CN109651404B - 一种氮杂环丙烷衍生物及其制备方法和应用 - Google Patents
一种氮杂环丙烷衍生物及其制备方法和应用 Download PDFInfo
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- CN109651404B CN109651404B CN201910078854.4A CN201910078854A CN109651404B CN 109651404 B CN109651404 B CN 109651404B CN 201910078854 A CN201910078854 A CN 201910078854A CN 109651404 B CN109651404 B CN 109651404B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 24
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 239000003208 petroleum Substances 0.000 claims description 10
- 238000006352 cycloaddition reaction Methods 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- CPPKAGUPTKIMNP-UHFFFAOYSA-N cyanogen fluoride Chemical compound FC#N CPPKAGUPTKIMNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 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
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
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- 238000007239 Wittig reaction Methods 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims description 2
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 claims description 2
- 150000002540 isothiocyanates Chemical class 0.000 claims description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 claims description 2
- KJTULOVPMGUBJS-UHFFFAOYSA-N tert-butyl-[tert-butyl(diphenyl)silyl]oxy-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C(C)(C)C)O[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 KJTULOVPMGUBJS-UHFFFAOYSA-N 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- LGSAOJLQTXCYHF-UHFFFAOYSA-N tri(propan-2-yl)-tri(propan-2-yl)silyloxysilane Chemical compound CC(C)[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)C(C)C LGSAOJLQTXCYHF-UHFFFAOYSA-N 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 4
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- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
- 150000001413 amino acids Chemical class 0.000 abstract 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- 239000003444 phase transfer catalyst Substances 0.000 abstract 1
- 125000003367 polycyclic group Chemical group 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 320
- 238000005160 1H NMR spectroscopy Methods 0.000 description 83
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 81
- 125000001424 substituent group Chemical group 0.000 description 75
- 239000000758 substrate Substances 0.000 description 74
- 238000003786 synthesis reaction Methods 0.000 description 74
- 230000015572 biosynthetic process Effects 0.000 description 73
- -1 dicarboxylamino Chemical group 0.000 description 14
- 239000003480 eluent Substances 0.000 description 8
- 125000001246 bromo group Chemical group Br* 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 4
- 150000001335 aliphatic alkanes Chemical group 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 238000010276 construction Methods 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000011630 iodine Chemical group 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 2
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 2
- 238000003476 Darzens condensation reaction Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- MSZDOMFSWXWKTK-UHFFFAOYSA-N chloro-[(2-methylpropan-2-yl)oxy]-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(OC(C)(C)C)C1=CC=CC=C1 MSZDOMFSWXWKTK-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
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- 125000003003 spiro group Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- GMKMEZVLHJARHF-UHFFFAOYSA-N (2R,6R)-form-2.6-Diaminoheptanedioic acid Natural products OC(=O)C(N)CCCC(N)C(O)=O GMKMEZVLHJARHF-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- 241000073677 Changea Species 0.000 description 1
- 108010001625 Diaminopimelate epimerase Proteins 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000810818 Streptomyces sahachiroi Species 0.000 description 1
- QIKVYJOCQXXRSJ-PKDLRSQSSA-N [(1s)-2-[[(1e)-1-[(1s,2r,3r)-3-acetyloxy-2-hydroxy-5-azabicyclo[3.1.0]hexan-4-ylidene]-2-[[(z)-1-hydroxy-3-oxobut-1-en-2-yl]amino]-2-oxoethyl]amino]-1-[(2s)-2-methyloxiran-2-yl]-2-oxoethyl] 3-methoxy-5-methylnaphthalene-1-carboxylate Chemical compound C[C@@]1([C@@H](C(=O)N\C(C(=O)N\C(=C/O)C(C)=O)=C/2N3C[C@H]3[C@@H](O)[C@@H]\2OC(C)=O)OC(=O)C=2C=C(C=C3C(C)=CC=CC3=2)OC)CO1 QIKVYJOCQXXRSJ-PKDLRSQSSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- QIKVYJOCQXXRSJ-UHFFFAOYSA-N azinomycin B Natural products C=12C=CC=C(C)C2=CC(OC)=CC=1C(=O)OC(C(=O)NC(C(=O)NC(=CO)C(C)=O)=C1N2CC2C(O)C1OC(C)=O)C1(C)CO1 QIKVYJOCQXXRSJ-UHFFFAOYSA-N 0.000 description 1
- 108010010082 azinomycin B Proteins 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- GMKMEZVLHJARHF-SYDPRGILSA-N meso-2,6-diaminopimelic acid Chemical compound [O-]C(=O)[C@@H]([NH3+])CCC[C@@H]([NH3+])C([O-])=O GMKMEZVLHJARHF-SYDPRGILSA-N 0.000 description 1
- 125000004492 methyl ester group Chemical group 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical group [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- IVZTVZJLMIHPEY-UHFFFAOYSA-N triphenyl(triphenylsilyloxy)silane Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C=1C=CC=CC=1)O[Si](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 IVZTVZJLMIHPEY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
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Abstract
本发明提供了一种氮杂环丙烷衍生物及其制备方法和应用，制备过程以磺内酰胺为底物，以季鏻盐为催化剂，发生环加成即得目标化合物。本发明所用催化剂为天然氨基酸衍生的手性季鏻盐相转移催化剂，催化剂廉价易得、对水和氧气稳定；本发明为构建多取代并环类和多取代螺环类的手性氮杂环丙烷衍生物提供了一种简单高效的新制备方法；本发明构建的手性氮杂环丙烷衍生物是一类具有潜在生物活性的重要杂环分子，同时获得的目标产物具有高度立体选择性。
Description
技术领域
本发明属于化工技术领域，具体涉及一种氮杂环丙烷衍生物及其制备方法和应用。
背景技术
氮杂环丙烷因其本身具有特别的化学与生物活性而被广泛应用于有机化学中，是一类重要的杂环结构。许多含有氮杂环丙烷结构的天然产物和合成化合物，都表现出了很好的生物活性。如从链霉菌属sahachiroi中提取的天然产物Azinomycin B，是一种重要的抗肿瘤抗生素；以α-(卤甲基)二氨基庚二酸为起始原料构建的含二羧基氨基的氮杂环丙烷化合物，是重要的二氨基庚二酸差向异构酶的抑制剂。在过去，化学家们以醛亚胺为底物通过Aza-Darzens反应一步构建氮杂环丙烷类化合物已见诸多报道，而以酮亚胺为底物一步构建氮杂环丙烷类化合物却鲜有报道。
发明内容
针对现有技术中存在的上述问题，本发明提供一种氮杂环丙烷衍生物及其制备方法和应用，本发明以环状醛亚胺为底物，通过Aza-Darzens反应，实现了磺内酰胺一步高效构建多取代氮杂环丙烷，同时通过环状酮亚胺首次实现了磺内酰胺一步高效构建多取代并环类和多取代螺环类氮杂环丙烷，同时获得的目标产物具有高度立体选择性。
为实现上述目的，本发明解决其技术问题所采用的技术方案是：
一种氮杂环丙烷衍生物，包括结构通式I及其相应的消旋体、对映体、非对映异构体和开环衍生物：
其中，化合物I中R1为氢、烷基、烷氧基、芳基或杂原子；R2为氢或拉电子取代基；R3为氢、烷基、烷氧基、芳基或杂原子；X为碳原子或杂原子；n为0、1、2、3、4、5。
进一步地，芳基为苯基、取代苯基(苯基上的氢被其他原子或基团取代)、联苯基，并苯基、杂芳基及取代杂芳基(杂芳基上的氢被其他原子或基团取代)；杂原子为NH2、OH、SH、NO2、卤素；拉电子取代基为甲酯、乙酯、异丙酯、丁酯、氰基、CF3。
进一步地，氮杂环丙烷衍生物的具体结构式为：
进一步地，开环衍生物的结构通式为：
进一步地，开环衍生物的具体结构式为：
上述氮杂环丙烷衍生物的制备方法，包括以下步骤：
将磺内酰胺和化合物2溶于有机溶剂中，然后加入碱和催化剂进行环加成反应，反应温度为25～40℃，反应时间为1～48h，制得氮杂环丙烷衍生物(化合物I)；其中，磺内酰胺和化合物2的摩尔比为1:1～3；磺内酰胺和碱的摩尔比为1:1-6；磺内酰胺和催化剂的摩尔比为1:0.01～0.2；化合物I在强酸或者强碱作用下可得到相应的开环衍生产物(化合物II)。
进一步地，磺内酰胺和化合物2的摩尔比为1:1.2；磺内酰胺和碱的摩尔比为1:2；磺内酰胺和催化剂的摩尔比为1:0.1，反应温度为25℃，反应时间为12h。
进一步地，有机溶剂为1,4-二氧六环、乙腈、甲醇、N,N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、四氢呋喃、乙醚、甲基叔丁基醚、二氯甲烷、二氯乙烷、三氯甲烷、甲苯、二甲苯、均三甲苯、氟苯、氯苯、石油醚、正己烷、正戊烷和正庚烷中的一种或几种。
进一步地，碱为NaOAc、NaHCO3、K3PO4、Na2CO3、Cs2CO3、LiOH、NaOH、KOH、CsOH·H2O、K3PO4·3H2O、K3PO4·7H2O、NEt3、DIPEA或DABCO。
进一步地，强酸为浓硫酸、浓盐酸、三氟乙酸；强碱为乙醇钠、乙醇钾、叔丁醇钾或正丁基锂。
进一步地，催化剂为季鏻盐催化剂，其结构式为：
其中，R1为甲基、异丙基、叔丁基、三甲基硅醚、三异丙基硅醚、叔丁基二甲基硅醚、叔丁基二苯基硅醚或三苯基硅醚；
R2为烷基、取代苄基(优选为苄基上的氢被烷基、烷氧基、氰基、氟、氯、溴、硝基、三氟甲基或三氟甲氧基取代)、萘、蒽、菲；
R3为氢、烷基、烷氧基、氰基、氟、氯、溴、硝基、三氟甲基、取代苯甲酰基、烷酰基、叔丁氧羰基、取代异硫氰酸酯；
R4为甲基、异丙基、叔丁基，取代芳基(优选为芳基上的氢被烷基、烷氧基、氰基、氟、氯、溴、硝基、三氟甲基或三氟甲氧基取代)；
X为氯、溴、碘、三氟甲磺酰基。
进一步地，上述催化剂的制备方法包括以下步骤：
在氮气保护下，将三价膦通过wittig反应，一步制得季鏻盐催化剂，R3和R4是制备三价膦过程中引入的取代基，三价膦的制备方法可通过以下两种通用合成路线合成：
按照上面的两种合成路线制得了相应的三价膦，然后按照以下步骤制备季鏻盐催化剂：
当X为卤素，R2为烷烃时，向氮气保护下的史莱克管中加入三价膦1mmol，卤代烷烃1.2mmol，二氯甲烷10mL，室温下反应4h，脱溶，少量甲苯洗涤，得到季鏻盐催化剂A1-A6；
当X为卤素，R2为取代苄基时，向氮气保护下的史莱克管中加入三价膦1mmol，卤代取代苄化物1.2mmol，甲苯10mL，回流反应4h，减压脱溶除掉部分溶剂，于2～8℃冰冻过夜，抽滤，少量甲苯洗涤，得到季鏻盐催化剂A1-A6；
当X为卤素，R2为烷烃时，向氮气保护下的史莱克管中加入三价膦1mmol，卤代烷烃1.2mmol，二氯甲烷10mL，室温下反应4h，脱溶，少量甲苯洗涤，得到季鏻盐催化剂B1-B8；
当X为卤素，R2为取代苄基时，向氮气保护下的史莱克管中加入三价膦1mmol，卤代取代苄化物1.2mmol，甲苯10mL，回流反应4h，减压脱溶除掉部分溶剂，于2～8℃冰冻过夜，抽滤，少量甲苯洗涤，得到季鏻盐催化剂B1-B8；
当X为其他基团时，将制得的A1-A6或B1-B8与含这些基团的盐按摩尔比为1:1溶于甲苯溶液中，室温反应0.5h，抽滤，洗涤，制得。
上述氮杂环丙烷衍生物在制备抗肿瘤药物、抗炎药物、转录酶抑制剂或拮抗剂中的应用。
本发明提供的氮杂环丙烷衍生物及其制备方法和应用，具有以下有益效果：
磺内酰胺是一类含磺酰胺官能团且结构独特的环状胺类化合物，很多具有显著的生理活性，如HIV-1转录酶抑制剂、5-羟色胺拮抗剂、抗肿瘤、抗炎等，此外，它们也是合成很多重要有机和药物分子的关键中间体。手性四取代的磺内酰胺通常难以构建，要获得高光学纯度更是挑战。本发明不但以环状醛亚胺为底物，通过Aza-Darzens反应，实现了磺内酰胺一步高效构建多取代氮杂环丙烷，同时通过环状酮亚胺首次实现了磺内酰胺一步高效构建多取代并环类和多取代螺环类氮杂环丙烷，同时获得的目标产物具有高度立体选择性。
本发明在合成过程中所用的催化剂是手性季鏻盐催化剂，该类催化剂对空气和水十分稳定，且具有良好的水溶性，对环境友好。
具体实施方式
实施例1
向反应管中加入18.1mg(0.1mmol)1-1，18.6mg(0.12mmol)2，27.6mg(0.2mmol)K2CO3和1mL二氯甲烷，加入5.7mg(0.01mmol)A2(R1为异丙基，R2为甲基，X为碘)，25℃下进行环加成反应，12h后停止反应，浓缩过柱，洗脱剂为石油醚：乙酸乙酯＝3:1(V/V)，得到27.8mg产物I1，收率93％。
I1的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.11-8.09(m,2H),7.67-7.63(m,2H),7.52(t,J＝7.7Hz,2H),7.44(s,1H),7.41(d,J＝8.1Hz,1H),4.57(d,J＝3.2Hz,1H),3.89(d,J＝3.2Hz,1H),2.49(s,3H)；13C NMR(100MHz,CDCl3)δ189.31,145.30,135.69,135.13,134.75,131.78,130.91,129.22,129.20,126.27,123.34,55.00,46.37,21.87.
实施例2
参照实施例1的合成方法，仅改变底物取代基，得到I2，收率96％。
I2的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.11-8.02(m,2H),7.65(d,J＝8.0Hz,1H),7.54-7.47(m,2H),7.46-7.36(m,2H),4.57(d,J＝3.1Hz,1H),3.82(d,J＝3.2Hz,1H),2.49(s,3H)；13C NMR(100MHz,CDCl3)δ188.27,145.39,141.48,135.55,133.38,131.87,130.80,130.62,129.60,126.30,123.37,54.96,46.27,21.88.
实施例3
参照实施例1的合成方法，仅改变底物取代基，得到I3，收率92％。
I3的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.74-7.68(m,1H),7.65(d,J＝8.0Hz,1H),7.61(dd,J＝2.4,1.7Hz,1H),7.44(s,1H),7.41(dd,J＝8.0,2.6Hz,2H),7.19(ddd,J＝8.3,2.6,0.9Hz,1H),4.57(d,J＝3.2Hz,1H),3.87(d,J＝3.9Hz,4H),2.49(s,3H)；13C NMR(100MHz,CDCl3)δ189.14,160.18,145.30,136.34,135.72,131.78,130.89,130.22,126.27,123.35,121.91,112.74,55.73,55.24,46.33,21.88.
实施例4
参照实施例1的合成方法，仅改变底物取代基，得到I4，收率90％。
I4的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.13-8.04(m,2H),7.77(dd,J＝8.5,4.6Hz,1H),7.70-7.61(m,1H),7.57-7.48(m,2H),7.38-7.28(m,2H),4.61(d,J＝3.2Hz,1H),3.95(d,J＝3.2Hz,1H)；13C NMR(100MHz,CDCl3)δ188.81,165.87(d,J＝257.2Hz),138.47(d,J＝10.0Hz),134.92,129.58,129.26,129.23,125.96(d,J＝10.2Hz),118.89(d,J＝24.2Hz),113.40(d,J＝24.7Hz),54.92,45.63(d,J＝2.6Hz).
实施例5
参照实施例1的合成方法，仅改变底物取代基，得到I5，收率96％。
I5的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.10(d,J＝7.4Hz,2H),7.77-7.62(m,3H),7.62-7.48(m,3H),4.61(d,J＝3.0Hz,1H),3.93(d,J＝3.2Hz,1H)；13C NMR(100MHz,CDCl3)δ188.77,140.68,137.29,134.93,132.16,131.41,129.28,129.24,126.31,124.82,54.90,45.74.
实施例6
参照实施例1的合成方法，仅改变底物取代基，得到I6，收率92％。
I6的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.16-8.08(m,2H),7.71-7.61(m,2H),7.52(dd,J＝10.6,4.8Hz,2H),7.14-7.03(m,2H),4.56(d,J＝3.2Hz,1H),3.92(d,J＝3.2Hz,1H),3.91(s,3H)；13C NMR(100MHz,CDCl3)δ189.23,164.10,137.93,134.97,134.68,129.15,129.10,125.13,124.90,117.49,109.90,56.09,54.76,45.91.
实施例7
参照实施例1的合成方法，仅改变底物取代基，得到I7，收率91％。
I7的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.79(dd,J＝7.9,1.0Hz,1H),7.50(ddd,J＝8.8,6.0,2.2Hz,2H),7.45-7.35(m,2H),7.32-7.23(m,1H),4.30(s,1H),3.58(ddd,J＝16.2,11.6,4.3Hz,1H),3.03(dt,J＝16.7,3.9Hz,1H),2.67-2.53(m,1H),2.51(s,3H),2.07(dt,J＝13.8,4.0Hz,1H)；13C NMR(100MHz,CDCl3)δ187.26,144.93,142.83,135.19,134.52,133.31,132.02,131.77,128.85,128.02,127.17,126.93,121.91,63.29,61.07,32.16,27.19,22.09.
实施例8
向反应管中加入23.9mg(0.1mmol)1-8，16.6mg(0.12mmol)2，27.6mg(0.2mmol)K2CO3和1mL二氯甲烷，加入6.8mg(0.01mmol)A3(R1为异丙基，R2为苄基，R3为3,5-双三氟甲基，X为溴)，25℃下进行环加成反应。12h后停止反应，浓缩过柱，洗脱剂为石油醚：乙酸乙酯＝3:1(V/V)，得到33.9mg产物I8，收率95％。
I8的核磁数据如下：
1H NMR(400MHz,CDCl 3):δ8.11-8.09(m,2H),7.98-7.98(m,1H),7.68-7.62(m,2H),7.55-7.51(m,2H),7.49-7.47(m,1H),3.95(s,1H),3.85(s,3H),2.53(s,3H)；13C NMR(100MHz,CDCl 3):δ187.91,164.03,145.61,134.62,134.56,133.64,132.13,130.21,129.04,128.95,127.23,123.02,59.41,53.53,53.44,21.81.
实施例9
参照实施例8的合成方法，仅改变底物的取代基，得到I9，收率90％。
I9的核磁数据如下：
1H NMR(400MHz,CDCl3):δ8.13-8.09(d,J＝8.3Hz,2H),7.68-7.65(m,3H),7.56-7.52(t,J＝7.6Hz,2H),7.15-7.13(d,J＝8.7Hz,1H),3.96(s,1H),3.94(s,3H),3.84(s,3H)；13C NMR(100MHz,CDCl3):δ188.05,164.21,164.13,136.19,134.76,134.53,129.17,129.08,124.61,124.52,118.33,110.84,59.52,56.1,53.43,52.96.
实施例10
参照实施例8的合成方法，仅改变底物的取代基，得到I10，收率94％。
I10的核磁数据如下：
1H NMR(400MHz,CDCl3):δ8.12-8.09(m,2H),7.97-7.92(dd,J＝2.2Hz,8.3Hz,1H),7.82-7.76(dd,J＝4.6Hz,8.3Hz,1H),7.68-7.64(m,1H),7.57-7.51(m,2H),7.38-7.36(m,1H),3.99(s,1H),3.87(s,3H)；13C NMR(100MHz,CDCl3):δ187.59,167.15,163.73,136.76,134.98,134.43,129.27,129.14,129.06,125.76,119.42,115.07,59.88,53.65,52.51.
实施例11
参照实施例8的合成方法，仅改变底物的取代基，得到I11，收率97％。
I11的核磁数据如下：
1H NMR(400MHz,CDCl3):δ8.11-8.06(m,3H),7.68-7.63(t,J＝7.3Hz,1H),7.59-7.52(m,4H),3.94(s,1H),3.84(s,3H),2.50(s,3H)；13C NMR(100MHz,CDCl3):δ188.01,164.17,142.39,135.16,134.73,134.68,133.21,130.63,129.18,129.03,126.75,123.22,59.79,53.53,53.41,21.37.
实施例12
参照实施例8的合成方法，仅改变底物的取代基，得到I11，收率93％。
I12的核磁数据如下：
1H NMR(400MHz,CDCl3):δ8.66(s,1H),8.33(s,1H),8.11-8.09(m,2H),8.05-8.01(m,2H),7.75-7.643(m,3H),7.55-7.51(m,2H),4.03(s,1H),3.88(s,3H)；13C NMR(100MHz,CDCl3):δ187.98,164.34,135.37,134.72,133.33,130.66,129.83,129.32,129.17,129.03,128.81,128.67,128.02,127.06,124.73,58.89,53.84,53.56.
实施例13
参照实施例8的合成方法，仅改变底物的取代基，得到I13，收率92％。
I13的核磁数据如下：
1H NMR(400MHz,CDCl3):δ8.22-8.20(m,1H),8.13-8.111(m,2H),7.73-7.71(d,J＝0.8Hz,2H),7.66-7.64(m,1H),7.55-7.51(m,2H),3.98(s,1H),3.86(s,3H),1.42(s,9H)；13CNMR(100MHz,CDCl3):δ188.11,164.28,158.86,134.62,134.60,133.54,130.18,129.13,128.96,128.87,123.74,122.83,59.55,53.53,53.31,35.67,31.08.
实施例14
参照实施例8的合成方法，仅改变底物的取代基，得到I14，收率92％。
I14的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.18(dd,J＝3.9,1.0Hz,1H),7.99(s,1H),7.81(dd,J＝4.9,1.0Hz,1H),7.65(d,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,1H),7.24(dd,J＝4.9,4.0Hz,1H),4.39-4.15(m,1H),3.78(s,1H),2.53(s,3H),1.23(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ180.61,163.53,145.68,141.29,136.54,135.88,133.93,132.26,130.38,129.02,127.71,123.17,61.26,59.95,53.04.
实施例15
向反应管中加入25.3mg(0.1mmol)1-15，23.9mg(0.12mmol)2，27.6mg(0.2mmol)K2CO3和1mL二氯甲烷，加入6.0mg(0.01mmol)A4(R1为异丙基，R2为苄基，R3为4-氟，X为溴)，25℃下进行环加成反应。12h后停止反应，浓缩过柱，洗脱剂为石油醚：乙酸乙酯＝3:1(V/V)，得到35.6mg产物I15，收率94％。
I15的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.17-8.06(m,2H),8.01(s,1H),7.71-7.61(m,2H),7.57-7.49(m,2H),7.46(d,J＝8.0Hz,1H),4.41-4.20(m,2H),3.90(s,1H),2.53(s,3H),1.25(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ188.20,163.96,145.86,135.03,134.98,134.25,132.43,130.74,129.53,129.36,127.75,123.42,63.39,60.11,53.80,22.23,14.12.
实施例16
参照实施例15的合成方法，仅改变底物的取代基，得到I16，收率92％。
I16的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.16-8.06(m,2H),7.72-7.62(m,3H),7.53(dd,J＝7.7Hz,J＝7.7Hz,2H),7.13(dd,J＝8.7,2.2Hz,1H),4.40-4.21(m,2H),3.94(s,3H),3.93(s,1H),1.26(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ188.09,164.39,163.79,136.50,134.82,134.78,129.39,129.17,124.80,124.77,118.47,111.11,63.21,59.92,56.28,53.08,13.92.
实施例17
参照实施例15的合成方法，仅改变底物的取代基，得到I17，收率95％。
I17的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.26(d,J＝1.7Hz,1H),8.14-8.07(m,2H),7.72(d,J＝8.3Hz,1H),7.70-7.62(m,2H),7.58-7.48(m,2H),4.45-4.18(m,2H),3.94(s,1H),1.26(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ187.48,163.26,141.04,135.64,135.00,134.54,131.90,131.66,129.35,129.25,127.83,124.60,63.52,59.95,52.90,13.90.
实施例18
参照实施例15的合成方法，仅改变底物的取代基，得到I18，收率96％。
I18的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.14-8.04(m,3H),7.70-7.61(m,1H),7.59-7.48(m,4H),4.41-4.19(m,2H),3.90(s,1H),2.49(s,3H),1.25(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.99,163.73,142.38,135.23,134.83,134.76,133.45,130.95,129.31,129.15,126.98,123.38,63.17,60.12,53.71,21.48,13.92.
实施例19
参照实施例15的合成方法，仅改变底物的取代基，得到I19，收率93％。
I19的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.32(d,J＝8.2Hz,1H),8.23-8.16(m,2H),8.17-8.11(m,2H),8.03(d,J＝8.2Hz,1H),7.82-7.62(m,3H),7.58-7.49(m,2H),4.44-4.25(m,2H),4.05(s,1H),1.28(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.89,163.63,135.21,134.87,134.82,134.48,133.43,129.86,129.35,129.18,129.00,128.76,126.42,122.91,122.31,63.32,60.84,53.77,13.95.
实施例20
参照实施例15的合成方法，仅改变底物的取代基，得到I20，收率97％。
I20的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.20(dd,J＝1.8Hz,J＝1.8Hz,1H),8.13-8.05(m,1H),7.99(s,1H),7.78(ddd,J＝8.0,1.9,0.9Hz,1H),7.66(d,J＝8.0Hz,1H),7.47(dd,J＝8.0,0.6Hz,1H),7.42(dd,J＝7.9Hz,J＝7.9Hz,1H),4.43-4.21(m,2H),3.85(s,1H),2.53(s,3H),1.27(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ186.97,163.55,145.79,137.62,136.40,133.76,132.35,131.98,130.75,130.37,128.08,127.58,123.47,123.25,63.35,59.47,53.59,22.06,13.94.
实施例21
参照实施例15的合成方法，仅改变底物的取代基，得到I21，收率94％。
I21的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.73-7.68(m,1H),7.65(d,J＝8.0Hz,1H),7.62(dd,J＝2.4,1.7Hz,1H),7.51-7.36(m,2H),7.19(ddd,J＝8.3,2.6,0.9Hz,1H),4.41-4.23(m,2H),3.89(s,1H),3.87(s,3H),2.53(s,3H),1.27(t,J＝7.2Hz,4H)；13C NMR(100MHz,CDCl3)δ187.77,163.76,160.13,145.67,136.00,134.07,132.22,130.49,130.19,127.55,123.19,122.04,121.95,112.81,63.18,60.03,55.74,53.58,22.03,13.94.
实施例22
参照实施例15的合成方法，仅改变底物的取代基，得到I22，收率95％。
I22的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.25(d,J＝8.2Hz,2H),8.00(s,1H),7.81(d,J＝8.3Hz,2H),7.67(d,J＝8.0Hz,1H),7.47(d,J＝8.1Hz,1H),4.40-4.17(m,2H),3.87(s,1H),2.54(s,3H),1.26(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.58,163.51,145.83,137.43,135.79(d,J＝32.9Hz),133.74,132.40,130.43,129.73,127.71,126.21(q,J＝3.7Hz),123.49(d,J＝273.1Hz),123.27,63.37,59.66,53.58,22.05,13.94.
实施例23
参照实施例15的合成方法，仅改变底物的取代基，得到I23，收率96％。
I23的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.17(d,J＝2.0Hz,1H),8.067.94(m,2H),7.64(dd,J＝12.8,8.2Hz,2H),7.47(d,J＝8.0Hz,1H),4.40-4.22(m,2H),3.81(s,1H),2.53(s,3H),1.27(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ186.31,163.45,145.83,139.64,134.27,134.05,133.69,132.39,131.33,131.01,130.33,128.45,127.66,123.25,63.38,59.39,53.53,22.05,13.95.
实施例24
参照实施例15的合成方法，仅改变底物的取代基，得到I24，收率93％。
I24的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.17(dd,J＝3.9,1.0Hz,1H),7.98(s,1H),7.80(dd,J＝4.9,1.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.45(d,J＝8.0Hz,1H),7.21(dd,J＝4.9,4.0Hz,1H),4.39-4.16(m,1H),3.79(s,1H),2.52(s,3H),1.22(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ180.60,163.50,145.67,141.28,136.53,135.88,133.91,132.27,130.37,129.01,127.70,123.16,63.26,59.85,53.34,22.02,13.81.
实施例25
向反应管中加入23.9mg(0.1mmol)1-25，27.0mg(0.12mmol)2，27.6mg(0.2mmol)K2CO3和1mL二氯甲烷，加入6.1mg(0.01mmol)A6(R1异丙基，R2甲基，R4为异丙基，X为碘)，25℃下进行环加成反应。12h后停止反应，浓缩过柱，洗脱剂为石油醚：乙酸乙酯＝3:1(V/V)，得到37.5mg产物I25，收率98％。
I25的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.98(d,J＝7.9Hz,1H),7.77-7.69(m,2H),7.677-7.59(m,2H),7.50(td,J＝7.6,1.2Hz,1H),7.32-7.21(m,2H),4.51-4.32(m,2H),3.60-3.44(m,1H),3.08(dt,J＝16.8,4.3Hz,1H),2.51(ddd,J＝13.9,10.8,4.4Hz,1H),2.24(dt,J＝13.7,4.3Hz,1H),1.40(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.08,164.34,142.81,137.86,134.56,133.70,133.21,131.65,130.80,128.85,128.00,127.16,126.77,122.15,64.81,63.36,61.11,32.00,27.18,14.34.
实施例26
参照实施例25的合成方法，仅改变底物的取代基，得到I26，收率97％。
I26的核磁数据如下：
1H NMR(400MHz,CDCl3)1H NMR(400MHz,CDCl3)δ7.89(d,J＝7.3Hz,1H),7.78(dd,J＝7.8,0.8Hz,1H),7.65(dd,J＝7.9Hz,J＝7.9Hz,1H),7.58-7.54(m,1H),7.52(td,J＝7.6,1.3Hz,1H),7.35-7.24(m,2H),4.50-4.35(m,2H),3.61-3.44(m,1H),3.09(dt,J＝16.8,4.2Hz,1H),2.52(ddd,J＝13.8,11.0,4.4Hz,1H),2.22(dt,J＝13.7,4.2Hz,1H),1.40(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ186.91,164.01,142.83,135.91,134.84,134.70,134.32,133.11,131.48,129.46,128.86,128.20,127.28,125.00,64.94,63.54,60.05,32.04,27.16,14.34.
实施例27
参照实施例25的合成方法，仅改变底物的取代基，得到I27，收率95％。
I27的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.83(d,J＝8.0Hz,1H),7.75(dd,J＝7.9,1.0Hz,1H),7.56-7.46(m,2H),7.44(s,1H),7.32-7.21(m,2H),4.51-4.29(m,2H),3.63-3.39(m,1H),3.08(dt,J＝16.8,4.4Hz,1H),2.56-2.40(m,4H),2.24(dt,J＝13.7,4.4Hz,1H),1.39(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.22,164.47,142.83,141.66,137.98,134.79,134.51,133.27,128.84,128.81,127.98,127.13,126.36,122.21,64.72,63.26,61.03,31.99,27.18,21.54,14.33.
实施例28
参照实施例25的合成方法，仅改变底物的取代基，得到I28，收率89％。
I28的核磁数据如下：
1H NMR(400MHz,CDCl3)7.96(d,J＝1.5Hz,1H),7.75(dd,J＝7.9,1.0Hz,1H),7.65(dd,J＝8.3,1.6Hz,1H),7.56(d,J＝8.3Hz,1H),7.49(td,J＝7.6,1.3Hz,1H),7.31-7.21(m,2H),4.58-4.30(m,2H),3.63-3.45(m,1H),3.07(dt,J＝16.8,4.2Hz,1H),2.51(ddd,J＝13.7,11.0,4.4Hz,1H),2.21(dt,J＝13.7,4.2Hz,1H),1.44-1.37(m,12H)；13C NMR(100MHz,CDCl3)δ187.14,164.51,158.08,142.77,135.01,134.43,133.34,131.79,128.84,128.29,127.99,127.09,123.40,121.67,64.77,63.20,61.27,35.70,32.08,31.32,27.20,14.37.
实施例29
参照实施例25的合成方法，仅改变底物的取代基，得到I29，收率86％。
I29的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.16(d,J＝1.3Hz,1H),7.83(dd,J＝8.1,1.5Hz,1H),7.77(dd,J＝7.9,1.0Hz,1H),7.70(d,J＝8.1Hz,1H),7.68-7.62(m,2H),7.55-7.41(m,4H),7.34-7.23(m,2H),4.54-4.33(m,2H),3.64-3.45(m,1H),3.10(dt,J＝16.8,4.4Hz,1H),2.53(ddd,J＝13.9,10.7,4.4Hz,1H),2.26(dt,J＝13.7,4.3Hz,1H),1.41(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.06,164.47,147.19,142.83,139.13,136.51,134.58,133.26,132.45,129.85,129.23,128.92,128.87,128.07,127.72,127.21,125.13,122.39,64.78,63.40,61.07,32.10,27.22,14.40.
实施例30
参照实施例25的合成方法，仅改变底物的取代基，得到I30，收率93％。
I30的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.77(dd,J＝7.9,1.1Hz,1H),7.53(d,J＝8.6Hz,1H),7.49(dd,J＝7.5,1.3Hz,1H),7.43(d,J＝2.3Hz,1H),7.32-7.21(m,2H),7.10(dd,J＝8.7,2.3Hz,1H),4.55-4.29(m,2H),3.92(s,3H),3.62-3.45(m,1H),3.06(dt,J＝16.8,4.1Hz,1H),2.51(ddd,J＝13.6,11.3,4.4Hz,1H),2.17(dt,J＝13.6,4.0Hz,1H),1.40(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.25,164.46,164.16,142.80,134.51,133.36,129.64,128.87,128.01,127.18,123.54,117.41,110.98,64.73,63.32,60.64,56.07,32.09,27.20,14.37.
实施例31
参照实施例25的合成方法，仅改变底物的取代基，得到I31，收率92％。
I31的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.39(s,1H),8.19(s,1H),8.04-7.91(m,2H),7.71(dd,J＝7.9,1.0Hz,1H),7.69-7.59(m,2H),7.49(td,J＝7.5,1.3Hz,1H),7.29(d,J＝7.6Hz,1H),7.23(dd,J＝7.6Hz,J＝7.6Hz,1H),4.54-4.37(m,2H),3.57-3.42(m,1H),3.12(dt,J＝16.7,4.7Hz,1H),2.53(ddd,J＝14.3,10.2,4.3Hz,1H),2.31(dt,J＝9.5,4.5Hz,1H),1.42(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.05,164.67,142.96,135.92,135.42,134.61,133.36,133.06,129.59,129.23,128.87,128.82,128.30,128.03,127.16,126.67,126.35,122.57,63.54,63.37,61.27,32.16,27.10,14.37.
实施例32
参照实施例25的合成方法，仅改变底物的取代基，得到I61，收率95％。
I61的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.71(d,J＝2.3Hz,1H),7.53(d,J＝8.0Hz,1H),7.47-7.39(m,2H),7.24(d,J＝8.0Hz,1H),4.49-4.32(m,2H),3.58-3.38(m,1H),3.04(dt,J＝16.9,4.1Hz,1H),2.58-2.41(m,4H),2.17(dt,J＝13.7,4.1Hz,1H),1.39(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ186.43,164.30,145.12,141.03,134.92,134.42,134.41,133.50,131.90,130.42,127.62,126.97,122.01,64.20,63.38,61.01,31.88,26.66,22.09,14.34.
实施例33
参照实施例25的合成方法，仅改变底物的取代基，得到I62，收率96％。
I62的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.57(s,1H),7.53(d,J＝8.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.31(d,J＝7.7Hz,1H),7.17(d,J＝7.8Hz,1H),4.54-4.30(m,2H),3.57-3.36(m,1H),3.03(dt,J＝16.6,4.1Hz,1H),2.61-2.40(m,4H),2.27(s,3H),2.17(dt,J＝13.5,4.0Hz,1H),1.39(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.43,164.56,144.90,140.04,136.92,135.63,135.21,133.09,132.10,131.74,128.76,128.06,126.94,121.88,64.76,63.27,61.09,32.32,26.79,22.08,21.01,14.36.
实施例34
参照实施例25的合成方法，仅改变底物的取代基，得到I63，收率91％。
I63的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.53(d,J＝8.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.24-7.15(m,2H),7.08(dd,J＝8.5,2.8Hz,1H),4.56-4.26(m,2H),3.72(s,3H),3.56-3.35(m,1H),3.00(dt,J＝16.5,4.2Hz,1H),2.65-2.4438(m,4H),2.17(dt,J＝13.6,4.2Hz,1H),1.39(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.18,164.51,158.64,144.90,135.67,135.26,134.03,132.04,131.76,130.05,126.92,123.32,121.87,109.60,64.59,63.29,61.07,55.57,32.52,26.39,22.08,14.34.
实施例35
参照实施例25的合成方法，仅改变底物的取代基，得到I64，收率96％。
I64的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.57(d,J＝2.4Hz,1H),8.32(dd,J＝8.5,2.4Hz,1H),7.78(s,1H),7.50(dt,J＝16.6,8.0Hz,3H),4.52-4.34(m,2H),3.76-3.55(m,1H),3.20(dt,J＝17.5,3.8Hz,1H),2.62-2.45(m,4H),2.22(dt,J＝13.9,3.9Hz,1H),1.40(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ186.03,164.08,148.97,147.35,145.39,134.59,134.14,132.11,131.84,130.44,128.12,127.09,123.21,122.23,63.84,63.53,60.99,31.28,27.37,22.12,14.35.
实施例36
参照实施例25的合成方法，仅改变底物的取代基，得到I65，收率91％。
I65的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.60(d,J＝8.5Hz,1H),7.52(d,J＝8.0Hz,1H),7.48(s,1H),7.45-7.35(m,2H),4.48-4.34(m,2H),3.58-3.47(m,1H),3.04(dt,J＝17.0,4.1Hz,1H),2.55-2.42(m,4H),2.17(dt,J＝13.7,4.1Hz,1H),1.39(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ186.62,164.34,145.07,144.34,135.00,132.15,131.93,131.85,131.83,130.73,129.98,129.53,126.94,121.99,64.29,63.37,61.03,31.83,26.94,22.08,14.34.
实施例37
参照实施例25的合成方法，仅改变底物的取代基，得到I66，收率93％。
I66的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.51(d,J＝8.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.35(d,J＝7.3Hz,1H),7.22(t,J＝8.0Hz,1H),7.03(d,J＝7.6Hz,1H),4.57-4.32(m,2H),3.87(s,3H),3.27-3.11(m,2H),2.56-2.35(m,4H),2.19(dt,J＝13.8,4.3Hz,1H),1.40(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.52,164.56,156.72,144.89,135.01,134.37,132.12,131.90,131.74,127.52,126.96,121.93,119.39,115.24,64.74,63.28,60.83,55.85,31.16,22.09,20.96,14.37.
实施例38
参照实施例25的合成方法，仅改变底物的取代基，得到I67，收率88％。
I67的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.72-7.62(m,2H),7.59(d,J＝8.0Hz,1H),7.55-7.47(m,1H),7.45(d,J＝8.0Hz,1H),7.09-6.92(m,2H),4.59(s,2H),4.51-4.32(m,2H),2.48(s,3H),1.40(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ181.59,163.79,161.03,144.95,137.16,135.60,132.29,130.09,127.87,127.41,122.42,122.01,121.58,118.20,70.33,63.71,59.13,58.53(d,J＝18.7Hz),22.02,14.26.
实施例39
参照实施例25的合成方法，仅改变底物的取代基，得到I68，收率92％。
I68的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.51(d,J＝8.0Hz,1H),7.44(s,1H),7.40(d,J＝8.0Hz,1H),7.20(s,1H),4.50-4.35(m,2H),3.31-3.20(m,1H),2.99(dt,J＝17.0,4.3Hz,1H),2.53-2.42(m,4H),2.29(s,3H),2.25-2.16(m,4H),1.40(t,J＝7.1Hz,3H)；13CNMR(100MHz,CDCl3)δ187.72,164.64,148.27,144.87,138.32,137.15,136.40,135.07,133.49,132.20,131.71,126.99,125.95,121.91,64.68,63.24,60.89,31.34,24.07,22.08,20.91,19.42,14.37.
实施例40
参照实施例25的合成方法，仅改变底物的取代基，得到I69，收率92％。
I69的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.66(s,1H),7.49(d,J＝8.0Hz,1H),7.43(td,J＝7.5,1.4Hz,1H),7.40-7.33(m,2H),7.24(d,J＝7.4Hz,1H),7.16(dd,J＝8.0Hz,J＝8.0Hz,1H),4.53-4.28(m,2H),3.59(ddd,J＝15.6,11.2,4.5Hz,1H),2.98(dt,J＝15.5,4.7Hz,1H),2.45(s,3H),2.32-1.84(m,4H),1.39(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ192.62,164.87,145.03,141.97,136.53,134.09,133.62,132.99,131.66,130.54,129.50,127.47,126.62,122.00,68.71,63.22,60.46,31.27,28.73,22.59,22.02,14.36.
实施例41
向反应管中加入18.1mg(0.1mmol)1-1，18.6mg(0.12mmol)2，42.4mg(0.2mmol)K3PO4和1mL甲苯，加入8.8mg(0.01mmol)B2(R1为叔丁基二甲基硅醚，R2为苄基，R3为叔丁氧羰基，X为溴)，25℃下进行环加成反应。12h后停止反应，浓缩过柱，洗脱剂为石油醚：乙酸乙酯＝3:1(V/V)，得到27.2mg产物I70，收率91％，94％ee。
I70的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.11-8.09(m,2H),7.67-7.63(m,2H),7.52(t,J＝7.7Hz,2H),7.44(s,1H),7.41(d,J＝8.1Hz,1H),4.57(d,J＝3.2Hz,1H),3.89(d,J＝3.2Hz,1H),2.49(s,3H)；13C NMR(100MHz,CDCl3)δ189.31,145.30,135.69,135.13,134.75,131.78,130.91,129.22,129.20,126.27,123.34,55.00,46.37,21.87.
实施例42
参照实施例41的合成方法，仅改变底物取代基，得到I71，收率93％，98％ee。
I71的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.11-8.02(m,2H),7.65(d,J＝8.0Hz,1H),7.54-7.47(m,2H),7.46-7.36(m,2H),4.57(d,J＝3.1Hz,1H),3.82(d,J＝3.2Hz,1H),2.49(s,3H)；13C NMR(100MHz,CDCl3)δ188.27,145.39,141.48,135.55,133.38,131.87,130.80,130.62,129.60,126.30,123.37,54.96,46.27,21.88.
实施例43
参照实施例41的合成方法，仅改变底物取代基，得到I72，收率92％，90％ee。
I72的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.74-7.68(m,1H),7.65(d,J＝8.0Hz,1H),7.61(dd,J＝2.4,1.7Hz,1H),7.44(s,1H),7.41(dd,J＝8.0,2.6Hz,2H),7.19(ddd,J＝8.3,2.6,0.9Hz,1H),4.57(d,J＝3.2Hz,1H),3.87(d,J＝3.9Hz,4H),2.49(s,3H)；13C NMR(100MHz,CDCl3)δ189.14,160.18,145.30,136.34,135.72,131.78,130.89,130.22,126.27,123.35,121.91,112.74,55.73,55.24,46.33,21.88.
实施例44
参照实施例41的合成方法，仅改变底物取代基，得到I73，收率95％，90％ee。
I73的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.13-8.04(m,2H),7.77(dd,J＝8.5,4.6Hz,1H),7.70-7.61(m,1H),7.57-7.48(m,2H),7.38-7.28(m,2H),4.61(d,J＝3.2Hz,1H),3.95(d,J＝3.2Hz,1H)；13C NMR(100MHz,CDCl3)δ188.81,165.87(d,J＝257.2Hz),138.47(d,J＝10.0Hz),134.92,129.58,129.26,129.23,125.96(d,J＝10.2Hz),118.89(d,J＝24.2Hz),113.40(d,J＝24.7Hz),54.92,45.63(d,J＝2.6Hz).
实施例45
参照实施例41的合成方法，仅改变底物取代基，得到I74，收率97％，85％ee。
I74的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.10(d,J＝7.4Hz,2H),7.77-7.62(m,3H),7.62-7.48(m,3H),4.61(d,J＝3.0Hz,1H),3.93(d,J＝3.2Hz,1H)；13C NMR(100MHz,CDCl3)δ188.77,140.68,137.29,134.93,132.16,131.41,129.28,129.24,126.31,124.82,54.90,45.74.
实施例46
参照实施例41的合成方法，仅改变底物取代基，得到I75，收率94％，98％ee。
I75的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.16-8.08(m,2H),7.71-7.61(m,2H),7.52(dd,J＝10.6,4.8Hz,2H),7.14-7.03(m,2H),4.56(d,J＝3.2Hz,1H),3.92(d,J＝3.2Hz,1H),3.91(s,3H)；13C NMR(100MHz,CDCl3)δ189.23,164.10,137.93,134.97,134.68,129.15,129.10,125.13,124.90,117.49,109.90,56.09,54.76,45.91.
实施例47
参照实施例41的合成方法，仅改变底物取代基，得到I76，收率90％，91％ee。
I76的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.79(dd,J＝7.9,1.0Hz,1H),7.50(ddd,J＝8.8,6.0,2.2Hz,2H),7.45-7.35(m,2H),7.32-7.23(m,1H),4.30(s,1H),3.58(ddd,J＝16.2,11.6,4.3Hz,1H),3.03(dt,J＝16.7,3.9Hz,1H),2.67-2.53(m,1H),2.51(s,3H),2.07(dt,J＝13.8,4.0Hz,1H)；13C NMR(100MHz,CDCl3)δ187.26,144.93,142.83,135.19,134.52,133.31,132.02,131.77,128.85,128.02,127.17,126.93,121.91,63.29,61.07,32.16,27.19,22.09.
实施例48
向反应管中加入23.9mg(0.1mmol)1-8，16.6mg(0.12mmol)2，42.4mg(0.2mmol)K3PO4和1mL甲苯，加入9.0mg(0.01mmol)B7(R1为叔丁基二苯基氯硅醚，R2为苄基，R3为叔丁氧羰基，X为溴)，25℃下进行环加成反应。12h后停止反应，浓缩过柱，洗脱剂为石油醚：乙酸乙酯＝3:1(V/V)，得到33.9mg产物I77，收率95％，94％ee。
I77的核磁数据如下：
1H NMR(400MHz,CDCl 3):δ8.11-8.09(m,2H),7.98-7.98(m,1H),7.68-7.62(m,2H),7.55-7.51(m,2H),7.49-7.47(m,1H),3.95(s,1H),3.85(s,3H),2.53(s,3H)；13C NMR(100MHz,CDCl 3):δ187.91,164.03,145.61,134.62,134.56,133.64,132.13,130.21,129.04,128.95,127.23,123.02,59.41,53.53,53.44,21.81.
实施例49
参照实施例48的合成方法，仅改变底物的取代基，得到I78，收率93％，95％ee。
I78的核磁数据如下：
1H NMR(400MHz,CDCl3):δ8.13-8.09(d,J＝8.3Hz,2H),7.68-7.65(m,3H),7.56-7.52(t,J＝7.6Hz,2H),7.15-7.13(d,J＝8.7Hz,1H),3.96(s,1H),3.94(s,3H),3.84(s,3H)；13C NMR(100MHz,CDCl3):δ188.05,164.21,164.13,136.19,134.76,134.53,129.17,129.08,124.61,124.52,118.33,110.84,59.52,56.1,53.43,52.96.
实施例50
参照实施例48的合成方法，仅改变底物的取代基，得到I79，收率93％，91％ee。
I79的核磁数据如下：
1H NMR(400MHz,CDCl3):δ8.12-8.09(m,2H),7.97-7.92(dd,J＝2.2Hz,8.3Hz,1H),7.82-7.76(dd,J＝4.6Hz,8.3Hz,1H),7.68-7.64(m,1H),7.57-7.51(m,2H),7.38-7.36(m,1H),3.99(s,1H),3.87(s,3H)；13C NMR(100MHz,CDCl3):δ187.59,167.15,163.73,136.76,134.98,134.43,129.27,129.14,129.06,125.76,119.42,115.07,59.88,53.65,52.51.
实施例51
参照实施例48的合成方法，仅改变底物的取代基，得到I80，收率98％，98％ee。
I80的核磁数据如下：
1H NMR(400MHz,CDCl3):δ8.11-8.06(m,3H),7.68-7.63(t,J＝7.3Hz,1H),7.59-7.52(m,4H),3.94(s,1H),3.84(s,3H),2.50(s,3H)；13C NMR(100MHz,CDCl3):δ188.01,164.17,142.39,135.16,134.73,134.68,133.21,130.63,129.18,129.03,126.75,123.22,59.79,53.53,53.41,21.37.
实施例52
参照实施例48的合成方法，仅改变底物的取代基，得到I81，收率92％，96％ee。
I81的核磁数据如下：
1H NMR(400MHz,CDCl3):δ8.66(s,1H),8.33(s,1H),8.11-8.09(m,2H),8.05-8.01(m,2H),7.75-7.643(m,3H),7.55-7.51(m,2H),4.03(s,1H),3.88(s,3H)；13C NMR(100MHz,CDCl3):δ187.98,164.34,135.37,134.72,133.33,130.66,129.83,129.32,129.17,129.03,128.81,128.67,128.02,127.06,124.73,58.89,53.84,53.56.
实施例53
参照实施例48的合成方法，仅改变底物的取代基，得到I82，收率90％，93％ee。
I82的核磁数据如下：
1H NMR(400MHz,CDCl3):δ8.22-8.20(m,1H),8.13-8.111(m,2H),7.73-7.71(d,J＝0.8Hz,2H),7.66-7.64(m,1H),7.55-7.51(m,2H),3.98(s,1H),3.86(s,3H),1.42(s,9H)；13CNMR(100MHz,CDCl3):δ188.11,164.28,158.86,134.62,134.60,133.54,130.18,129.13,128.96,128.87,123.74,122.83,59.55,53.53,53.31,35.67,31.08.
实施例54
参照实施例48的合成方法，仅改变底物的取代基，得到I83，收率95％，98％ee。
I83的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.18(dd,J＝3.9,1.0Hz,1H),7.99(s,1H),7.81(dd,J＝4.9,1.0Hz,1H),7.65(d,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,1H),7.24(dd,J＝4.9,4.0Hz,1H),4.39-4.15(m,1H),3.78(s,1H),2.53(s,3H),1.23(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ180.61,163.53,145.68,141.29,136.54,135.88,133.93,132.26,130.38,129.02,127.71,123.17,61.26,59.95,53.04.
实施例55
向反应管中加入25.3mg(0.1mmol)1-15，23.9mg(0.12mmol)2，42.4mg(0.2mmol)K3PO4和1mL甲苯，加入10.1mg(0.01mmol)B3(R1叔丁基二苯基氯硅醚，R2为3,5-二叔丁基取代苄基，R3为叔丁氧羰基，X为溴)，25℃下进行环加成反应。12h后停止反应，浓缩过柱，洗脱剂为石油醚：乙酸乙酯＝3:1(V/V)，得到34.5mg产物I84，收率93％，99.2％ee。
I84的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.17-8.06(m,2H),8.01(s,1H),7.71-7.61(m,2H),7.57-7.49(m,2H),7.46(d,J＝8.0Hz,1H),4.41-4.20(m,2H),3.90(s,1H),2.53(s,3H),1.25(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ188.20,163.96,145.86,135.03,134.98,134.25,132.43,130.74,129.53,129.36,127.75,123.42,63.39,60.11,53.80,22.23,14.12.
实施例56
参照实施例55的合成方法，仅改变底物的取代基，得到I85，收率90％，98％ee。
I85的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.16-8.06(m,2H),7.72-7.62(m,3H),7.53(dd,J＝7.7Hz,J＝7.7Hz,2H),7.13(dd,J＝8.7,2.2Hz,1H),4.40-4.21(m,2H),3.94(s,3H),3.93(s,1H),1.26(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ188.09,164.39,163.79,136.50,134.82,134.78,129.39,129.17,124.80,124.77,118.47,111.11,63.21,59.92,56.28,53.08,13.92.
实施例57
参照实施例55的合成方法，仅改变底物的取代基，得到I86，收率96％，99％ee。
I86的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.26(d,J＝1.7Hz,1H),8.14-8.07(m,2H),7.72(d,J＝8.3Hz,1H),7.70-7.62(m,2H),7.58-7.48(m,2H),4.45-4.18(m,2H),3.94(s,1H),1.26(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ187.48,163.26,141.04,135.64,135.00,134.54,131.90,131.66,129.35,129.25,127.83,124.60,63.52,59.95,52.90,13.90.
实施例58
参照实施例55的合成方法，仅改变底物的取代基，得到I87，收率94％，87％ee。
I87的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.14-8.04(m,3H),7.70-7.61(m,1H),7.59-7.48(m,4H),4.41-4.19(m,2H),3.90(s,1H),2.49(s,3H),1.25(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.99,163.73,142.38,135.23,134.83,134.76,133.45,130.95,129.31,129.15,126.98,123.38,63.17,60.12,53.71,21.48,13.92.
实施例59
参照实施例55的合成方法，仅改变底物的取代基，得到I88，收率87％，92％ee。
I88的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.32(d,J＝8.2Hz,1H),8.23-8.16(m,2H),8.17-8.11(m,2H),8.03(d,J＝8.2Hz,1H),7.82-7.62(m,3H),7.58-7.49(m,2H),4.44-4.25(m,2H),4.05(s,1H),1.28(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.89,163.63,135.21,134.87,134.82,134.48,133.43,129.86,129.35,129.18,129.00,128.76,126.42,122.91,122.31,63.32,60.84,53.77,13.95.
实施例60
参照实施例55的合成方法，仅改变底物的取代基，得到I89，收率96％，97％ee。
I89的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.20(dd,J＝1.8Hz,J＝1.8Hz,1H),8.13-8.05(m,1H),7.99(s,1H),7.78(ddd,J＝8.0,1.9,0.9Hz,1H),7.66(d,J＝8.0Hz,1H),7.47(dd,J＝8.0,0.6Hz,1H),7.42(dd,J＝7.9Hz,J＝7.9Hz,1H),4.43-4.21(m,2H),3.85(s,1H),2.53(s,3H),1.27(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ186.97,163.55,145.79,137.62,136.40,133.76,132.35,131.98,130.75,130.37,128.08,127.58,123.47,123.25,63.35,59.47,53.59,22.06,13.94.
实施例61
参照实施例55的合成方法，仅改变底物的取代基，得到I90，收率92％，99.55％ee。
I90的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.73-7.68(m,1H),7.65(d,J＝8.0Hz,1H),7.62(dd,J＝2.4,1.7Hz,1H),7.51-7.36(m,2H),7.19(ddd,J＝8.3,2.6,0.9Hz,1H),4.41-4.23(m,2H),3.89(s,1H),3.87(s,3H),2.53(s,3H),1.27(t,J＝7.2Hz,4H)；13C NMR(100MHz,CDCl3)δ187.77,163.76,160.13,145.67,136.00,134.07,132.22,130.49,130.19,127.55,123.19,122.04,121.95,112.81,63.18,60.03,55.74,53.58,22.03,13.94.
实施例62
参照实施例55的合成方法，仅改变底物的取代基，得到I91，收率93％，99.2％ee。
I91的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.25(d,J＝8.2Hz,2H),8.00(s,1H),7.81(d,J＝8.3Hz,2H),7.67(d,J＝8.0Hz,1H),7.47(d,J＝8.1Hz,1H),4.40-4.17(m,2H),3.87(s,1H),2.54(s,3H),1.26(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.58,163.51,145.83,137.43,135.79(d,J＝32.9Hz),133.74,132.40,130.43,129.73,127.71,126.21(q,J＝3.7Hz),123.49(d,J＝273.1Hz),123.27,63.37,59.66,53.58,22.05,13.94.
实施例63
参照实施例55的合成方法，仅改变底物的取代基，得到I92，收率97％，99％。
I92的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.17(d,J＝2.0Hz,1H),8.067.94(m,2H),7.64(dd,J＝12.8,8.2Hz,2H),7.47(d,J＝8.0Hz,1H),4.40-4.22(m,2H),3.81(s,1H),2.53(s,3H),1.27(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ186.31,163.45,145.83,139.64,134.27,134.05,133.69,132.39,131.33,131.01,130.33,128.45,127.66,123.25,63.38,59.39,53.53,22.05,13.95.
实施例64
参照实施例55的合成方法，仅改变底物的取代基，得到I93，收率98％，99.91％ee。
I93的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.17(dd,J＝3.9,1.0Hz,1H),7.98(s,1H),7.80(dd,J＝4.9,1.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.45(d,J＝8.0Hz,1H),7.21(dd,J＝4.9,4.0Hz,1H),4.39-4.16(m,1H),3.79(s,1H),2.52(s,3H),1.22(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ180.60,163.50,145.67,141.28,136.53,135.88,133.91,132.27,130.37,129.01,127.70,123.16,63.26,59.85,53.34,22.02,13.81.
实施例65
向反应管中加入23.9mg(0.1mmol)1-25，27.0mg(0.12mmol)2，42.4mg(0.2mmol)K3PO4和1mL甲苯，加入10.3mg(0.01mmol)B3(R1叔丁基二苯基氯硅醚，R2为3,5-双三氟取代苄基，R3为叔丁氧羰基，X为溴)，25℃下进行环加成反应。12h后停止反应，浓缩过柱，洗脱剂为石油醚：乙酸乙酯＝3:1(V/V)，得到37.2mg产物I94，收率97％，99.92％ee。
I94的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.98(d,J＝7.9Hz,1H),7.77-7.69(m,2H),7.677-7.59(m,2H),7.50(td,J＝7.6,1.2Hz,1H),7.32-7.21(m,2H),4.51-4.32(m,2H),3.60-3.44(m,1H),3.08(dt,J＝16.8,4.3Hz,1H),2.51(ddd,J＝13.9,10.8,4.4Hz,1H),2.24(dt,J＝13.7,4.3Hz,1H),1.40(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.08,164.34,142.81,137.86,134.56,133.70,133.21,131.65,130.80,128.85,128.00,127.16,126.77,122.15,64.81,63.36,61.11,32.00,27.18,14.34.
实施例66
参照实施例65的合成方法，仅改变底物的取代基，得到I95，收率96％，99.96％ee。
I95的核磁数据如下：
1H NMR(400MHz,CDCl3)1H NMR(400MHz,CDCl3)δ7.89(d,J＝7.3Hz,1H),7.78(dd,J＝7.8,0.8Hz,1H),7.65(dd,J＝7.9Hz,J＝7.9Hz,1H),7.58-7.54(m,1H),7.52(td,J＝7.6,1.3Hz,1H),7.35-7.24(m,2H),4.50-4.35(m,2H),3.61-3.44(m,1H),3.09(dt,J＝16.8,4.2Hz,1H),2.52(ddd,J＝13.8,11.0,4.4Hz,1H),2.22(dt,J＝13.7,4.2Hz,1H),1.40(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ186.91,164.01,142.83,135.91,134.84,134.70,134.32,133.11,131.48,129.46,128.86,128.20,127.28,125.00,64.94,63.54,60.05,32.04,27.16,14.34.
实施例67
参照实施例65的合成方法，仅改变底物的取代基，得到I96，收率93％，97％ee。
I96的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.83(d,J＝8.0Hz,1H),7.75(dd,J＝7.9,1.0Hz,1H),7.56-7.46(m,2H),7.44(s,1H),7.32-7.21(m,2H),4.51-4.29(m,2H),3.63-3.39(m,1H),3.08(dt,J＝16.8,4.4Hz,1H),2.56-2.40(m,4H),2.24(dt,J＝13.7,4.4Hz,1H),1.39(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.22,164.47,142.83,141.66,137.98,134.79,134.51,133.27,128.84,128.81,127.98,127.13,126.36,122.21,64.72,63.26,61.03,31.99,27.18,21.54,14.33.
实施例68
参照实施例65的合成方法，仅改变底物的取代基，得到I97，收率88％，95％ee。
I97的核磁数据如下：
1H NMR(400MHz,CDCl3)7.96(d,J＝1.5Hz,1H),7.75(dd,J＝7.9,1.0Hz,1H),7.65(dd,J＝8.3,1.6Hz,1H),7.56(d,J＝8.3Hz,1H),7.49(td,J＝7.6,1.3Hz,1H),7.31-7.21(m,2H),4.58-4.30(m,2H),3.63-3.45(m,1H),3.07(dt,J＝16.8,4.2Hz,1H),2.51(ddd,J＝13.7,11.0,4.4Hz,1H),2.21(dt,J＝13.7,4.2Hz,1H),1.44-1.37(m,12H)；13C NMR(100MHz,CDCl3)δ187.14,164.51,158.08,142.77,135.01,134.43,133.34,131.79,128.84,128.29,127.99,127.09,123.40,121.67,64.77,63.20,61.27,35.70,32.08,31.32,27.20,14.37.
实施例69
参照实施例65的合成方法，仅改变底物的取代基，得到I98，收率90％，95％ee。
I98的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.16(d,J＝1.3Hz,1H),7.83(dd,J＝8.1,1.5Hz,1H),7.77(dd,J＝7.9,1.0Hz,1H),7.70(d,J＝8.1Hz,1H),7.68-7.62(m,2H),7.55-7.41(m,4H),7.34-7.23(m,2H),4.54-4.33(m,2H),3.64-3.45(m,1H),3.10(dt,J＝16.8,4.4Hz,1H),2.53(ddd,J＝13.9,10.7,4.4Hz,1H),2.26(dt,J＝13.7,4.3Hz,1H),1.41(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.06,164.47,147.19,142.83,139.13,136.51,134.58,133.26,132.45,129.85,129.23,128.92,128.87,128.07,127.72,127.21,125.13,122.39,64.78,63.40,61.07,32.10,27.22,14.40.
实施例70
参照实施例65的合成方法，仅改变底物的取代基，得到I99，收率91％，97％ee。
I99的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.77(dd,J＝7.9,1.1Hz,1H),7.53(d,J＝8.6Hz,1H),7.49(dd,J＝7.5,1.3Hz,1H),7.43(d,J＝2.3Hz,1H),7.32-7.21(m,2H),7.10(dd,J＝8.7,2.3Hz,1H),4.55-4.29(m,2H),3.92(s,3H),3.62-3.45(m,1H),3.06(dt,J＝16.8,4.1Hz,1H),2.51(ddd,J＝13.6,11.3,4.4Hz,1H),2.17(dt,J＝13.6,4.0Hz,1H),1.40(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.25,164.46,164.16,142.80,134.51,133.36,129.64,128.87,128.01,127.18,123.54,117.41,110.98,64.73,63.32,60.64,56.07,32.09,27.20,14.37.
实施例71
参照实施例65的合成方法，仅改变底物的取代基，得到I100，收率90％，91％ee。
I100的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.39(s,1H),8.19(s,1H),8.04-7.91(m,2H),7.71(dd,J＝7.9,1.0Hz,1H),7.69-7.59(m,2H),7.49(td,J＝7.5,1.3Hz,1H),7.29(d,J＝7.6Hz,1H),7.23(dd,J＝7.6Hz,J＝7.6Hz,1H),4.54-4.37(m,2H),3.57-3.42(m,1H),3.12(dt,J＝16.7,4.7Hz,1H),2.53(ddd,J＝14.3,10.2,4.3Hz,1H),2.31(dt,J＝9.5,4.5Hz,1H),1.42(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.05,164.67,142.96,135.92,135.42,134.61,133.36,133.06,129.59,129.23,128.87,128.82,128.30,128.03,127.16,126.67,126.35,122.57,63.54,63.37,61.27,32.16,27.10,14.37；
实施例72
参照实施例65的合成方法，仅改变底物的取代基，得到I130，收率96％，99.92％ee。
I130的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.71(d,J＝2.3Hz,1H),7.53(d,J＝8.0Hz,1H),7.47-7.39(m,2H),7.24(d,J＝8.0Hz,1H),4.49-4.32(m,2H),3.58-3.38(m,1H),3.04(dt,J＝16.9,4.1Hz,1H),2.58-2.41(m,4H),2.17(dt,J＝13.7,4.1Hz,1H),1.39(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ186.43,164.30,145.12,141.03,134.92,134.42,134.41,133.50,131.90,130.42,127.62,126.97,122.01,64.20,63.38,61.01,31.88,26.66,22.09,14.34.
实施例73
参照实施例65的合成方法，仅改变底物的取代基，得到I131，收率95％，99％ee。
I131的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.57(s,1H),7.53(d,J＝8.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.31(d,J＝7.7Hz,1H),7.17(d,J＝7.8Hz,1H),4.54-4.30(m,2H),3.57-3.36(m,1H),3.03(dt,J＝16.6,4.1Hz,1H),2.61-2.40(m,4H),2.27(s,3H),2.17(dt,J＝13.5,4.0Hz,1H),1.39(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.43,164.56,144.90,140.04,136.92,135.63,135.21,133.09,132.10,131.74,128.76,128.06,126.94,121.88,64.76,63.27,61.09,32.32,26.79,22.08,21.01,14.36.
实施例74
参照实施例65的合成方法，仅改变底物的取代基，得到I132，收率92％，99％ee。
I132的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.53(d,J＝8.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.24-7.15(m,2H),7.08(dd,J＝8.5,2.8Hz,1H),4.56-4.26(m,2H),3.72(s,3H),3.56-3.35(m,1H),3.00(dt,J＝16.5,4.2Hz,1H),2.65-2.4438(m,4H),2.17(dt,J＝13.6,4.2Hz,1H),1.39(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.18,164.51,158.64,144.90,135.67,135.26,134.03,132.04,131.76,130.05,126.92,123.32,121.87,109.60,64.59,63.29,61.07,55.57,32.52,26.39,22.08,14.34.
实施例75
参照实施例65的合成方法，仅改变底物的取代基，得到I133，收率86％，99.5％ee。
I133的核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.57(d,J＝2.4Hz,1H),8.32(dd,J＝8.5,2.4Hz,1H),7.78(s,1H),7.50(dt,J＝16.6,8.0Hz,3H),4.52-4.34(m,2H),3.76-3.55(m,1H),3.20(dt,J＝17.5,3.8Hz,1H),2.62-2.45(m,4H),2.22(dt,J＝13.9,3.9Hz,1H),1.40(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ186.03,164.08,148.97,147.35,145.39,134.59,134.14,132.11,131.84,130.44,128.12,127.09,123.21,122.23,63.84,63.53,60.99,31.28,27.37,22.12,14.35.
实施例76
参照实施例65的合成方法，仅改变底物的取代基，得到I134，收率93％，99.94％ee。
I134的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.60(d,J＝8.5Hz,1H),7.52(d,J＝8.0Hz,1H),7.48(s,1H),7.45-7.35(m,2H),4.48-4.34(m,2H),3.58-3.47(m,1H),3.04(dt,J＝17.0,4.1Hz,1H),2.55-2.42(m,4H),2.17(dt,J＝13.7,4.1Hz,1H),1.39(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ186.62,164.34,145.07,144.34,135.00,132.15,131.93,131.85,131.83,130.73,129.98,129.53,126.94,121.99,64.29,63.37,61.03,31.83,26.94,22.08,14.34.
实施例77
参照实施例65的合成方法，仅改变底物的取代基，得到I135，收率91％，99％ee。
I135的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.51(d,J＝8.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.35(d,J＝7.3Hz,1H),7.22(t,J＝8.0Hz,1H),7.03(d,J＝7.6Hz,1H),4.57-4.32(m,2H),3.87(s,3H),3.27-3.11(m,2H),2.56-2.35(m,4H),2.19(dt,J＝13.8,4.3Hz,1H),1.40(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ187.52,164.56,156.72,144.89,135.01,134.37,132.12,131.90,131.74,127.52,126.96,121.93,119.39,115.24,64.74,63.28,60.83,55.85,31.16,22.09,20.96,14.37.
实施例78
参照实施例65的合成方法，仅改变底物的取代基，得到I136，收率86％，92％ee。
I136的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.72-7.62(m,2H),7.59(d,J＝8.0Hz,1H),7.55-7.47(m,1H),7.45(d,J＝8.0Hz,1H),7.09-6.92(m,2H),4.59(s,2H),4.51-4.32(m,2H),2.48(s,3H),1.40(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ181.59,163.79,161.03,144.95,137.16,135.60,132.29,130.09,127.87,127.41,122.42,122.01,121.58,118.20,70.33,63.71,59.13,58.53(d,J＝18.7Hz),22.02,14.26.
实施例79
参照实施例65的合成方法，仅改变底物的取代基，得到I137，收率88％，96％ee。
I137的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.51(d,J＝8.0Hz,1H),7.44(s,1H),7.40(d,J＝8.0Hz,1H),7.20(s,1H),4.50-4.35(m,2H),3.31-3.20(m,1H),2.99(dt,J＝17.0,4.3Hz,1H),2.53-2.42(m,4H),2.29(s,3H),2.25-2.16(m,4H),1.40(t,J＝7.1Hz,3H)；13CNMR(100MHz,CDCl3)δ187.72,164.64,148.27,144.87,138.32,137.15,136.40,135.07,133.49,132.20,131.71,126.99,125.95,121.91,64.68,63.24,60.89,31.34,24.07,22.08,20.91,19.42,14.37.
实施例80
参照实施例65的合成方法，仅改变底物的取代基，得到I138，收率94％，99.4％ee。
I138的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.66(s,1H),7.49(d,J＝8.0Hz,1H),7.43(td,J＝7.5,1.4Hz,1H),7.40-7.33(m,2H),7.24(d,J＝7.4Hz,1H),7.16(dd,J＝8.0Hz,J＝8.0Hz,1H),4.53-4.28(m,2H),3.59(ddd,J＝15.6,11.2,4.5Hz,1H),2.98(dt,J＝15.5,4.7Hz,1H),2.45(s,3H),2.32-1.84(m,4H),1.39(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ192.62,164.87,145.03,141.97,136.53,134.09,133.62,132.99,131.66,130.54,129.50,127.47,126.62,122.00,68.71,63.22,60.46,31.27,28.73,22.59,22.02,14.36.
实施例81
向史莱克管中加入37.1mg(1mmol)化合物I84，1mL浓H2SO4，50℃反应1h，加入水5mL，饱和Na2CO3中和，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，即可得到目标产物I141，收率99％，99％ee。
I141的核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.95-7.87(m,2H),7.70(d,J＝8.0Hz,1H),7.62-7.56(m,1H),7.50-7.40(m,4H),6.03(s,1H),4.40-4.23(m,2H),4.08(d,J＝17.8Hz,1H),3.70(d,J＝17.7Hz,1H),2.50(s,3H),1.31(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ196.21,169.87,144.98,137.33,135.76,134.11,132.99,131.88,128.92,128.33,124.50,121.76,65.45,63.57,49.44,22.02,14.10.
放大试验：为了验证该反应的用途，对产物I84进行了规模合成，合成反应式如下：
上述规模合成获得的收率较高(1.29g，88％)，产物保持了优异的对映选择性(99％ee)，表明该反应具有工业化应用价值。
Claims (2)
1.氮杂环丙烷衍生物的制备方法，其特征在于，包括以下步骤：
将磺内酰胺和化合物2溶于有机溶剂中，然后加入碱和催化剂进行环加成反应，反应温度为25～40℃，反应时间为1～48h，制得化合物I；其中，磺内酰胺和化合物2的摩尔比为1:1～3；磺内酰胺和碱的摩尔比为1:1-6；磺内酰胺和催化剂的摩尔比为1:0.01～0.2；
所述氮杂环丙烷衍生物的具体结构式为：
有机溶剂为1,4-二氧六环、乙腈、甲醇、N,N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、四氢呋喃、乙醚、甲基叔丁基醚、二氯甲烷、二氯乙烷、三氯甲烷、甲苯、二甲苯、均三甲苯、氟苯、氯苯、石油醚、正己烷、正戊烷和正庚烷中的一种或几种；
碱为NaOAc、NaHCO3、K3PO4、Na2CO3、Cs2CO3、LiOH、NaOH、KOH、CsOH·H2O、K3PO4·3H2O、K3PO4·7H2O、NEt3、DIPEA或DABCO；
催化剂为季鏻盐催化剂，结构式为：
其中，R1为甲基、异丙基、叔丁基、三甲基硅醚、三异丙基硅醚、叔丁基二甲基硅醚、叔丁基二苯基硅醚或三苯基硅醚；
R2为烷基、取代苄基、萘、蒽、菲；
R3为氢、烷基、烷氧基、氰基、氟、氯、溴、硝基、三氟甲基、取代苯甲酰基、烷酰基、叔丁氧羰基、取代异硫氰酸酯；
R4为甲基、异丙基、叔丁基，取代芳基；
X为氯、溴、碘、三氟甲磺酰基；
所述催化剂通过以下方法制备得到：在氮气保护下，将三价膦通过wittig反应，一步制得季鏻盐催化剂。
2.根据权利要求1所述的氮杂环丙烷衍生物的制备方法，其特征在于，磺内酰胺和化合物2的摩尔比为1:1.2；磺内酰胺和碱的摩尔比为1:2；磺内酰胺和催化剂的摩尔比为1:0.1，反应温度为25℃，反应时间为12h。
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