(s,3H),1.46(s,3H).13C NMR(100MHz,CDCl3)δ＝162.44,154.89,142.21,141.83,135.86,132.39,128.93,127.50,126.41,126.20,124.91,119.60,116.61,115.22,110.93,79.27,58.56,46.08,43.33,38.82,28.99,25.84,23.39,18.02.[α]20 D＝+11.53°(c＝1.0,CHCl3,73％ee).
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D14)。
3、中间产物(E14)的制备：
按照实施例1制备中间产物E1的方法制备,收率为85％。
4、产物(F14)的制备：
按照实施例1制备产物F1的方法制备,收率为66％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝8.33–8.26(m,2H),8.10–8.04(m,1H),7.97(d,J＝21.8Hz,1H),7.36–7.22(m,5H),6.93(d,J＝30.2Hz,1H),6.77(d,J＝30.2Hz,1H),6.57(s,1H),6.25(d,J＝21.8Hz,1H),5.55–5.47(m,1H),4.94(s,2H),4.33(td,J＝17.4,12.4Hz,1H),3.92(s,6H),1.90(dd,J＝24.7,17.4Hz,1H),1.82(d,J＝2.0Hz,3H),1.73–1.58(m,4H),1.34(s,3H).13C NMR(125MHz,CDCl3)δ＝161.90,161.30,157.95,155.84,155.81,153.71,147.17,143.78,139.23,136.93,136.87,133.33,129.55,128.53,128.41,128.04,123.26,122.44,120.23,118.66,115.68,111.57,111.02,106.00,104.69,95.44,83.72,56.83,49.04,41.18,34.13,26.36,25.63,18.93.
实施例15化合物F15的制备
1、中间产物(B15)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A15和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.77(d,J＝2.0Hz,1H),7.31–7.20(m,6H),7.15(d,J＝8.8Hz,1H),6.81(d,J＝10.0Hz,1H),5.56(d,J＝10.0Hz,1H),5.52(s,2H),3.00–2.91(m,1H),1.56(s,6H),1.27(s,3H),1.25(s,3H).13C NMR(100MHz,CDCl3)δ＝161.16,155.66,142.48,137.17,137.00,129.55,128.73,127.11,126.63,126.22,120.32,118.10,116.17,115.03,105.55,78.93,45.84,33.58,28.36,24.02.
2、中间产物(D15)的制备：
按照实施例1制备中间产物D1的方法制备,收率为67％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.70(d,J＝2.0Hz,1H),7.30–7.23(m,3H),7.23–7.10(m,4H),5.51(s,2H),5.08(d,J＝8.0Hz,1H),3.98(t,J＝6.0Hz,2H),3.79(dd,J＝16.4,8.8Hz,1H),2.99–2.90(m,1H),2.13–2.07(m,2H),2.01(dd,J＝14.0,7.2Hz,1H),1.88–1.83(m,1H),1.81(d,J＝1.2Hz,3H),1.75(s,3H),1.43(s,3H),1.24(d,J＝7.2Hz,7H).13C NMR(100MHz,CDCl3)δ＝162.58,155.25,142.14,137.15,136.57,131.32,128.85,128.63,127.37,126.94,126.53,119.94,116.47,114.78,109.21,78.46,58.87,45.63,43.41,39.17,33.56,28.97,25.88,24.08,24.01,23.10,17.99.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D15)。
3、中间产物(E15)的制备：
按照实施例1制备中间产物E1的方法制备,收率为84％。
4、产物(F15)的制备：
按照实施例1制备产物F1的方法制备,收率为65％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝7.97(d,J＝21.8Hz,1H),7.81(d,J＝15.0Hz,1H),7.71(d,J＝2.9Hz,1H),7.36–7.24(m,6H),6.92(d,J＝30.2Hz,1H),6.57(s,1H),6.45(d,J＝30.2Hz,1H),6.25(d,J＝21.8Hz,1H),5.65–5.57(m,1H),4.94(s,2H),4.57(dt,J＝12.3,8.0Hz,1H),3.92(s,6H),2.88(dq,J＝25.4,12.7Hz,1H),1.92(dd,J＝24.8,8.0Hz,1H),1.82(d,J＝2.0Hz,3H),1.72–1.60(m,4H),1.34(s,3H),1.21(s,3H),1.19(s,3H).13C NMR(125MHz,CDCl3)δ＝161.90,161.30,157.95,155.84,155.81,153.71,140.00,139.34,139.23,136.93,136.87,133.33,128.74,128.53,128.41,128.04,125.90,123.26,122.44,122.18,114.31,111.57,111.02,106.00,104.69,95.44,83.72,56.83,49.04,41.18,34.26,34.13,26.36,25.63,23.38,18.93.
实施例16化合物F16的制备
1、中间产物(B16)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A16和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.91(d,J＝2.4Hz,1H),7.45(dd,J＝8.8,2.4Hz,1H),7.31–7.20(m,6H),7.16(d,J＝8.8Hz,1H),6.81(d,J＝10.0Hz,1H),5.56(d,J＝10.0Hz,1H),5.52(s,2H),1.56(s,6H),1.34(s,9H).13C NMR(100MHz,CDCl3)δ＝161.17,155.78,144.76,137.04,136.87,128.80,128.72,127.10,126.65,126.14,118.91,118.13,115.85,114.74,105.53,78.92,45.81,34.41,31.31,28.37.
2、中间产物(D16)的制备：
按照实施例1制备中间产物D1的方法制备,收率为64％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.85(d,J＝2.4Hz,1H),7.43(dd,J＝9.2,2.4Hz,1H),7.29–7.24(m,2H),7.21–7.12(m,4H),5.51(s,2H),5.08(d,J＝8.4Hz,1H),4.00–3.95(m,2H),3.80(dd,J＝16.0,8.4Hz,1H),2.15–1.97(m,3H),1.87–1.83(m,1H),1.81(s,3H),1.75(s,3H),1.44(s,3H),1.32(s,9H).13C NMR(100MHz,CDCl3)δ＝162.61,155.35,144.43,137.19,136.28,131.31,128.63,128.11,127.37,126.94,126.57,118.55,116.12,114.52,109.22,78.51,58.90,45.62,43.49,39.36,34.38,31.33,29.00,25.88,22.94,17.99.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D16)。
3、中间产物(E16)的制备：
按照实施例1制备中间产物E1的方法制备,收率为89％。
4、产物(F16)的制备：
按照实施例1制备产物F1的方法制备,收率为61％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝7.97(d,J＝21.8Hz,1H),7.72(dd,J＝15.3,9.1Hz,2H),7.37(dd,J＝15.0,3.1Hz,1H),7.34–7.24(m,5H),6.92(d,J＝30.2Hz,1H),6.57(s,1H),6.42(d,J＝30.2Hz,1H),6.25(d,J＝21.8Hz,1H),5.66–5.56(m,1H),4.94(s,2H),4.57(dt,J＝12.5,8.0Hz,1H),3.92(s,6H),1.92(dd,J＝24.7,8.1Hz,1H),1.82(d,J＝2.0Hz,3H),1.70(d,J＝2.0Hz,3H),1.65(dd,J＝24.8,8.0Hz,1H),1.34(s,3H),1.32(s,9H).13C NMR(125MHz,CDCl3)δ＝161.90,161.30,157.95,155.84,155.81,153.71,145.23,144.21,139.23,136.93,136.87,133.33,128.53,128.41,128.04,126.77,123.26,122.44,122.16,120.64,118.80,111.57,111.02,106.00,104.69,95.44,83.72,56.83,49.04,41.18,35.35,34.13,31.36,26.36,25.63,18.93.
实施例17化合物F17的制备
1、中间产物(B17)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A17和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝8.16(d,J＝2.0Hz,1H),7.66–7.57(m,3H),7.47–7.42(m,2H),7.38–7.22(m,7H),6.82(d,J＝10.0Hz,1H),5.59(d,J＝10.0Hz,3H),1.57(s,6H).13C NMR(100MHz,CDCl3)δ＝161.11,155.61,140.06,138.12,136.79,134.96,129.85,128.87,128.78,127.36,127.20,127.00,126.60,126.52,121.25,117.95,116.64,115.43,105.87,79.13,45.89,28.39.
2、中间产物(D17)的制备：
按照实施例1制备中间产物D1的方法制备,收率为61％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝8.09(d,J＝2.4Hz,1H),7.65–7.55(m,3H),7.46–7.41(m,2H),7.36–7.25(m,5H),7.23–7.18(m,3H),5.56(dd,J＝34,17.6Hz,2H),5.11(d,J＝8.4Hz,1H),3.97(t,J＝6.4Hz,2H),3.82(dd,J＝16.0,8.4Hz,1H),2.14–2.09(m,2H),2.04(dd,J＝14.0,7.0Hz,1H),1.91–1.84(m,1H),1.82(s,3H),1.76(s,3H),1.44(s,3H).13C NMR(100MHz,CDCl3)δ＝162.57,155.33,140.19,137.60,136.94,134.62,131.53,129.24,128.90,128.70,127.25,127.21,127.05,126.95,126.52,120.96,116.99,115.19,109.62,78.55,58.82,45.69,43.40,39.07,29.01,25.88,23.27,18.01.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D17)。
3、中间产物(E17)的制备：
按照实施例1制备中间产物E1的方法制备,收率为86％。
4、产物(F17)的制备：
按照实施例1制备产物F1的方法制备,收率为64％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝7.99(dd,J＝18.4,15.5Hz,2H),7.82(dd,J＝15.0,2.9Hz,1H),7.76(dt,J＝4.6,2.2Hz,1H),7.73(dt,J＝6.7,3.4Hz,1H),7.67(d,J＝3.0Hz,1H),7.53–7.36(m,3H),7.35–7.23(m,5H),6.92(d,J＝30.2Hz,1H),6.57(s,1H),6.38(d,J＝30.2Hz,1H),6.25(d,J＝21.8Hz,1H),5.72–5.63(m,1H),4.94(s,2H),4.55(dt,J＝12.5,8.0Hz,1H),3.92(s,6H),1.92(dd,J＝24.7,8.1Hz,1H),1.82(d,J＝2.0Hz,3H),1.70(d,J＝2.0Hz,3H),1.65(dd,J＝24.7,8.1Hz,1H),1.34(s,3H).13C NMR(125MHz,CDCl3)δ＝161.90,161.30,157.95,155.84,155.81,153.71,139.96,139.23,138.20,136.93,136.87,136.00,133.33,128.72,128.53,128.41,128.13,128.13,128.04,127.36,123.26,122.83,122.44,121.75,119.77,111.57,111.02,106.00,104.69,95.44,83.72,56.83,49.04,41.18,34.13,26.36,25.63,18.93.
实施例18化合物F18的制备
1、中间产物(B18)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A18和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝8.42(d,J＝8.4Hz,1H),7.94(d,J＝8.8Hz,1H),7.87(d,J＝7.6Hz,1H),7.62–7.47(m,3H),6.79(d,J＝10.0Hz,1H),5.57(d,J＝10.0Hz,1H),4.04(s,3H),1.55(s,6H).13C NMR(100MHz,CDCl3)δ＝163.32,155.96,139.14,135.88,128.77,127.13,126.53,125.75,124.94,123.82,123.39,119.30,117.80,113.78,105.64,78.99,40.16,28.33.
2、中间产物(D18)的制备：
按照实施例1制备中间产物D1的方法制备,收率为56％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝8.38(d,J＝8.4Hz,1H),7.88(d,J＝8.8Hz,2H),7.63–7.47(m,3H),5.01(d,J＝8.4Hz,1H),4.02–3.97(m,5H),3.78(dd,J＝17.2,8.8Hz,1H),2.11(t,J＝6.4Hz,2H),2.00(dd,J＝14.0,7.2Hz,1H),1.86(s,3H),1.87–1.77(m,4H),1.42(s,3H).13C NMR(100MHz,CDCl3)δ＝164.85,155.72,138.35,135.43,131.95,128.64,126.87,126.60,125.67,124.85,123.77,123.14,119.09,114.46,109.26,78.70,58.71,43.90,39.79,38.95,28.81,25.90,22.66,18.05.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D18)。
3、中间产物(E18)的制备：
按照实施例1制备中间产物E1的方法制备,收率为86％。
4、产物(F18)的制备：
按照实施例1制备产物F1的方法制备,收率为66％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝8.03–7.93(m,2H),7.74–7.68(m,1H),7.64(d,J＝14.9Hz,1H),7.40–7.29(m,3H),6.92(d,J＝30.2Hz,1H),6.69(d,J＝30.2Hz,1H),6.57(s,1H),6.25(d,J＝21.8Hz,1H),5.64–5.56(m,1H),4.50(dt,J＝12.5,8.0Hz,1H),3.92(s,6H),3.46(s,3H),1.91(dd,J＝24.9,8.1Hz,1H),1.82(d,J＝2.0Hz,3H),1.72–1.60(m,4H),1.34(s,3H).13C NMR(125MHz,CDCl3)δ＝162.78,161.30,158.60,157.95,155.81,153.71,139.23,138.04,136.87,134.38,133.33,128.86,127.80,127.69,126.05,125.65,124.34,123.26,122.44,122.32,115.97,111.91,111.02,106.00,104.69,95.44,83.72,56.83,41.18,34.13,33.87,26.36,25.63,18.93.
实施例19化合物F19的制备
1、中间产物(B19)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A19和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝9.51(d,J＝8.8Hz,1H),7.81–7.76(m,2H),7.64–7.57(m,1H),7.51–7.41(m,2H),7.33–7.19(m,5H),6.93(d,J＝10.0Hz,1H),5.72(s,2H),5.64(d,J＝10.0Hz,1H),1.69(s,6H).13C NMR(100MHz,CDCl3)δ＝160.59,159.14,139.44,136.82,132.69,130.03,129.68,128.85,128.59,127.81,127.21,126.81,126.40,125.95,125.14,118.79,115.57,109.90,106.95,79.38,46.77,28.29.
2、中间产物(D19)的制备：
按照实施例1制备中间产物D1的方法制备,收率为53％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝9.41(d,J＝8.8Hz,1H),7.83–7.73(m,2H),7.62–7.55(m,1H),7.46–7.40(m,2H),7.29–7.14(m,5H),5.73(s,2H),5.12(d,J＝8.4Hz,1H),4.01(t,J＝6.8Hz,2H),3.91(dd,J＝16.4,8.4Hz,1H),2.32–2.20(m,2H),2.12(dd,J＝14.0,7.6Hz,1H),1.95(dd,J＝14.0,8.8Hz,1H),1.84(s,3H),1.76(s,4H),1.51(s,3H).13C NMR(100MHz,CDCl3)δ＝161.03,158.24,137.53,136.00,130.95,130.54,128.86,128.65,127.73,127.59,126.61,126.53,126.02,125.80,125.28,123.78,114.47,109.31,109.21,77.97,57.82,45.48,42.75,37.64,28.46,24.85,22.17,17.03.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D19)。
3、中间产物(E19)的制备：
按照实施例1制备中间产物E1的方法制备,收率为88％。
4、产物(F19)的制备：
按照实施例1制备产物F1的方法制备,收率为64％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝8.08(dd,J＝15.0,2.9Hz,1H),7.98(d,J＝9.5Hz,1H),7.95(d,J＝2.6Hz,1H),7.76(dd,J＝14.9,3.0Hz,1H),7.69(dt,J＝14.9,3.0Hz,1H),7.44(td,J＝14.9,3.1Hz,1H),7.35–7.21(m,6H),6.92(d,J＝30.2Hz,1H),6.57(s,1H),6.47(d,J＝30.2Hz,1H),6.25(d,J＝21.8Hz,1H),5.79–5.71(m,1H),4.94(s,2H),4.60(dt,J＝12.5,8.0Hz,1H),3.92(s,6H),1.92(dd,J＝24.8,8.0Hz,1H),1.82(d,J＝2.0Hz,3H),1.70(d,J＝2.0Hz,3H),1.65(dd,J＝24.7,8.1Hz,1H),1.34(s,3H).13C NMR(125MHz,CDCl3)δ＝164.69,161.90,161.30,157.95,155.81,153.71,140.19,139.23,136.93,136.87,133.33,132.70,130.31,130.29,128.53,128.41,128.04,127.76,127.11,125.96,124.12,123.26,122.44,117.75,111.02,110.93,106.00,104.69,99.19,95.44,83.72,56.83,49.04,41.18,34.13,26.36,25.63,18.93.
实施例20化合物F20的制备
1、中间产物(B20)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A20和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝9.79(d,J＝8.8Hz,1H),8.89–8.82(m,1H),8.07(d,J＝9.6Hz,1H),7.69(d,J＝9.6Hz,1H),7.52–7.47(m,1H),7.34–7.21(m,5H),6.92(d,J＝10.0Hz,1H),5.73(s,2H),5.67(d,J＝10.0Hz,1H),1.69(s,6H).13C NMR(100MHz,CDCl3)δ＝160.56,158.68,148.86,144.80,139.02,136.44,134.82,133.62,128.96,127.42,126.45,126.39,125.60,122.08,119.09,118.57,109.40,107.43,79.72,46.82,28.37.
2、中间产物(D20)的制备：
按照实施例1制备中间产物D1的方法制备,收率为54％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝9.75(d,J＝9.2Hz,1H),8.84(d,J＝4.0Hz,1H),8.05(d,J＝9.6Hz,1H),7.68(d,J＝9.6Hz,1H),7.47(dd,J＝9.2,4.4Hz,1H),7.31–7.15(m,5H),5.69(s,2H),5.11(d,J＝7.6Hz,1H),4.02–3.97(m,2H),3.94–3.87(m,1H),2.31–2.21(m,2H),2.14(dd,J＝14.0,7.6Hz,1H),1.97(dd,J＝14.0,9.2Hz,1H),1.84(s,3H),1.77(s,3H),1.52(s,3H).13C NMR(100MHz,CDCl3)δ＝161.99,158.85,148.50,144.75,138.29,136.69,135.00,132.95,131.94,128.86,127.22,126.32,125.49,121.82,119.01,111.04,109.69,79.28,58.77,46.55,43.72,38.54,29.46,25.87,23.37,18.07.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D20)。
3、中间产物(E20)的制备：
按照实施例1制备中间产物E1的方法制备,收率为87％。
4、产物(F20)的制备：
按照实施例1制备产物F1的方法制备,收率为63％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝8.74–8.65(m,2H),8.04–7.93(m,2H),7.64(d,J＝15.0Hz,1H),7.36–7.23(m,5H),7.12(t,J＝14.9Hz,1H),6.92(d,J＝30.2Hz,1H),6.57(s,1H),6.44(d,J＝30.2Hz,1H),6.25(d,J＝21.8Hz,1H),5.78–5.67(m,1H),4.94(s,2H),4.61(dt,J＝12.3,8.0Hz,1H),3.92(s,6H),1.92(dd,J＝24.8,8.0Hz,1H),1.82(d,J＝2.0Hz,3H),1.72–1.59(m,4H),1.34(s,3H).13C NMR(125MHz,CDCl3)δ＝164.69,161.90,161.30,157.95,155.81,153.71,146.25,144.28,142.48,139.65,139.23,136.93,136.87,133.33,130.75,128.53,128.41,128.04,124.19,123.26,122.44,122.16,116.83,112.20,111.02,106.00,104.69,99.19,95.44,83.72,56.83,49.04,41.18,34.13,26.36,25.63,18.93.
实施例21化合物F21的制备
1、中间产物(B21)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A21和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.57(dd,J＝8.0,0.8Hz,1H),7.30(dd,J＝7.2,0.8Hz,1H),7.11(dd,J＝8.0,7.6Hz,1H),6.76(d,J＝10.0Hz,1H),5.50(d,J＝10.0Hz,1H),4.45–4.33(m,2H),3.39(t,J＝8.0Hz,2H),1.51(s,6H).13C NMR(100MHz,CDCl3)δ＝159.54,155.94,141.85,130.36,125.79,125.16,122.68,119.31,118.00,113.14,107.50,78.71,46.61,28.16,27.33.
2、中间产物(D21)的制备：
按照实施例1制备中间产物D1的方法制备,收率为47％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.49(d,J＝8.0Hz,1H),7.28(d,J＝8.0Hz,1H),7.09(t,J＝7.6Hz,1H),5.02(d,J＝8.4Hz,1H),4.46–4.27(m,2H),4.01–3.89(m,2H),3.73(dd,J＝16.4,8.8Hz,1H),3.41–3.32(m,2H),2.13–1.93(m,4H),1.81(s,3H),1.75(s,3H),1.36(s,3H).13C NMR(100MHz,CDCl3)δ＝161.29,155.52,141.25,131.55,130.15,126.89,124.67,122.39,119.03,113.45,110.98,78.47,58.77,46.64,43.42,39.23,28.92,27.29,25.89,22.74,18.00.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D21)。
3、中间产物(E21)的制备：
按照实施例1制备中间产物E1的方法制备,收率为87％。
4、产物(F21)的制备：
按照实施例1制备产物F1的方法制备,收率为62％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝8.30(dd,J＝14.7,3.4Hz,1H),7.97(d,J＝21.8Hz,1H),7.36–7.20(m,2H),6.87(q,J＝30.2Hz,2H),6.57(s,1H),6.25(d,J＝21.8Hz,1H),5.62–5.53(m,1H),4.43(dt,J＝12.5,8.1Hz,1H),4.12(t,J＝15.4Hz,2H),3.92(s,6H),3.20(t,J＝15.4Hz,2H),1.91(dd,J＝24.8,8.0Hz,1H),1.82(d,J＝2.0Hz,3H),1.72–1.59(m,4H),1.34(s,3H).13C NMR(125MHz,CDCl3)δ＝161.30,157.98,157.95,157.46,155.81,153.71,139.23,136.87,135.41,133.33,127.99,126.45,125.17,123.26,122.44,120.60,113.43,111.33,111.02,106.00,104.69,95.44,83.72,56.83,46.78,41.18,34.13,31.29,26.36,25.63,18.93.
实施例22化合物F22的制备
1、中间产物(B22)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A22和醛G1(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.79(d,J＝8.0Hz,1H),7.27(d,J＝6.4Hz,1H),7.10(t,J＝7.6Hz,1H),6.76(d,J＝10.0Hz,1H),5.53(d,J＝10.0Hz,1H),4.23–4.13(m,2H),2.95(t,J＝6.2Hz,2H),2.12–2.04(m,2H),1.51(s,6H).13C NMR(101MHz,CDCl3)δ＝160.55,155.24,136.11,130.11,126.34,124.69,121.21,120.97,117.90,115.80,105.63,78.60,42.10,28.20,27.96,20.83.
2、中间产物(D22)的制备：
按照实施例1制备中间产物D1的方法制备,收率为56％。其表征数据为：
1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.0Hz,1H),7.27–7.24(m,2H),7.08(t,J＝8.0Hz,1H),5.03(d,J＝8.4Hz,1H),4.30–4.22(m,1H),4.08–4.00(m,1H),3.95(t,J＝6.4Hz,2H),3.73(dd,J＝16.4,8.4Hz,1H),2.95(t,J＝6.0Hz,2H),2.09–2.03(m,4H),1.96(dd,J＝14.0,7.2Hz,1H),1.84–1.77(m,4H),1.75(s,3H),1.37(s,3H).13C NMR(100MHz,CDCl3)δ162.16,154.97,135.58,131.29,129.52,127.23,124.42,120.97,120.58,116.19,109.19,78.27,58.79,43.46,41.91,39.20,28.84,27.94,25.88,22.96,20.92,17.95.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D22)。
3、中间产物(E22)的制备：
按照实施例1制备中间产物E1的方法制备,收率为89％。
4、产物(F22)的制备：
按照实施例1制备产物F1的方法制备,收率为67％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝8.30(dd,J＝14.7,3.4Hz,1H),7.97(d,J＝21.8Hz,1H),7.33(dd,J＝15.0,3.3Hz,1H),7.24(t,J＝14.8Hz,1H),6.93(d,J＝30.2Hz,1H),6.77(d,J＝30.2Hz,1H),6.57(s,1H),6.25(d,J＝21.8Hz,1H),5.66–5.50(m,1H),4.40(dt,J＝12.5,8.1Hz,1H),3.92(s,6H),3.18(t,J＝10.6Hz,2H),2.79(t,J＝11.8Hz,2H),1.96–1.74(m,6H),1.74–1.60(m,4H),1.34(s,3H).13C NMR(125MHz,CDCl3)δ＝161.30,158.50,157.95,157.46,155.81,153.71,139.23,138.49,136.87,133.33,128.70,124.76,123.68,123.26,122.44,122.06,114.24,111.33,111.02,106.00,104.69,95.44,83.72,56.83,42.86,41.18,34.13,26.44,26.36,25.63,22.79,18.93.
实施例23化合物F23的制备
1、中间产物(B23)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A2和醛G2(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝7.94(dd,J＝8.0,1.5Hz,1H),7.57–7.52(m,1H),7.32(d,J＝8.5Hz,1H),7.25–7.20(m,1H),6.80(dd,J＝10.0,1.5Hz,1H),5.59(dd,J＝10.0,3.5Hz,1H),5.24-5.17(m,1H),3.69(s,3H),1.52(d,J＝6.5Hz,3H).13C NMR(100MHz,CDCl3)δ＝160.97,155.77,139.41,130.96,123.13,122.30,121.76,119.39,115.83,114.06,106.58,73.15,29.30,21.45.
2、中间产物(D23)的制备：
按照实施例1制备中间产物D1的方法制备,收率为54％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.89(d,J＝8.0Hz,1H),7.53(t,J＝7.2Hz,1H),7.31(d,J＝8.4Hz,1H),7.20(t,J＝7.6Hz,1H),5.66–5.53(m,2H),3.96(t,J＝6.8Hz,2H),3.68(s,3H),3.54(dd,J＝14.0,7.2Hz,1H),2.11–1.95(m,4H),1.72(d,J＝5.2Hz,3H),1.37(s,3H).13C NMR(100MHz,CDCl3)δ＝162.62,155.06,138.93,133.15,130.38,125.07,122.86,121.48,116.49,113.78,108.65,78.47,58.74,43.35,39.92,32.35,29.23,23.17,18.08.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D23)。
3、中间产物(E23)的制备：
按照实施例1制备中间产物E1的方法制备,收率为87％。
4、产物(F23)的制备：
按照实施例1制备产物F1的方法制备,收率为65％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝8.40(dd,J＝15.0,3.0Hz,1H),8.08(td,J＝15.0,3.0Hz,1H),7.97(d,J＝21.8Hz,1H),7.86(dd,J＝15.0,3.1Hz,1H),7.59(td,J＝14.9,3.1Hz,1H),6.86(q,J＝30.2Hz,2H),6.57(s,1H),6.25(d,J＝21.8Hz,1H),5.68(dddd,J＝30.2,12.3,3.7,1.9Hz,1H),5.34(dqd,J＝30.0,12.6,1.8Hz,1H),4.01–3.87(m,7H),3.46(s,3H),1.89(dd,J＝24.8,17.3Hz,1H),1.71–1.57(m,4H),1.34(s,3H).13C NMR(125MHz,CDCl3)δ＝163.18,161.30,157.95,157.36,155.81,153.71,141.60,139.23,133.33,131.81,128.92,126.95,123.31,122.44,122.32,115.53,114.32,113.67,111.02,106.00,104.69,95.44,83.72,56.83,41.97,33.40,32.33,26.36,18.29.
实施例24化合物F24的制备
1、中间产物(B24)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A5和醛G3(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝7.97(d,J＝8.0Hz,1H),7.38(t,J＝7.5Hz,1H),7.30–7.26(m,2H),7.24–7.15(m,5H),6.91(d,J＝10.0Hz,1H),5.52(s,2H),5.42(d,J＝10.0Hz,1H),1.91-1.82(m,2H),1.77–1.38(m,2H),0.99(t,J＝7.0Hz,6H).13C NMR(100MHz,CDCl3)δ＝161.26,156.41,138.89,136.89,130.80,128.75,127.14,126.61,123.78,123.08,121.82,119.42,116.08,114.95,105.00,85.11,45.82,32.94,7.82.
2、中间产物(D24)的制备：
按照实施例1制备中间产物D1的方法制备,收率为58％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.91–7.86(m,1H),7.39–7.33(m,1H),7.28–7.23(m,2H),7.23–7.11(m,5H),5.53(s,2H),5.01(d,J＝8.4Hz,1H),3.97(t,J＝6.8Hz,2H),3.84(dd,J＝16.0,8.4Hz,1H),2.38–2.27(m,1H),2.26–2.17(m,1H),2.14–1.97(m,5H),1.87(dd,J＝14.0,8.8Hz,1H),1.43(s,3H),1.11(t,J＝7.6Hz,3H),0.99(t,J＝7.6Hz,3H).13CNMR(100MHz,CDCl3)δ＝162.59,155.12,142.51,138.32,137.03,130.25,128.65,126.97,126.49,125.29,122.80,121.49,116.69,114.66,109.62,78.49,58.86,45.58,43.47,39.91,28.69,28.48,23.59,23.24,13.32,12.74.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D24)。
3、中间产物(E24)的制备：
按照实施例1制备中间产物E1的方法制备,收率为86％。
4、产物(F24)的制备：
按照实施例1制备产物F1的方法制备,收率为66％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝8.40(dd,J＝14.9,3.1Hz,1H),7.97(d,J＝21.8Hz,1H),7.86(dd,J＝14.9,3.2Hz,1H),7.74(tt,J＝16.6,8.4Hz,1H),7.59(td,J＝14.9,3.2Hz,1H),7.37–7.22(m,5H),6.92(d,J＝30.2Hz,1H),6.57(s,1H),6.48(d,J＝30.2Hz,1H),6.25(d,J＝21.8Hz,1H),5.51–5.39(m,1H),4.94(s,2H),4.68(dt,J＝12.3,8.3Hz,1H),3.92(s,6H),2.50(qd,J＝13.4,2.0Hz,4H),1.92(dd,J＝24.8,8.3Hz,1H),1.64(dd,J＝24.8,8.3Hz,1H),1.34(s,3H),0.96(t,J＝13.4Hz,6H).13C NMR(125MHz,CDCl3)δ＝161.90,161.30,157.95,155.81,155.07,153.71,143.73,139.23,138.50,136.93,133.33,131.33,128.53,128.41,128.04,124.28,123.07,122.69,122.44,117.01,112.74,111.75,111.02,106.00,104.69,95.44,83.72,56.83,49.04,41.18,33.75,27.71,26.77,26.36,13.15.
实施例25化合物F25的制备
1、中间产物(B25)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A5和醛G4(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.96(dd,J＝8.0,1.2Hz,1H),7.41–7.35(m,1H),7.32–7.14(m,7H),6.86(d,J＝10.0Hz,1H),5.52(s,2H),5.44(d,J＝10.0Hz,1H),1.89–1.79(m,2H),1.73–1.65(m,2H),1.48–1.38(m,4H),1.37–1.26(m,4H),0.88(t,J＝7.2Hz,6H).13CNMR(100MHz,CDCl3)δ＝161.25,156.20,138.92,136.91,130.74,128.73,127.12,126.62,124.44,123.10,121.78,118.82,116.14,114.91,104.94,84.60,45.83,40.44,25.61,23.01,14.03.
2、中间产物(D25)的制备：
按照实施例1制备中间产物D1的方法制备,收率为62％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.88(dd,J＝8.0,1.2Hz,1H),7.39–7.32(m,1H),7.28–7.23(m,2H),7.22–7.10(m,5H),5.62(d,J＝12.8Hz,1H),5.41(d,J＝13.2Hz,1H),5.01(d,J＝8.8Hz,1H),3.97(t,J＝6.8Hz,2H),3.82(dd,J＝16.0,8.4Hz,1H),2.39–2.28(m,1H),2.18–2.06(m,3H),2.06–1.95(m,3H),1.86(dd,J＝14.0,9.2Hz,2H),1.60-1.52(m,1H),1.42(s,3H),1.41–1.22(m,8H),0.94(t,J＝7.2Hz,3H),0.86(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ＝162.48,155.01,139.88,138.33,137.04,130.20,128.61,126.94,126.66,126.49,122.75,121.44,116.66,114.61,109.62,78.46,58.82,45.56,43.53,39.90,36.21,30.79,30.33,30.31,28.55,23.20,23.06,22.42,14.13,14.08.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D25)。
3、中间产物(E25)的制备：
按照实施例1制备中间产物E1的方法制备,收率为87％。
4、产物(F25)的制备：
按照实施例1制备产物F1的方法制备,收率为62％。其表征数据为：
1H NMR(500MHz,CDCl3)δ＝8.40(dd,J＝14.9,3.1Hz,1H),7.97(d,J＝21.8Hz,1H),7.86(dd,J＝14.9,3.2Hz,1H),7.75(td,J＝14.9,3.0Hz,1H),7.59(td,J＝14.9,3.2Hz,1H),7.36–7.21(m,5H),6.92(d,J＝30.2Hz,1H),6.57(s,1H),6.40(d,J＝30.2Hz,1H),6.25(d,J＝21.8Hz,1H),5.54–5.45(m,1H),4.94(s,2H),4.84(dt,J＝12.3,8.2Hz,1H),3.92(s,6H),2.10(td,J＝15.1,1.9Hz,4H),1.92(dd,J＝24.8,8.1Hz,1H),1.64(dd,J＝24.7,8.2Hz,1H),1.47–1.18(m,11H),0.98–0.86(m,6H).13C NMR(125MHz,CDCl3)δ＝161.90,161.30,157.95,155.81,155.07,153.71,139.23,138.50,138.26,136.93,133.33,131.33,128.53,128.41,128.04,124.99,124.28,123.07,122.44,117.01,112.74,111.75,111.02,106.00,104.69,95.44,83.72,56.83,49.04,41.18,37.89,33.75,32.25,30.55,26.36,22.40,14.00.
实施例26化合物F26的制备
1、中间产物(B26)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A5和醛G5(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.90(dd,J＝8.0,1.6Hz,1H),7.41–7.35(m,1H),7.32–7.12(m,7H),6.83(d,J＝10.0Hz,1H),5.60(d,J＝10.0Hz,1H),5.54(s,2H),2.35–2.22(m,2H),2.07–1.98(m,2H),1.87–1.65(m,5H).13C NMR(100MHz,CDCl3)δ＝161.23,155.54,138.79,136.83,130.86,128.76,127.16,126.58,125.17,123.07,121.88,118.85,116.46,114.96,106.30,89.87,45.80,40.16,23.38.
2、中间产物(D26)的制备：
按照实施例1制备中间产物D1的方法制备,收率为52％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.90(d,J＝7.6Hz,1H),7.37(t,J＝8.0Hz,1H),7.29–7.23(m,3H),7.21–7.11(m,5H),5.53(dd,J＝24.4,13.6Hz,2H),5.25(d,J＝8.0Hz,1H),3.96(t,J＝6.8Hz,2H),3.69(dd,J＝16.0,6.4Hz,1H),2.62–2.49(m,1H),2.46–2.33(m,1H),2.27–2.19(m,2H),2.14–2.00(m,3H),1.90(dd,J＝14.0,8.8Hz,1H),1.76–1.59(m,4H),1.42(s,3H).13C NMR(100MHz,CDCl3)δ＝162.68,155.14,143.13,138.29,136.98,130.25,128.65,126.96,126.45,122.84,122.65,121.52,116.70,114.67,109.35,78.51,58.83,45.61,43.31,38.59,33.70,30.39,28.54,26.50,26.33,23.36.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D26)。
3、中间产物(E26)的制备：
按照实施例1制备中间产物E1的方法制备,收率为89％。
4、产物(F26)的制备：
按照实施例1制备产物F1的方法制备,收率为64％。其表征数据为：
1H NMR(500MHz,Chloroform)δ8.40(dd,J＝14.9,3.1Hz,1H),7.97(d,J＝21.8Hz,1H),7.86(dd,J＝14.9,3.2Hz,1H),7.75(td,J＝14.9,3.0Hz,1H),7.59(td,J＝14.9,3.2Hz,1H),7.38–7.21(m,5H),6.92(d,J＝30.2Hz,1H),6.57(s,1H),6.44(d,J＝30.2Hz,1H),6.25(d,J＝21.8Hz,1H),5.54–5.43(m,1H),4.97–4.84(m,3H),3.92(s,6H),2.30(td,J＝13.5,1.9Hz,4H),1.92(dd,J＝24.8,8.1Hz,1H),1.73–1.56(m,5H),1.34(s,3H).13C NMR(125MHz,CDCl3)δ＝161.90,161.30,157.95,155.81,155.07,153.71,141.34,139.23,138.50,136.93,133.33,131.33,128.53,128.41,128.04,124.28,123.07,122.44,119.28,117.01,112.74,111.75,111.02,106.00,104.69,95.44,83.72,56.83,49.04,41.18,35.20,33.75,32.63,26.36,25.75.
实施例27化合物F27的制备
1、中间产物(B27)的制备:
按照实施例1制备中间产物B1的方法制备，反应中加入喹啉酮A5和醛G6(底物的具体结构见表1)，收率为74％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝8.01(dd,J＝8.0,1.6Hz,1H),7.46–7.35(m,1H),7.33–7.15(m,7H),6.80(d,J＝10.0Hz,1H),5.64–5.45(m,3H),2.15–2.00(m,2H),1.87–1.82(m,2H),1.77–1.66(m,1H),1.66–1.55(m,5H).13C NMR(100MHz,CDCl3)δ＝161.23,155.55,138.92,136.87,130.86,128.75,127.15,126.62,126.25,123.14,121.90,118.41,116.53,114.99,106.34,79.78,45.80,36.25,25.25,21.04.
2、中间产物(D27)的制备：
按照实施例1制备中间产物D1的方法制备,收率为56％。其表征数据为：
1H NMR(400MHz,CDCl3)δ＝7.89(d,J＝8.0Hz,1H),7.37(t,J＝7.6Hz,1H),7.29–7.22(m,3H),7.22–7.12(m,5H),5.52(d,J＝13.2Hz,2H),5.07(d,J＝8.0Hz,1H),3.97(t,J＝6.8Hz,2H),3.85(dd,J＝16.0,8.4Hz,1H),2.41–2.32(m,1H),2.29–2.18(m,2H),2.12–2.06(m,3H),2.04–1.96(m,2H),1.91–1.84(m,1H),1.81–1.72(m,2H),1.68–1.56(m,4H),1.43(s,3H).13C NMR(100MHz,CDCl3)δ＝161.62,154.19,138.45,137.31,136.02,129.22,127.63,125.96,125.50,123.09,121.79,120.49,115.68,113.65,108.48,77.45,57.86,44.60,42.32,38.92,36.05,28.18,27.59,27.08,26.91,25.88,22.32.
若采用手性的催化剂1a或1b替换哌啶，按照相同的操作即可得到手性的中间产物(D27)。
3、中间产物(E27)的制备：
按照实施例1制备中间产物E1的方法制备,收率为86％。
4、产物(F27)的制备：
按照实施例1制备产物F1的方法制备,收率为62％。其表征数据为：
1H NMR(500MHz,Chloroform)δ8.40(dd,J＝14.9,3.1Hz,1H),7.97(d,J＝21.8Hz,1H),7.86(dd,J＝14.9,3.2Hz,1H),7.74(tt,J＝16.6,8.4Hz,1H),7.59(td,J＝14.9,3.2Hz,1H),7.37–7.23(m,5H),6.92(d,J＝30.2Hz,1H),6.57(s,1H),6.41(d,J＝30.2Hz,1H),6.25(d,J＝21.8Hz,1H),5.63–5.50(m,1H),4.94(s,2H),4.44(dt,J＝12.5,8.1Hz,1H),3.92(s,6H),2.37(td,J＝11.7,2.0Hz,4H),1.91(dd,J＝24.8,8.0Hz,1H),1.70–1.60(m,1H),1.59–1.48(m,7H),1.34(s,3H).13C NMR(125MHz,CDCl3)δ＝161.90,161.30,157.95,155.81,155.07,153.71,143.27,139.23,138.50,136.93,133.33,131.33,128.53,128.41,128.04,124.28,123.07,122.44,119.77,117.01,112.74,111.75,111.02,106.00,104.69,95.44,83.72,56.83,49.04,41.18,33.75,32.37,29.48,26.36,25.04,24.90.
表1.实施例1～27中制备中间产物(B)所加入的初始底物和醛。
实施例28目标分子生物活性评价
磷酸二酯酶4抑制活性测试方法
①磷酸二酯酶4抑制活性以PDE4D2催化域的抑制活性进行评价，以cAMP为底物，以Rolipram为阳性对照。
②将含有20mM Tris/HCl缓冲液(pH 7.5)、10mM MgCl2、1mM DTT和10–30nM特异性荧光底物3H-cAMP(20,000-30,000c.p.m./assay，GE Healthcare)的分析缓冲液和待测化合物在室温(25℃)下孵育15分钟。
③加入0.2M ZnSO4终止反应。用0.2M Ba(OH)2使反应产物3H-AMP沉淀析出，未反应的3H-cAMP留在上清液中。
④用液体闪烁计数仪(PerkinElmer 2910 liquid scintillation counter)测定上清液的放射性。
⑤对于IC50的测定，至少使用8种不同的待测化合物浓度。
⑥每次测量至少重复三次。采用非线性回归方法计算IC50值。
⑦磷酸二酯酶4抑制活性测试方法可参考：
a.J.Nat.Prod.2014,77,955-962
b.Eur.J.Med.Chem.2016,114,134-140.
c.Biochem.Pharmacol.2017,130,51-59.
⑧结果分析，结果如表2所示。
表2.目标分子生物活性评价表
以上生物活性结果表明，本发明中的分子对磷酸二酯酶4有较强的抑制效果，部分化合物达到纳摩尔水平的活性级别，远远大于阳性对照Rolipram。预示此类分子具有开发成新型磷酸二酯酶4抑制剂的潜力。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (10)
1.一种Toddacoumalone类化合物或其药学上可接受的盐，其特征在于，所述Toddacoumalone类化合物的分子结构通式为式I、式II、式III或式I、式II、式III各自结构通式的四种对映体，所示如下：
其中，R1选自氢，甲基，苯基或苄基；R2选自氢或烷烃；R3选自氢，卤素，三氟甲基，烷基，芳基或取代芳基；R4和R5独立地选自氢或烷基；M选自碳或氮；n＝0或1。
2.根据权利要求1所述的一种Toddacoumalone类化合物或其药学上可接受的盐，其特征在于，所述式I具有F1-F27所示的如下结构或如下结构式各自的4种对映体：
3.一种制备权利要求1或2所述Toddacoumalone类化合物或其药学上可接受的盐的方法，其特征在于，具体的步骤如下所示：
其中：R1，R2，R3，R4，R5，R6，M与权利要求1中所述一致；
(1)由喹啉酮类化合物A和不饱和醛G为起始原料，在碱1催化下，通过Knoevenagel缩合反应制备中间产物B；
(2)将溶剂2、催化剂1、添加剂1、步骤(1)所得中间产物B与异戊烯醛混合均匀，然后通过Diels-Alder反应制备乙醛类中间产物C；
(3)将步骤(2)所得中间产物C与还原剂1、溶剂3混合后，通过还原反应制备乙醇类中间产物D；
(4)将步骤(3)所得中间产物D和2-硝基苯基硒基氰酸酯溶于溶剂4后，加入催化剂2进行催化反应，得到硒化物，然后将硒化物溶于溶剂5中，与氧化剂1混合后，通过Grieco消除反应制备中间产物E；
(5)将步骤(4)所得中间产物E、碘代香豆素H、催化剂3、碱2与溶剂6混合均匀，通过Heck反应制备得到目标化合物F。
4.根据权利要求3所述的Toddacoumalone类化合物或其药学上可接受的盐的制备方法，其特征在于：
步骤(1)所述Knoevenagel缩合反应在溶剂1中进行；所述溶剂1包括但不限定为吡啶、甲苯、二氯甲烷、四氢呋喃、乙醇和甲醇中的至少一种；步骤(1)所述碱1包括但不限定为哌啶、四氢吡咯、吡啶、1,6-二甲基吡啶和吡咯中的至少一种；
步骤(1)所述喹啉酮类化合物A与不饱和醛G的摩尔比为5:5～5:10；步骤(1)所述碱1的用量满足每1mmol喹啉酮类化合物对应加入0.1～3mL的碱1；
步骤(1)所述Knoevenagel缩合反应为在60～130℃下回流反应0.5～5h。
5.根据权利要求3所述的Toddacoumalone类化合物或其药学上可接受的盐的制备方法，其特征在于：
步骤(2)所述的溶剂2包括但不限定为二氧六环、氯仿、乙腈、二氯甲烷和四氢呋喃中的至少一种；步骤(2)所述添加剂1包括但不限定为苯甲酸、水杨酸、乙酸、氯乙酸和邻硝基苯甲酸中的至少一种；步骤(2)所述的催化剂1包括但不限定为手性催化剂和非手性催化剂；其中非手性催化剂为哌啶、四氢吡咯和脯氨酸中的至少一种，手性催化剂为脯氨酸衍生的二级胺手性催化剂；
步骤(2)所述溶剂2的用量满足每1mmol的中间产物B对应加入250～2000μL溶剂2；步骤(2)所述中间产物B、异戊烯醛、添加剂1和催化剂1的摩尔比为1～3：1～6：0.1～0.5：0.1～0.5；
步骤(2)所述Diels-Alder反应的时间为12～72h。
6.根据权利要求3所述的Toddacoumalone类化合物或其药学上可接受的盐的制备方法，其特征在于：
步骤(3)所述溶剂3包括但不限定为乙醇、氯仿、甲醇、二氯甲烷和四氢呋喃中的至少一种；步骤(3)所述还原剂1包括但不限定为硼氢化钠、氰基硼氢化钠和四氢铝锂的至少一种；
步骤(3)所述溶剂3的用量满足每0.25mmol的中间产物B1对应加入250～2000μL溶剂3；步骤(3)所述反应物C与还原剂1的摩尔比为1：1.5～1：4；
步骤(3)所述还原反应为在冰浴下反应0.1～2h。
7.根据权利要求3所述的Toddacoumalone类化合物或其药学上可接受的盐的制备方法，其特征在于：
步骤(4)所述的溶剂4和溶剂5独立地包括但不限定为二氧六环、氯仿、乙醚、二氯甲烷和四氢呋喃中的至少一种；步骤(4)所述催化剂2为三正丁基磷；步骤(4)所述氧化剂1包括但不限定于过氧化氢和间氯过氧苯甲酸中的至少一种；
步骤(4)所述溶剂4的用量满足每0.1mmol的中间产物D对应加入5～20mL有机溶剂4；步骤(4)所述溶剂5的用量满足每1mg硒化物对应加入20～60μL溶剂5；步骤(4)所述中间产物D、2-硝基苯基硒基氰酸酯和催化剂2的摩尔比为0.1～0.3：0.2～0.6：0.2～0.6；步骤(4)所述氧化剂1的用量满足每1g硒化物对应加入500～650μL过氧化氢水溶液；
步骤(4)所述Grieco消除反应为在-40～10℃下反应5～48h。
8.根据权利要求3所述的Toddacoumalone类化合物或其药学上可接受的盐的制备方法，其特征在于：
步骤(5)所述溶剂6包括但不限定为二甲基甲酰胺、二甲基丙烯酰胺和二甲基亚砜中的至少一种；步骤(5)所述催化剂3为乙酸钯、氯化钯、四三苯基膦钯和二氯二三苯基膦钯中的至少一种；步骤(5)所述碱2为氢氧化锂、氢氧化镁、氢氧化铵、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾和三乙胺中的至少一种；步骤(5)还加入了添加剂2，所述添加剂2为四丁基溴化铵、苄基三乙基氯化铵和四丁基氯化铵中的至少一种；
步骤(5)所述中间产物E、碘代香豆素H、催化剂3和碱2的摩尔比为0.1～0.5：0.1～0.5：0.04～0.1：0.1～1；
步骤(5)所述添加剂2和碱2的摩尔比为0.1～0.5：0.1～1；
步骤(5)所述Heck反应为在60～120℃下反应10～36h。
9.根据权利要求1或2所述Toddacoumalone类化合物或其药学上可接受的盐在制备抗磷酸二酯酶4药物中的应用。
10.一种抗磷酸二酯酶4的组合物，其活性成分包括权利要求1或2所述的Toddacoumalone类化合物或其药学上可接受的盐。
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| CN114163446B (zh) * | 2021-12-16 | 2023-11-21 | 中山大学 | 一种喹啉酮骨架的pde4抑制剂及其制备方法与应用 |
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