CN112321481B - 一种手性吲哚类化合物及其制备方法 - Google Patents
一种手性吲哚类化合物及其制备方法 Download PDFInfo
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- CN112321481B CN112321481B CN202011058377.4A CN202011058377A CN112321481B CN 112321481 B CN112321481 B CN 112321481B CN 202011058377 A CN202011058377 A CN 202011058377A CN 112321481 B CN112321481 B CN 112321481B
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- methyl
- phenyl
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- -1 indole compound Chemical class 0.000 title claims abstract description 45
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 28
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims abstract description 23
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical class O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000003446 ligand Substances 0.000 claims abstract description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 12
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 10
- 238000010523 cascade reaction Methods 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 5
- OWVIRVJQDVCGQX-VSGBNLITSA-N [(4r,5r)-5-[hydroxy(diphenyl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)([C@H]1[C@@H](OC(O1)(C)C)C(O)(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 OWVIRVJQDVCGQX-VSGBNLITSA-N 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 144
- 238000006243 chemical reaction Methods 0.000 claims description 126
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 62
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 35
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 31
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical compound Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 claims description 28
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 10
- 150000002475 indoles Chemical class 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- 150000002940 palladium Chemical class 0.000 claims description 9
- 239000012429 reaction media Substances 0.000 claims description 7
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Natural products C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 4
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 239000000575 pesticide Substances 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 150000003440 styrenes Chemical class 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 8
- 229910052763 palladium Inorganic materials 0.000 abstract description 4
- 238000006467 substitution reaction Methods 0.000 abstract description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 abstract description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 abstract description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 abstract description 2
- 239000011630 iodine Substances 0.000 abstract description 2
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 abstract description 2
- 125000004421 aryl sulphonamide group Chemical group 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 239000000376 reactant Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 154
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 129
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 114
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 114
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 96
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 85
- 239000003208 petroleum Substances 0.000 description 44
- 239000000047 product Substances 0.000 description 44
- 239000011734 sodium Substances 0.000 description 43
- 239000007787 solid Substances 0.000 description 43
- 229910052757 nitrogen Inorganic materials 0.000 description 42
- 239000002904 solvent Substances 0.000 description 42
- 238000003786 synthesis reaction Methods 0.000 description 40
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 39
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- 230000015572 biosynthetic process Effects 0.000 description 39
- 238000005160 1H NMR spectroscopy Methods 0.000 description 38
- 238000004128 high performance liquid chromatography Methods 0.000 description 38
- 239000000741 silica gel Substances 0.000 description 38
- 229910002027 silica gel Inorganic materials 0.000 description 38
- 238000010926 purge Methods 0.000 description 35
- BBUCOOWLWJJNJQ-UHFFFAOYSA-N 3-(2-iodophenyl)-3-methylcyclobutan-1-one Chemical compound IC1=C(C=CC=C1)C1(CC(C1)=O)C BBUCOOWLWJJNJQ-UHFFFAOYSA-N 0.000 description 28
- 238000000926 separation method Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- 239000001301 oxygen Substances 0.000 description 10
- 229910052760 oxygen Inorganic materials 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- CIGWQUAFBMGUMB-SANMLTNESA-N (3S)-3-methyl-3-[(1-methylsulfonyl-2-phenylindol-3-yl)methyl]-2H-inden-1-one Chemical compound C[C@](CC(C1=CC=CC=C11)=C(C2=CC=CC=C2)N1S(C)(=O)=O)(C1)C2=CC=CC=C2C1=O CIGWQUAFBMGUMB-SANMLTNESA-N 0.000 description 8
- IXXNKLZUSURNKP-UHFFFAOYSA-N n-[2-(2-phenylethynyl)phenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=CC=C1C#CC1=CC=CC=C1 IXXNKLZUSURNKP-UHFFFAOYSA-N 0.000 description 8
- AURRNFKMNUMODY-QHCPKHFHSA-N (3S)-3-methyl-3-[(1-methylsulfonyl-2-trimethylsilylindol-3-yl)methyl]-2H-inden-1-one Chemical compound C[C@](CC(C1=CC=CC=C1N1S(C)(=O)=O)=C1[Si](C)(C)C)(C1)C2=CC=CC=C2C1=O AURRNFKMNUMODY-QHCPKHFHSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- JSYWLBIBOWJMTB-YTTGMZPUSA-N C[C@](CC(C1=CC=CC=C11)=C(C2=CC=CC=C2)N1C1=C(C)C=CC=C1)(C1)C2=CC=CC=C2C1=O Chemical compound C[C@](CC(C1=CC=CC=C11)=C(C2=CC=CC=C2)N1C1=C(C)C=CC=C1)(C1)C2=CC=CC=C2C1=O JSYWLBIBOWJMTB-YTTGMZPUSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical class C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 description 3
- SNWQUNCRDLUDEX-UHFFFAOYSA-N inden-1-one Chemical group C1=CC=C2C(=O)C=CC2=C1 SNWQUNCRDLUDEX-UHFFFAOYSA-N 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- MKUCMKHKRZVQRY-UHFFFAOYSA-N n-[2-(2-trimethylsilylethynyl)phenyl]methanesulfonamide Chemical compound C[Si](C)(C)C#CC1=CC=CC=C1NS(C)(=O)=O MKUCMKHKRZVQRY-UHFFFAOYSA-N 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- COHIGYQPBKIVBY-SANMLTNESA-N (3S)-3-methyl-3-[(5-methyl-2-phenyl-1H-indol-3-yl)methyl]-2H-inden-1-one Chemical compound C[C@](CC1=C(C2=CC=CC=C2)NC2=CC=C(C)C=C12)(C1)C2=CC=CC=C2C1=O COHIGYQPBKIVBY-SANMLTNESA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 102100033639 Acetylcholinesterase Human genes 0.000 description 2
- 108010022752 Acetylcholinesterase Proteins 0.000 description 2
- CATMPQFFVNKDEY-YPMHNXCESA-N Golotimod Chemical compound C1=CC=C2C(C[C@H](NC(=O)CC[C@@H](N)C(O)=O)C(O)=O)=CNC2=C1 CATMPQFFVNKDEY-YPMHNXCESA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000985245 Spodoptera litura Species 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000005888 cyclopropanation reaction Methods 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 229950009391 golotimod Drugs 0.000 description 2
- 108010049353 golotimod Proteins 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 230000000607 poisoning effect Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- XADYJEMNNMTZEX-MHZLTWQESA-N (3S)-3,5,6-trimethyl-3-[(2-phenyl-1H-indol-3-yl)methyl]-2H-inden-1-one Chemical compound C[C@](CC1=C(C2=CC=CC=C2)NC2=CC=CC=C12)(C1)C2=CC(C)=C(C)C=C2C1=O XADYJEMNNMTZEX-MHZLTWQESA-N 0.000 description 1
- ZHWAAJUWVRSLPP-SANMLTNESA-N (3S)-3,5-dimethyl-3-[(2-phenyl-1H-indol-3-yl)methyl]-2H-inden-1-one Chemical compound C[C@](CC1=C(C2=CC=CC=C2)NC2=CC=CC=C12)(C1)C2=CC(C)=CC=C2C1=O ZHWAAJUWVRSLPP-SANMLTNESA-N 0.000 description 1
- YZZIEXWEGRVDLL-FQEVSTJZSA-N (3S)-3-[(2-bromo-1-methylsulfonylindol-3-yl)methyl]-3-methyl-2H-inden-1-one Chemical compound C[C@](CC(C1=CC=CC=C1N1S(C)(=O)=O)=C1Br)(C1)C2=CC=CC=C2C1=O YZZIEXWEGRVDLL-FQEVSTJZSA-N 0.000 description 1
- SDJUFMWORITBIN-DEOSSOPVSA-N (3S)-3-[(2-butyl-1-methylsulfonylindol-3-yl)methyl]-3-methyl-2H-inden-1-one Chemical compound CCCCC1=C(C[C@@](C)(C2)C3=CC=CC=C3C2=O)C2=CC=CC=C2N1S(C)(=O)=O SDJUFMWORITBIN-DEOSSOPVSA-N 0.000 description 1
- ZLEGZBDQPPTGAF-FQEVSTJZSA-N (3S)-3-[(2-iodo-1-methylsulfonylindol-3-yl)methyl]-3-methyl-2H-inden-1-one Chemical compound C[C@](CC(C1=CC=CC=C1N1S(C)(=O)=O)=C1I)(C1)C2=CC=CC=C2C1=O ZLEGZBDQPPTGAF-FQEVSTJZSA-N 0.000 description 1
- SHTLIMFLGXDQIR-VWLOTQADSA-N (3S)-3-[(5-chloro-2-phenyl-1H-indol-3-yl)methyl]-3-methyl-2H-inden-1-one Chemical compound C[C@](CC(C1=C2)=C(C3=CC=CC=C3)NC1=CC=C2Cl)(C1)C2=CC=CC=C2C1=O SHTLIMFLGXDQIR-VWLOTQADSA-N 0.000 description 1
- UBCNRYSLSDZWNJ-VWLOTQADSA-N (3S)-3-[(5-fluoro-2-phenyl-1H-indol-3-yl)methyl]-3-methyl-2H-inden-1-one Chemical compound C[C@](CC(C1=C2)=C(C3=CC=CC=C3)NC1=CC=C2F)(C1)C2=CC=CC=C2C1=O UBCNRYSLSDZWNJ-VWLOTQADSA-N 0.000 description 1
- HPMHEWMDIXCSKJ-SANMLTNESA-N (3S)-3-[[2-(4-fluorophenyl)-1-methylsulfonylindol-3-yl]methyl]-3-methyl-2H-inden-1-one Chemical compound C[C@](CC(C1=CC=CC=C11)=C(C(C=C2)=CC=C2F)N1S(C)(=O)=O)(C1)C2=CC=CC=C2C1=O HPMHEWMDIXCSKJ-SANMLTNESA-N 0.000 description 1
- IUXQXZCBHQUZGQ-SANMLTNESA-N (3S)-3-ethyl-3-[(2-phenyl-1H-indol-3-yl)methyl]-2H-inden-1-one Chemical compound CC[C@](CC1=C(C2=CC=CC=C2)NC2=CC=CC=C12)(C1)C2=CC=CC=C2C1=O IUXQXZCBHQUZGQ-SANMLTNESA-N 0.000 description 1
- BJOQJLOILLRRRK-DEOSSOPVSA-N (3S)-3-methyl-3-[(1-methylsulfonyl-2-thiophen-2-ylindol-3-yl)methyl]-2H-inden-1-one Chemical compound C[C@](CC(C1=CC=CC=C11)=C(C2=CC=CS2)N1S(C)(=O)=O)(C1)C2=CC=CC=C2C1=O BJOQJLOILLRRRK-DEOSSOPVSA-N 0.000 description 1
- OCNHLJRYYLUKBL-FQEVSTJZSA-N (3S)-3-methyl-3-[(1-methylsulfonylindol-3-yl)methyl]-2H-inden-1-one Chemical compound C[C@](CC(C1=CC=CC=C11)=CN1S(C)(=O)=O)(C1)C2=CC=CC=C2C1=O OCNHLJRYYLUKBL-FQEVSTJZSA-N 0.000 description 1
- BQQHRMXEJKOPMM-VWLOTQADSA-N (3S)-3-methyl-3-[(2-phenyl-1H-indol-3-yl)methyl]-2H-inden-1-one Chemical compound C[C@](CC1=C(C2=CC=CC=C2)NC2=CC=CC=C12)(C1)C2=CC=CC=C2C1=O BQQHRMXEJKOPMM-VWLOTQADSA-N 0.000 description 1
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- OCHSAWDEMIAKMX-VWLOTQADSA-N (3S)-5-chloro-3-methyl-3-[(2-phenyl-1H-indol-3-yl)methyl]-2H-inden-1-one Chemical compound C[C@](CC1=C(C2=CC=CC=C2)NC2=CC=CC=C12)(C1)C2=CC(Cl)=CC=C2C1=O OCHSAWDEMIAKMX-VWLOTQADSA-N 0.000 description 1
- NSLHEAPMGKRRNW-SANMLTNESA-N (3S)-5-methoxy-3-methyl-3-[(2-phenyl-1H-indol-3-yl)methyl]-2H-inden-1-one Chemical compound C[C@](CC1=C(C2=CC=CC=C2)NC2=CC=CC=C12)(C1)C2=CC(OC)=CC=C2C1=O NSLHEAPMGKRRNW-SANMLTNESA-N 0.000 description 1
- CREOHKRPSSUXCW-UHFFFAOYSA-N 2-iodo-1-phenylethanone Chemical compound ICC(=O)C1=CC=CC=C1 CREOHKRPSSUXCW-UHFFFAOYSA-N 0.000 description 1
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical compound NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- DNQGYOMXYKNVPQ-UHFFFAOYSA-N 3-(2-iodo-4,5-dimethylphenyl)-3-methylcyclobutan-1-one Chemical compound CC(C1)(CC1=O)C(C=C(C)C(C)=C1)=C1I DNQGYOMXYKNVPQ-UHFFFAOYSA-N 0.000 description 1
- TXYYEQCGOCLHCD-UHFFFAOYSA-N 3-(2-iodo-5-methoxyphenyl)-3-methylcyclobutan-1-one Chemical compound CC(C1)(CC1=O)C(C=C(C=C1)OC)=C1I TXYYEQCGOCLHCD-UHFFFAOYSA-N 0.000 description 1
- ORYNPINPYMBEPD-UHFFFAOYSA-N 3-(2-iodo-5-methylphenyl)-3-methylcyclobutan-1-one Chemical compound CC(C1)(CC1=O)C(C=C(C)C=C1)=C1I ORYNPINPYMBEPD-UHFFFAOYSA-N 0.000 description 1
- DFCYGEKOLJAJFP-UHFFFAOYSA-N 3-(2-iodo-5-thiophen-2-ylphenyl)-3-methylcyclobutan-1-one Chemical compound CC(C1)(CC1=O)C(C=C(C=C1)C2=CC=CS2)=C1I DFCYGEKOLJAJFP-UHFFFAOYSA-N 0.000 description 1
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- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- 101900297506 Human immunodeficiency virus type 1 group M subtype B Reverse transcriptase/ribonuclease H Proteins 0.000 description 1
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- HQWMOZBFQFGJNU-UHFFFAOYSA-N N-[2-[2-(4-fluorophenyl)ethynyl]phenyl]methanesulfonamide Chemical compound CS(NC(C=CC=C1)=C1C#CC(C=C1)=CC=C1F)(=O)=O HQWMOZBFQFGJNU-UHFFFAOYSA-N 0.000 description 1
- BKCVVJWPBINUDJ-UHFFFAOYSA-N N-[2-[2-(4-methylphenyl)ethynyl]phenyl]methanesulfonamide Chemical compound Cc1ccc(cc1)C#Cc1ccccc1NS(C)(=O)=O BKCVVJWPBINUDJ-UHFFFAOYSA-N 0.000 description 1
- NMHIWBFGSSYLSJ-UHFFFAOYSA-N N-[2-[2-(4-nitrophenyl)ethynyl]phenyl]methanesulfonamide Chemical compound CS(NC(C=CC=C1)=C1C#CC(C=C1)=CC=C1[N+]([O-])=O)(=O)=O NMHIWBFGSSYLSJ-UHFFFAOYSA-N 0.000 description 1
- SVEUMBVFLZEMNJ-UHFFFAOYSA-N N-[2-[2-[4-(trifluoromethyl)phenyl]ethynyl]phenyl]methanesulfonamide Chemical compound CS(NC(C=CC=C1)=C1C#CC1=CC=C(C(F)(F)F)C=C1)(=O)=O SVEUMBVFLZEMNJ-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical class [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- OMZAMQFQZMUNTP-UHFFFAOYSA-N acetic acid;1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methylindol-5-ol Chemical compound CC(O)=O.C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 OMZAMQFQZMUNTP-UHFFFAOYSA-N 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229960003713 bazedoxifene acetate Drugs 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 150000008300 phosphoramidites Chemical class 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 210000004988 splenocyte Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
- A01N43/38—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings condensed with carbocyclic rings
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2221—At least one oxygen and one phosphorous atom present as complexing atoms in an at least bidentate or bridging ligand
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si
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- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
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Abstract
本发明公开了一种手性吲哚类化合物及其制备方法。以苯环邻位具有碘取代的环丁酮类化合物和邻位具有乙炔基取代的芳基磺酰胺类化合物为反应物,在钯盐的催化下,以TADDOL衍生的亚磷酰胺类化合物为手性配体,在碱性条件下进行不对称开环环化‑串联反应合成式(I)所示的手性吲哚类化合物。该方法对有不同取代的环丁酮和磺酰胺都具有比较好的适应性,可以得到良好的产率和优异的对映选择性。
Description
技术领域
本发明涉及不对称合成技术领域,具体涉及一种手性吲哚类化合物及其制备方法。
背景技术
茚酮骨架和吲哚骨架为药物化学领域的重要结构单元,广泛应用于制药领域。Golotimod分子中含有吲哚母核和季碳手性中心,作为一种具有抗菌活性的免疫调节肽,可显著提高抗结核治疗的功效,刺激胸腺和脾细胞增殖,并改善巨噬细胞功能。DelavirdineMesylate和Bazedoxifene Acetate分子中的吲哚母核骨架与其能作为非核苷HIV-1逆转录酶抑制剂和治疗骨质疏松密切相关。Donepezil是一种有效的、可逆的、特异的和非竞争性acetylcholinesterase(AChE)抑制剂,分子中茚酮骨架起着不可替代的作用。
季碳手性中心广泛存在与天然产物和具有生物活性的分子中,构建含有季碳手性中性的化合物是化学家们一直在探索的主题。对于同一个含有季碳手性中心的化合物,由于构型的不同,其生物活性和药理活性则可能不尽相同甚至完全相反,要想高对映选择性地构建季碳手性中心一直都是化学家们在不断探索的难题。
环丁酮在有机合成和药物化学中占有重要地位,这是因为环丁酮具有较大的环张力,并且由于引入的羰基官能团,表现出类似于醛类化合物的性质,使其拥有独特的反应活性,区别于其它的环酮类化合物。除此之外,环丁酮的骨架在许多天然产物和具有生物活性的分子中都有发现,因此对环丁酮类化合物的研究具有重要意义。目前对环丁酮类化合物的反应研究并不少见,而涉及到环丁酮的不对称化构建含有季碳手性中心的化合物的报道却十分有限。
而吲哚类化合物广泛存在于天然产物之中,并且是众多具有生物活性的药物的重要骨架。因此构建含有吲哚骨架的化合物具有重要意义。2018年,Lin等报道了钯催化的Heck反应构建了含双吲哚骨架的反应(Palladium-Catalyzed Cascade Heck CyclizationTo Access Bisindoles Org.Lett.2018,20,3477)。然而美中不足的是该反应中虽然构建了新的季碳手性中心,然而并不能得到高对映选择性的目标产物。
2019年,Xu等报道了钯催化环丁酮的不对称开环扩环构建茚酮类化合物的反应(Enantioselective Cross-Exchange between C-I and C-CσBondsAngew.Chem.Int.Ed.2019,58,6747)。通过使用设计的独特的环丁酮实现了碘迁移反应。同年,该课题组又报道了利用该类环丁酮反应生成的重要中间体,实现了分子内的环丙烷化反应和与苯硼酸的偶联反应(Pd-Catalyzed Enantioselective Ring Opening/Cross-Coupling and Cyclopropanation of Cyclobutanones Angew.Chem.Int.Ed.2019,58,897),用钯和铜双金属共催化与末端炔烃的Sonogashira偶联反应(Enantioselectivepalladium/copper-catalyzed C–Cσ-bond activation synergized with Sonogashira-type C(sp3)–C(sp)cross-coupling alkynylation Chem.Sci.,2019,10,7579)。但至今没有高对映选择性的多官能团的吲哚类化合物不对称合成的报道。
发明内容:
本发明的目的在于提供一种高对映选择性的吲哚类化合物,该吲哚类化合物同时具有茚酮骨架和吲哚母核,并且季碳手性中心的对映选择性最高能达到>99.5:0.5er,为首次合成。
本发明提供一种高对映选择性的吲哚类化合物的制备方法,以高反应活性的环丁酮原料和邻位具有乙炔基取代的磺酰胺原料合成了分子中同时具有含季碳手性中心的茚酮骨架和吲哚骨架,这两种骨架都是抗肿瘤治疗领域和药物分子的重要结构单元。在催化剂钯盐、TADDOL衍生的亚磷酰胺类手性配体、碱的作用下,实现高产率和高对映选择性的环丁酮的开环扩环反应制备得到高对映选择性的多官能团的吲哚类化合物。
本发明的技术方案为:
一种如式(I)所示的手性吲哚类化合物:
其中,
R1分别独立地为H、F、Cl、Br、I、C1-3烷基、C1-3烷氧基或噻吩基;
R2为C1-3烷基或苯基;
R3为H、F、Cl、Br、I、C1-4烷基、三甲基硅基、苯基、5元杂芳基或萘基,所述的C1-4
烷基、苯基、5元杂芳基、萘基任选被1、2或3个F、Cl、Br、I、硝基、三氟甲基、甲
基、三甲基硅基取代;
R4为H、对甲苯磺酰基或甲磺酰基;
R5为F、Cl、Br、I或C1-3烷基。
R1分别独立地为H、Cl、甲氧基或噻吩基。
所述的R2优选为甲基、乙基或苯基。
R3为H、Br、I、正丁基、叔丁基、三甲基硅基、苯基、5元杂芳基,所述的苯基对位任选被F、硝基、三氟甲基、甲基取代。
所述的R3为H、Br、I、正丁基、叔丁基、三甲基硅基、苯基、对氟苯基、对甲基苯基、对三氟甲基苯基、对硝基苯基、噻吩基。
R5为F、Cl、Me。
本发明提供了式(I)所示的手性吲哚类化合物的制备方法在反应介质中,式(II)所示的环丁酮类化合物和式(III)所示的苯乙烯类化合物在催化剂钯盐、手性配体和碱的作用下,进行不对称开环环化-串联反应得到所述的式(I)所示的手性吲哚类化合物;
其中,R1、R2、R3、R4、R5如本发明所定义;
所述的手性配体为如式(R,R)-L1、(R,R)-L2、(R,R)-L3、(R,R)-L4、(R,R)-L5、(R,R)-L6所示的TADDOL衍生的亚磷酰胺类化合物。
所述的手性吲哚类化合物为:
所述的制备方法具体包括如下步骤:在惰性气体的保护下,将手性配体、催化剂钯盐、碱、式(II)所示的环丁酮类化合物和式(III)所示的苯乙烯类化合物依次加入反应介质中,进行不对称开环环化-串联反应得到式(I)所示的手性吲哚类化合物。
所述的催化剂钯盐为烯丙基氯化钯、三(二亚苄基丙酮)二钯、氯化钯、醋酸钯、三氟乙酸钯,优选为烯丙基氯化钯二聚体或三(二亚苄基丙酮)二钯,在此条件下反应生成的副产物更少,目标产物产率更高。
所述的碱为碳酸钾、碳酸钠、碳酸银、磷酸钾,优选为碳酸钾或碳酸钠,所述的碱的摩尔用量为式(II)所示的环丁酮类化合物的2.2~2.7倍,碱的使用能促进反应的发生,产率更高。
所述的不对称开环环化-串联反应的反应温度为25~100℃,反应时间为12~24h,优选为80-100℃,在加热的条件下能大幅度提高反应速率,减少副反应的发生,同时提高季碳手性中心的对映选择性。
所述的反应介质1,4-二氧六环、二氯甲烷、二氯乙烷、甲苯中,优选为1,4-二氧六环,二氯甲烷,在此条件下反应产率更高,且原料转化率高。式(II)所示的环丁酮类化合物的浓度为0.08~0.12mol/L。
所述的式(II)所示的环丁酮类化合物、式(III)所示的苯乙烯类化合物的摩尔比为1:1.1~1.3,此比例下原料生成的副产物少且目标产物产率更高。
所述的催化剂钯盐的用量为式(II)所示的环丁酮类化合物的3~6mol%;所述的手性配体的用量为式(II)所示的环丁酮类化合物的8~12mol%,在此比例下产物的对映选择性和产率最高。
本发明还提供了所述的手性吲哚类化合物在制备杀虫剂中的应用。
与现有技术相比,本发明具有如下的优点与技术效果:
(1)用于合成底物的原料廉价易获取,使用的钯催化剂相对更加廉价,最佳手性配体合成简便,前体作为商业化商品十分廉价,反应条件易控制且不用进行预搅操作,产物易分离且各种取代基的产物均为固体,易于进行结晶等操作。
(2)本发明反应条件温和,环境友好,本发明首次得到了同时具有茚酮骨架和吲哚母核的分子,并且季碳手性中心的对映选择性最高能达到>99.5:0.5er,能够作为杀虫剂,同时具有抑制AChE的药理活性。
具体实施方式:
本发明中使用的代表性环丁酮原料和手性配体(R,R)-L1的合成方法如下所示:
代表性环丁酮的制备:
在500mL史莱克反应瓶中加入MePPh3Br(32.22g,80.0mmol),KOtBu(11.22g,100.0mmol)抽真空,充氮气,在氮气的保护下加入200mL干燥后的THF。溶液呈现出黄色,室温下搅拌1h后加入原料2-碘苯乙酮(9.8g,40.0mmol,1.0equiv)后继续反应12h。饱和NH4Cl淬灭后,石油醚萃取,饱和食盐水洗涤三次后,Na2SO4干燥,减压旋蒸除去溶剂,最后用柱层析法,石油醚为洗脱剂,分离得到无色液体1-碘-2-(丙基-1-烯-2-基)苯(9.17g,94%)。
在500mL的三口瓶中加入Zn/Cu偶联试剂(7.8g,60mmol),抽真空,充氮气,在氮气的保护下加入干燥的乙醚溶剂120mL,在恒压滴液漏斗中加入30mL干燥后的乙醚溶剂,Cl3C℃l(60mmol,1.5equiv),P℃l3(1.05equiv,42mmol)室温下缓慢滴加1h,将原料1-碘-2-(丙基-1-烯-2-基)苯加入到反应中,放入40℃的油浴锅中加热回流10h。
反应结束后,将反应减压浓缩除去其中的乙醚溶剂,用硅藻土抽滤多次,二氯甲烷洗涤,加压浓缩后将反应物加入到250mL的单口瓶中,加入100mL乙酸溶液,向反应中加入活化锌粉(160mmol,4.0equiv),80℃下油浴加热12h。反应结束后用乙酸乙酯萃取,NaHCO3饱和溶液洗涤多次,除去其中的乙酸溶剂,再用饱和的食盐水多次洗涤,除去其中的NaHCO3,减压浓缩后,用柱层析法(石油醚/乙酸乙酯=30:1)分离得到白色固体产物(4.69g,41%)。
磺酰胺原料的制备:
取250mL的反应瓶,向其中加入邻碘苯胺(2.19g,10mmol),PdCl2(PPh3)2(0.14g,0.2mmol),CuI(0.076g,0.4mmol),在氮气保护下加入无水三乙胺30mL和苯乙炔(1.3mL,12mmol),反应12h后减压浓缩除去溶剂后,用柱层析法(石油醚/乙酸乙酯=10:1)分离得到白色固体产物(1.7g,90%)。
将得到的产物加入到250mL的反应瓶中,加入TsCl(2.1g,10.8mmol),加入二氯甲烷20mL和吡啶(1mL,11.7mmol),室温反应2h后,加入饱和氯化铵溶液除去吡啶后用二氯甲烷萃取减压浓缩后,用柱层析法(石油醚/乙酸乙酯=10:1)分离得到白色固体产物(2.8g,89%)。
手性配体的制备:
取一干燥的200mL史莱克反应瓶,放入搅拌子,加入(R,R)-TADDOL-S1(2.3g,5.0mmol,购于国药,安耐吉化学生产,编号A040563),把反应瓶接入双排管中,抽真空,充氮气下重复三次,在氮气氛围下,注入干燥的的THF(100mL)。之后,在无色的反应体系中注入超干三乙胺(2.5mL,20.0mmol,4.0equiv),反应溶液呈淡黄色。慢慢滴加除水的PCl3(0.5mL,5.25mmol,1.05equiv),溶液呈白色浑浊态,伴随着白色烟雾,并释放出热量。室温下搅拌1小时后,慢慢滴加二乙胺(0.8mL,7.5mmol,1.5equiv)并将反应体系在室温下反应2h。反应结束后,向反应体系中加入乙醚萃取,饱和NaCl水溶液洗涤三次,Na2SO4干燥,减压旋蒸除去溶剂,最后用柱层析法(石油醚/乙酸乙酯/三乙胺=100:1:1)分离得到白色固体(R,R)-L1(2.3g,81%)。
为了更好地理解本发明,通过实施例进行说明。
实施例1:(S)-3-甲基-3-((2-苯基-1-甲苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、4-甲基-N-(2-(苯乙炔基)苯基)苯磺酰胺(83.3mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1进行分离,得到83mg白色固体,目标产物的产率为85%。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=95:5,1.0mL/min,254nm,95:5er)。主要对映体tr=21.3分钟,次要对映体tr=16.9分钟。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C32H27NNaO3S,528.1604;found 528.1620。
1H NMR(400MHz,CDCl3)δ8.22(d,J=8.4Hz,1H),7.46(d,J=7.6Hz,1H),7.30(dd,J=14.8,7.6Hz,2H),7.25-7.09(m,6H),7.08-6.93(m,6H),6.91(d,J=7.6Hz,1H),2.91(d,J=14.4Hz,1H),2.84(d,J=14.4Hz,1H),2.42(d,J=18.8Hz,1H),2.21(s,3H),2.11(d,J=18.8Hz,1H),1.14(s,3H)。
13C NMR(100MHz,CDCl3)δ205.0,161.8,144.7,138.8,136.8,135.7,135.5,134.7,132.2,131.5,131.0,131.0,129.4,128.8,127.6,126.7,124.8,124.4,123.6,123.3,119.9,119.7,115.8,51.2,43.6,36.6,28.7,21.6。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C32H27NNaO3S,528.1604;found 528.1620。
实施例2:(S)-3-甲基-3-((2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、2,2,2-三氟-N-(2-(苯乙炔基)苯基)乙酰胺(69.4mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到58.2mg白色固体,目标产物的产率为83%。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C25H21NNaO,374.1515;found 374.1522。
用Chiralpak IC柱通过HPLC测定对映体过量(己烷:2-丙醇=97.5:2.5,1.0mL/min,230nm,96:4er);m/z(MH+)。主要对映体tr=46.1分钟,次要对映体tr=40.4分钟。
1H NMR(400MHz,CDCl3)δ8.10(s,1H),7.46(d,J=7.2Hz,1H),7.37-7.29(m,6H),7.29(s,1H),7.25(t,J=5.2Hz,2H),7.20(t,J=7.6Hz,1H),7.13(t,J=7.2Hz,1H),7.01(t,J=7.2Hz,1H),3.36(d,J=14.0Hz,1H),3.34(d,J=14.0Hz,1H),2.68(d,J=18.4Hz,1H),2.20(d,J=18.4Hz,1H),1.38(s,3H)。
13C NMR(100MHz,CDCl3)δ205.7,161.9,136.5,136.0,135.5,134.2,133.7,129.8,128.9,128.5,127.9,127.4,124.4,122.9,122.0,120.0,119.4,110.8,108.9,50.7,44.7,36.5,28.1。
实施例3:(S)-3-甲基-3-((1-(甲基磺酰基)-2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-(苯乙炔基)苯基)甲磺酰胺(65.1mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体66.3mg,目标产物的产率为77%。
通过HPLC使用Chiralpak AD-H柱(己烷:2-丙醇=95:5,1.0mL/min,254nm,99:1er)测定对映体过量。主要对映体tr=39.8分钟,次要对映体tr=34.1分钟。
1H NMR(400MHz,CDCl3)δ8.09(d,J=8.4Hz,1H),7.57(d,J=7.6Hz,1H),7.49-7.40(m,3H),7.39(s,1H),7.33-7.28(m,2H),7.25-7.22(m,2H),7.17(t,J=7.6Hz,2H),7.10(d,J=7.2Hz,1H),3.12(d,J=14.4Hz,1H),3.03(d,J=14.4Hz,1H),2.78(s,3H),2.64(d,J=18.4Hz,1H),2.28(d,J=18.4Hz,1H),1.32(s,3H)。
13C NMR(100MHz,CDCl3)δ205.1,161.6,138.7,136.3,135.9,134.7,131.0,130.8,129.0,128.0,127.7,125.1,124.4,123.8,123.3,120.0,119.3,115.1,51.3,43.7,40.6,36.7,28.5。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C26H23NNaO3S,452.1291;found 452.1300。
实施例4:(S)-3-甲基-3-((1-(甲基磺酰基)-2-(三甲基硅烷基)-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-((三甲基硅烷基)乙炔基)苯基)甲磺酰胺(64.2mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到42.5mg白色固体,目标产物的产率为50%,99:1er。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=95:5,1.0mL/min,230nm,99:1er)。主要对映体tr=9.6分钟,次要对映体tr=8.7分钟。
1H NMR(400MHz,CDCl3)δ7.91(d,J=8.4Hz,1H),7.59(d,J=5.2Hz,2H),7.36(d,J=6.4Hz,1H),7.27(s,1H),7.19(t,J=8.0Hz,1H),6.96(t,J=7.6Hz,1H),6.82(d,J=8.0Hz,1H),3.35(d,J=14.0Hz,1H),3.20(d,J=14.4Hz,1H),2.98(d,J=18.4Hz,1H),2.73(s,3H),2.41(d,J=18.4Hz,1H),1.67(s,3H),0.44(s,9H)。
13C NMR(100MHz,CDCl3)δ204.7,161.2,139.9,139.1,136.3,134.8,133.7,132.6,127.9,125.5,124.5,123.3,122.9,119.7,114.6,50.6,43.1,38.6,37.5,28.0,2.8。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C23H27NNaO3SSi,448.1373;found448.1380。
实施例5:(S)-3-甲基-3-((2-苯基-1-甲苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、4-甲基-N-(2-(苯乙炔基)苯基)苯磺酰胺(76.3mg,0.22mmol)、烯丙基氯化钯二聚体(2.2mg,0.006mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾(69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在20℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1进行分离,得到20.5mg白色固体,目标产物的产率为21%。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=95:5,1.0mL/min,254nm,56:44er)。主要对映体tr=21.6分钟,次要对映体tr=16.7分钟。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C32H27NNaO3S,528.1604;found 528.1620。
1H NMR(400MHz,CDCl3)δ8.22(d,J=8.4Hz,1H),7.46(d,J=7.6Hz,1H),7.30(dd,J=14.8,7.6Hz,2H),7.25-7.09(m,6H),7.08-6.93(m,6H),6.91(d,J=7.6Hz,1H),2.91(d,J=14.4Hz,1H),2.84(d,J=14.4Hz,1H),2.42(d,J=18.8Hz,1H),2.21(s,3H),2.11(d,J=18.8Hz,1H),1.14(s,3H)。
13C NMR(100MHz,CDCl3)δ205.0,161.8,144.7,138.8,136.8,135.7,135.5,134.7,132.2,131.5,131.0,131.0,129.4,128.8,127.6,126.7,124.8,124.4,123.6,123.3,119.9,119.7,115.8,51.2,43.6,36.6,28.7,21.6。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C32H27NNaO3S,528.1604;found 528.1620。
实施例6:(S)-3-((2-(4-氟苯基)-1-(甲基磺酰基)-1H-吲哚-3-基)甲基)-3-甲基-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-((4-氟苯基)乙炔基)苯基)甲磺酰胺(69.4mg,0.24mmol)、氯化钯(1.8mg,0.01mmol)、(R,R)-L3(11.3mg,0.02mmol)、碳酸银(137.9mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体80.8mg,目标产物的产率为90%。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=95∶5,1.0mL/min,254nm,94∶6er);m/z(MH+)。主要对映体tr=37.6分钟,次要对映体tr=32.4分钟。
1H NMR(400MHz,CDCl3)δ8.07(d,J=8.4Hz,1H),7.56(d,J=7.6Hz,1H),7.44(t,J=7.6Hz,1H),7.32(t,J=7.6Hz,2H),7.15(m,7H),3.11(d,J=14.4Hz,1H),3.03(d,J=14.4Hz,1H),2.76(s,3H),2.65(d,J=18.4Hz,1H),2.30(d,J=18.4Hz,1H),1.36(s,3H)。
13C NMR(100MHz,CDCl3)δ204.9,163.0(d,J=248.1Hz),161.4,137.6,136.4,136.0,134.8,133.3(d,J=66.8Hz),130.8,127.9,127.0(d,J=3.5Hz),125.3,124.4,124.0,123.4,120.1,119.7,115.2(d,J=26.4Hz),115.1,51.2,43.7,40.6,36.8,28.7.HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C26H22FNNaO3S,470.1197;found 470.1200。
实施例7:(S)-3-甲基-3-((1-(甲基磺酰基)-2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-(苯乙炔基)苯基)甲磺酰胺(65.1mg,0.24mmol)、醋酸钯(2.2mg,0.01mmol)、(R,R)-L3(13.8mg,0.02mmol)、碳酸钾(69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体66.3mg,目标产物的产率为77%。
通过HPLC使用Chiralpak AD-H柱(己烷:2-丙醇=95:5,1.0mL/min,254nm,87:13er)测定对映体过量。主要对映体tr=39.8分钟,次要对映体tr=34.1分钟。
1H NMR(400MHz,CDCl3)δ8.09(d,J=8.4Hz,1H),7.57(d,J=7.6Hz,1H),7.49-7.40(m,3H),7.39(s,1H),7.33-7.28(m,2H),7.25-7.22(m,2H),7.17(t,J=7.6Hz,2H),7.10(d,J=7.2Hz,1H),3.12(d,J=14.4Hz,1H),3.03(d,J=14.4Hz,1H),2.78(s,3H),2.64(d,J=18.4Hz,1H),2.28(d,J=18.4Hz,1H),1.32(s,3H)。
13C NMR(100MHz,CDCl3)δ205.1,161.6,138.7,136.3,135.9,134.7,131.0,130.8,129.0,128.0,127.7,125.1,124.4,123.8,123.3,120.0,119.3,115.1,51.3,43.7,40.6,36.7,28.5。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C26H23NNaO3S,452.1291;found 452.1300。
实施例8:(S)-3-甲基-3-((5-甲基-2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、2,2,2-三氟-N-(4-甲基-2-(苯乙炔基)苯基)乙酰胺(72.8mg,0.24mmol)、三氟乙酸钯(3.3mg,0.01mmol)、(R,R)-L3(13.7mg,0.02mmol)、碳酸钾(69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,二氯乙烷,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到60.0mg白色固体,目标产物的产率为82%。
用Chiralpak As-H柱通过HPLC测定对映体过量(己烷:2-丙醇=90:10,1.0mL/min,230nm,78:22er);m/z(MH+)。主要对映体tr=26.3分钟,次要对映体tr=30.4分钟。
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.43(d,J=7.6Hz,1H),7.36-7.27(m,6H),7.26-7.10(m,3H),6.91(d,J=7.6Hz,2H),3.36-3.25(dd,J=15.6Hz,14.8Hz,2H),2.66(d,J=18.4Hz,1H),2.34(s,3H),2.17(d,J=18.4Hz,1H),1.37(s,3H)。
13C NMR(100MHz,CDCl3)δ205.8,162.1,136.7,136.1,134.2,134.0,133.9,130.0,128.9,128.7,128.6,127.7,127.4,124.5,123.6,122.9,119.1,110.5,108.5,50.7,44.7,36.7,28.1,21.6。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C26H23NNaO,388.1672;found 388.1682。
实施例9:(S)-3-甲基-3-((1-(甲基磺酰基)-2-(对甲苯基)-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-(对甲苯乙炔基)苯基)甲磺酰胺(68.5mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到73.0mg白色固体,目标产物的产率为83%。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=95:5,1.0mL/min,254nm,94.5:5.5er);m/z。主要对映体tr=30.3分钟,次要对映体tr=26.2分钟。
1H NMR(400MHz,CDCl3)δ8.08(d,J=8.4Hz,1H),7.57(d,J=7.6Hz,1H),7.44(t,J=6.4Hz,1H),7.36-7.27(m,2H),7.23-7.17(m,3H),7.13(t,J=8.0Hz,3H),7.06(d,J=8.0Hz,1H),3.10(d,J=14.0Hz,1H),3.02(d,J=14.0Hz,1H),2.77(s,3H),2.65(d,J=18.4Hz,1H),2.42(s,3H),2.28(d,J=18.4Hz,1H),1.32(s,3H)。
13C NMR(100MHz,CDCl3)δ205.2,161.8,139.0,138.9,136.4,136.0,134.7,130.9,128.8,128.0,127.8,125.0,124.5,123.8,123.4,120.0,119.3,115.2,51.4,43.8,40.7,36.9,28.6,21.6。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C27H25NNaO3S,466.1447;found 466.1457。
实施例10:(S)-3-甲基-3-((1-(甲基磺酰基)-2-(4-(三氟甲基)苯基)-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-((4-(三氟甲基)苯基)乙炔基)苯基)甲磺酰胺(81.4mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到54.2mg白色固体,目标产物的产率为55%。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=95:5,1.0mL/min,230nm,92:8er);m/z(MH+)。主要对映体tr=29.1分钟,次要对映体tr=25.2分钟。
1H NMR(400MHz,CDCl3)δ8.06(d,J=8.4Hz,1H),7.62(s,1H),7.55(d,J=7.2Hz,2H),7.40-7.27(m,4H),7.24-7.11(m,3H),7.07(d,J=7.6Hz,1H),3.18(d,J=14.4Hz,1H),3.03(d,J=14.4Hz,1H),2.76(s,3H),2.64(d,J=18.4Hz,1H),2.31(d,J=18.4Hz,1H),1.37(s,3H)。
13C NMR(100MHz,CDCl3)δ204.7,161.1,137.0,136.6,136.0,135.0,134.8,130.9,130.7(q,J=32.4Hz),127.9,124.1(q,J=270.7Hz),125.8,124.9,124.3,123.4,120.4,120.3,115.2,51.0,43.7,40.4,36.7,29.0。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C27H22F3NNaO3S,520.1165;found520.1174。
实施例11:(S)-3-甲基-3-((1-(甲基磺酰基)-2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-(苯乙炔基)苯基)甲磺酰胺(65.1mg,0.24mmol)、醋酸钯(2.2mg,0.01mmol)、(R,R)-L4(14.8mg,0.02mmol)、碳酸银(137.9mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体66.3mg,目标产物的产率为77%。
通过HPLC使用Chiralpak AD-H柱(己烷:2-丙醇=95:5,1.0mL/min,254nm,64:36er)测定对映体过量。主要对映体tr=39.8分钟,次要对映体tr=34.1分钟。
1H NMR(400MHz,CDCl3)δ8.09(d,J=8.4Hz,1H),7.57(d,J=7.6Hz,1H),7.49-7.40(m,3H),7.39(s,1H),7.33-7.28(m,2H),7.25-7.22(m,2H),7.17(t,J=7.6Hz,2H),7.10(d,J=7.2Hz,1H),3.12(d,J=14.4Hz,1H),3.03(d,J=14.4Hz,1H),2.78(s,3H),2.64(d,J=18.4Hz,1H),2.28(d,J=18.4Hz,1H),1.32(s,3H)。
13C NMR(100MHz,CDCl3)δ205.1,161.6,138.7,136.3,135.9,134.7,131.0,130.8,129.0,128.0,127.7,125.1,124.4,123.8,123.3,120.0,119.3,115.1,51.3,43.7,40.6,36.7,28.5。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C26H23NNaO3S,452.1291;found 452.1300。
实施例12:(S)-3-甲基-3-((1-(甲基磺酰基)-2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-(苯乙炔基)苯基)甲磺酰胺(65.1mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钠(46.6mg,0.44mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应15h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体66.3mg,目标产物的产率为77%。
通过HPLC使用Chiralpak AD-H柱(己烷:2-丙醇=95:5,1.0mL/min,254nm,99:1er)测定对映体过量。主要对映体tr=39.8分钟,次要对映体tr=34.1分钟。
1H NMR(400MHz,CDCl3)δ8.09(d,J=8.4Hz,1H),7.57(d,J=7.6Hz,1H),7.49-7.40(m,3H),7.39(s,1H),7.33-7.28(m,2H),7.25-7.22(m,2H),7.17(t,J=7.6Hz,2H),7.10(d,J=7.2Hz,1H),3.12(d,J=14.4Hz,1H),3.03(d,J=14.4Hz,1H),2.78(s,3H),2.64(d,J=18.4Hz,1H),2.28(d,J=18.4Hz,1H),1.32(s,3H)。
13C NMR(100MHz,CDCl3)δ205.1,161.6,138.7,136.3,135.9,134.7,131.0,130.8,129.0,128.0,127.7,125.1,124.4,123.8,123.3,120.0,119.3,115.1,51.3,43.7,40.6,36.7,28.5。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C26H23NNaO3S,452.1291;found 452.1300。
实施例13:(S)-3-甲基-3-((1-(甲基磺酰基)-2-(噻吩-2-基)-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-(噻吩-2-乙炔基)苯基)甲磺酰胺(66.6mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到72.2mg白色固体,目标产物的产率为83%。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=95:5,1.0mL/min,254nm,95.5:4.5er);m/z(MH+)。主要对映体tr=34.7分钟,次要对映体tr=31.2分钟。
1H NMR(400MHz,CDCl3)δ8.08(d,J=8.4Hz,1H),7.58(d,J=7.6Hz,1H),7.51-7.48(m,2H),7.38-7.27(m,3H),7.15(t,J=7.2Hz,1H),7.07(m,2H),6.93(d,J=4.4Hz,1H),3.18(d,J=14.4Hz,1H),3.08(d,J=14.4Hz,1H),2.87(s,3H),2.76(d,J=18.4Hz,1H),2.37(d,J=18.4Hz,1H),1.44(s,3H)。
13C NMR(100MHz,CDCl3)δ205.0,161.7,136.8,136.0,134.8,131.9,130.6,130.4,130.2,128.4,127.9,127.2,125.5,124.5,123.7,123.4,122.4,120.2,115.1,51.3,43.4,40.8,37.4,28.6。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C24H21NNaO3S2,458.0855;found458.0865。
实施例14:(S)-3-甲基-3-((1-(甲基磺酰基)-2-(4-硝基苯基)-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-((4-硝基苯基)乙炔基)苯基)甲磺酰胺(75.9mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到黄色固体59.2mg,目标产物的产率为62%。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=90:10,1.0mL/min,254nm,94:6er);m/z(MH+)。主要对映体tr=46.9分钟,次要对映体tr=39.5分钟。
1H NMR(400MHz,CDCl3)δ8.19(m,2H),8.06(d,J=8.4Hz,1H),7.54(d,J=7.2Hz,1H),7.41-7.30(m,4H),7.26(d,J=2.8Hz,1H),7.23(d,J=7.2Hz,1H),7.19(d,J=7.6Hz,1H),7.11(d,J=7.2Hz,1H),3.19(d,J=14.4Hz,1H),3.05(d,J=14.4Hz,1H),2.76(s,3H),2.62(d,J=18.4Hz,1H),2.32(d,J=18.4Hz,1H),1.39(s,3H)。
13C NMR(100MHz,CDCl3)δ205.1,161.7,136.77,136.0,134.8,132.0,130.6,130.4,130.2,128.4,127.9,127.2,125.5,124.5,123.7,123.4,122.4,120.2,115.1,64.4,51.3,43.4,40.8,37.4,28.6,25.4.13C NMR(100MHz,CDCl3)δ204.5,160.8,147.7,138.1,136.8,136.1,136.1,134.8,130.8,128.1,126.2,124.5,124.3,123.5,123.1,121.1,120.5,115.2,51.,43.8,40.2,36.8,28.9。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C26H22N2NaO5S,497.1142;found497.1151。
实施例15:(S)-3-甲基-3-((1-(甲基磺酰基)-2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-(苯乙炔基)苯基)甲磺酰胺(65.1mg,0.24mmol)、三氟乙酸钯(3.3mg,0.01mmol)、(R,R)-L6(23.8mg,0.02mmol)、磷酸钾(106.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在70℃的油浴锅中反应18h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体36.2mg,目标产物的产率为42%。
通过HPLC使用Chiralpak AD-H柱(己烷:2-丙醇=95:5,1.0mL/min,254nm,78:22er)测定对映体过量。主要对映体tr=39.5分钟,次要对映体tr=34.4分钟。
1H NMR(400MHz,CDCl3)δ8.09(d,J=8.4Hz,1H),7.57(d,J=7.6Hz,1H),7.49-7.40(m,3H),7.39(s,1H),7.33-7.28(m,2H),7.25-7.22(m,2H),7.17(t,J=7.6Hz,2H),7.10(d,J=7.2Hz,1H),3.12(d,J=14.4Hz,1H),3.03(d,J=14.4Hz,1H),2.78(s,3H),2.64(d,J=18.4Hz,1H),2.28(d,J=18.4Hz,1H),1.32(s,3H)。
13C NMR(100MHz,CDCl3)δ205.1,161.6,138.7,136.3,135.9,134.7,131.0,130.8,129.0,128.0,127.7,125.1,124.4,123.8,123.3,120.0,119.3,115.1,51.3,43.7,40.6,36.7,28.5。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C26H23NNaO3S,452.1291;found 452.1300。
实施例16:(S)-3-甲基-3-((1-(甲基磺酰基)-2-(三甲基硅烷基)-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-((三甲基硅烷基)乙炔基)苯基)甲磺酰胺(64.2mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾(69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL二氯甲烷,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到33.2mg白色固体,目标产物的产率为39%,98:2er。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=95:5,1.0mL/min,230nm,98:2er)。主要对映体tr=9.4分钟,次要对映体tr=8.5分钟。
1H NMR(400MHz,CDCl3)δ7.91(d,J=8.4Hz,1H),7.59(d,J=5.2Hz,2H),7.36(d,J=6.4Hz,1H),7.27(s,1H),7.19(t,J=8.0Hz,1H),6.96(t,J=7.6Hz,1H),6.82(d,J=8.0Hz,1H),3.35(d,J=14.0Hz,1H),3.20(d,J=14.4Hz,1H),2.98(d,J=18.4Hz,1H),2.73(s,3H),2.41(d,J=18.4Hz,1H),1.67(s,3H),0.44(s,9H)。
13C NMR(100MHz,CDCl3)δ204.7,161.2,139.9,139.1,136.3,134.8,133.7,132.6,127.9,125.5,124.5,123.3,122.9,119.7,114.6,50.6,43.1,38.6,37.5,28.0,2.8。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C23H27NNaO3SSi,448.1373;found448.1380。
实施例17:(S)-3-甲基-3-((1-(甲基磺酰基)-2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-(苯乙炔基)苯基)甲磺酰胺(65.1mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(9.0mg,0.016mmol)、碳酸钠(53.0mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应15h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体66.3mg,目标产物的产率为77%。
通过HPLC使用Chiralpak AD-H柱(己烷:2-丙醇=95:5,1.0mL/min,254nm,82:18er)测定对映体过量。主要对映体tr=39.6分钟,次要对映体tr=34.0分钟。
1H NMR(400MHz,CDCl3)δ8.09(d,J=8.4Hz,1H),7.57(d,J=7.6Hz,1H),7.49-7.40(m,3H),7.39(s,1H),7.33-7.28(m,2H),7.25-7.22(m,2H),7.17(t,J=7.6Hz,2H),7.10(d,J=7.2Hz,1H),3.12(d,J=14.4Hz,1H),3.03(d,J=14.4Hz,1H),2.78(s,3H),2.64(d,J=18.4Hz,1H),2.28(d,J=18.4Hz,1H),1.32(s,3H)。
13C NMR(100MHz,CDCl3)δ205.1,161.6,138.7,136.3,135.9,134.7,131.0,130.8,129.0,128.0,127.7,125.1,124.4,123.8,123.3,120.0,119.3,115.1,51.3,43.7,40.6,36.7,28.5。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C26H23NNaO3S,452.1291;found 452.1300。
实施例18:(S)-3-甲基-3-((2-苯基-1-甲苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、4-甲基-N-(2-(苯乙炔基)苯基)苯磺酰胺(76.3mg,0.22mmol)、烯丙基氯化钯二聚体(2.2mg,0.006mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾(69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在70℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1进行分离,得到61.5mg白色固体,目标产物的产率为63%。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=95:5,1.0mL/min,254nm,76:24er)。主要对映体tr=21.6分钟,次要对映体tr=16.7分钟。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C32H27NNaO3S,528.1604;found 528.1620。
1H NMR(400MHz,CDCl3)δ8.22(d,J=8.4Hz,1H),7.46(d,J=7.6Hz,1H),7.30(dd,J=14.8,7.6Hz,2H),7.25-7.09(m,6H),7.08-6.93(m,6H),6.91(d,J=7.6Hz,1H),2.91(d,J=14.4Hz,1H),2.84(d,J=14.4Hz,1H),2.42(d,J=18.8Hz,1H),2.21(s,3H),2.11(d,J=18.8Hz,1H),1.14(s,3H)。
13C NMR(100MHz,CDCl3)δ205.0,161.8,144.7,138.8,136.8,135.7,135.5,134.7,132.2,131.5,131.0,131.0,129.4,128.8,127.6,126.7,124.8,124.4,123.6,123.3,119.9,119.7,115.8,51.2,43.6,36.6,28.7,21.6。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C32H27NNaO3S,528.1604;found 528.1620。
实施例19:(S)-3-((2-(叔丁基)-1-甲苯基-1H-吲哚-3-基)甲基)-3-甲基-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-(3,3-二甲基-1-内-1-基)苯基)-4-甲基苯磺酰胺(78.6mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体34.7mg,目标产物的产率为36%。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=90∶10,1.0mL/min,254nm,93∶7er);m/z(MH+)。主要对映体tr=12.0分钟,次要对映体tr=12.8分钟。
1H NMR(400MHz,CDCl3)δ8.17(d,J=8.4Hz,1H),7.68(d,J=7.6Hz,1H),7.39(d,J=8.4Hz,2H),7.31(t,J=7.2Hz,1H),7.23-7.12(m,2H),7.08(d,J=8.4Hz,2H),6.96(t,J=7.6Hz,1H),6.56(d,J=7.6Hz,2H),3.30(d,J=14.4Hz,1H),3.10(d,J=14.4Hz,1H),2.62(d,J=18.4Hz,1H),2.28(s,3H),2.10(d,J=18.4Hz,1H),1.67(s,9H),1.28(s,3H)。
13C NMR(100MHz,CDCl3)δ205.2,162.0,148.8,144.7,139.7,135.7,135.2,134.6,133.5,129.2,128.0,127.5,126.4,125.0,124.7,124.4,123.6,119.5,118.5,51.6,43.3,37.8,37.4,33.2,27.9,21.7。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C30H31NNaO3S,508.1917;found 508.1926。
实施例20:(S)-3-((2-丁基-1-(甲基磺酰基)-1H-吲哚-3-基)甲基)-3-甲基-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-(六角-1-内-1-基)苯基)甲磺酰胺(60.3mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到56.4mg白色固体,目标产物的产率为69%。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=90:10,0.8mL/min,230nm,95:5er);和。主要对映体tr=15.3分钟,次要对映体tr=12.8分钟。
1H NMR(400MHz,CDCl3)δ7.96(d,J=8.4Hz,1H),7.66-7.59(m,1H),7.53(dd,J=14.8,7.6Hz,2H),7.38(t,J=8.0Hz,1H),7.24-7.18(m,1H),7.17-7.06(m,2H),3.05(d,J=14.4Hz,1H),3.00(d,J=14.4Hz,1H),2.80(d,J=18.4Hz,1H),2.79(s,3H),2.40(d,J=18.4Hz,1H),2.20(t,J=7.6Hz,2H),1.70(s,3H),1.48-1.35(m,2H),1.22-1.07(m,2H),0.80(t,J=7.6Hz,3H)。
13C NMR(100MHz,CDCl3)δ204.7,161.0,140.6,136.8,136.6,134.9,131.6,128.3,124.6,124.4,123.9,123.1,119.1,117.4,115.0,51.0,43.9,39.7,37.5,32.6,27.7,25.9,22.5,13.9。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C24H27NNaO3S,432.1604;found 432.1613。
实施例21:(S)-3-甲基-3-((1-(甲基磺酰基)-2-(三甲基硅烷基)-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-((三甲基硅烷基)乙炔基)苯基)甲磺酰胺(64.2mg,0.24mmol)、氯化钯(1.8mg,0.01mmol)、(R,R)-L2(12.4mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL甲苯,在80℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到22.0mg白色固体,目标产物的产率为25%,67:33er。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=95:5,1.0mL/min,230nm,67:33er)。主要对映体tr=9.6分钟,次要对映体tr=8.7分钟。
1H NMR(400MHz,CDCl3)δ7.91(d,J=8.4Hz,1H),7.59(d,J=5.2Hz,2H),7.36(d,J=6.4Hz,1H),7.27(s,1H),7.19(t,J=8.0Hz,1H),6.96(t,J=7.6Hz,1H),6.82(d,J=8.0Hz,1H),3.35(d,J=14.0Hz,1H),3.20(d,J=14.4Hz,1H),2.98(d,J=18.4Hz,1H),2.73(s,3H),2.41(d,J=18.4Hz,1H),1.67(s,3H),0.44(s,9H)。
13C NMR(100MHz,CDCl3)δ204.7,161.2,139.9,139.1,136.3,134.8,133.7,132.6,127.9,125.5,124.5,123.3,122.9,119.7,114.6,50.6,43.1,38.6,37.5,28.0,2.8。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C23H27NNaO3SSi,448.1373;found448.1380。
实施例22:(S)-3-甲基-3-((1-(甲基磺酰基)-2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-(苯乙炔基)苯基)甲磺酰胺(65.1mg,0.24mmol)、氯化钯(1.8mg,0.01mmol)、(R,R)-L4(23.8mg,0.02mmol)、磷酸钠(53.0mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在70℃的油浴锅中反应18h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体68.1mg,目标产物的产率为79%。
通过HPLC使用Chiralpak AD-H柱(己烷:2-丙醇=95:5,1.0mL/min,254nm,77:23er)测定对映体过量。主要对映体tr=39.1分钟,次要对映体tr=34.3分钟。
1H NMR(400MHz,CDCl3)δ8.09(d,J=8.4Hz,1H),7.57(d,J=7.6Hz,1H),7.49-7.40(m,3H),7.39(s,1H),7.33-7.28(m,2H),7.25-7.22(m,2H),7.17(t,J=7.6Hz,2H),7.10(d,J=7.2Hz,1H),3.12(d,J=14.4Hz,1H),3.03(d,J=14.4Hz,1H),2.78(s,3H),2.64(d,J=18.4Hz,1H),2.28(d,J=18.4Hz,1H),1.32(s,3H)。
13C NMR(100MHz,CDCl3)δ205.1,161.6,138.7,136.3,135.9,134.7,131.0,130.8,129.0,128.0,127.7,125.1,124.4,123.8,123.3,120.0,119.3,115.1,51.3,43.7,40.6,36.7,28.5。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C26H23NNaO3S,452.1291;found 452.1300。
实施例23:(S)-3-甲基-3-((1-(甲基磺酰基)-2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、N-(2-(苯乙炔基)苯基)甲磺酰胺(65.1mg,0.24mmol)、三(二亚苄基丙酮)二钯(9.2mg,0.01mmol)、(R,R)-L1(13.5mg,0.024mmol)、碳酸钾(69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入1.7mL,1,4-二氧六环,在100℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体66.3mg,目标产物的产率为77%。
通过HPLC使用Chiralpak AD-H柱(己烷:2-丙醇=95:5,1.0mL/min,254nm,65:35er)测定对映体过量。主要对映体tr=39.9分钟,次要对映体tr=34.2分钟。
1H NMR(400MHz,CDCl3)δ8.09(d,J=8.4Hz,1H),7.57(d,J=7.6Hz,1H),7.49-7.40(m,3H),7.39(s,1H),7.33-7.28(m,2H),7.25-7.22(m,2H),7.17(t,J=7.6Hz,2H),7.10(d,J=7.2Hz,1H),3.12(d,J=14.4Hz,1H),3.03(d,J=14.4Hz,1H),2.78(s,3H),2.64(d,J=18.4Hz,1H),2.28(d,J=18.4Hz,1H),1.32(s,3H)。
13C NMR(100MHz,CDCl3)δ205.1,161.6,138.7,136.3,135.9,134.7,131.0,130.8,129.0,128.0,127.7,125.1,124.4,123.8,123.3,120.0,119.3,115.1,51.3,43.7,40.6,36.7,28.5。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C26H23NNaO3S,452.1291;found 452.1300。
实施例24:(S)-3-甲基-3-((5-甲基-2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、2,2,2-三氟-N-(4-甲基-2-(苯乙炔基)苯基)乙酰胺(72.8mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到41.7mg白色固体,目标产物的产率为57%。
用Chiralpak As-H柱通过HPLC测定对映体过量(己烷:2-丙醇=90:10,1.0mL/min,230nm,95:5er);m/z(MH+)。主要对映体tr=26.5分钟,次要对映体tr=30.2分钟。
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.43(d,J=7.6Hz,1H),7.36-7.27(m,6H),7.26-7.10(m,3H),6.91(d,J=7.6Hz,2H),3.36-3.25(dd,J=15.6Hz,14.8Hz,2H),2.66(d,J=18.4Hz,1H),2.34(s,3H),2.17(d,J=18.4Hz,1H),1.37(s,3H)。
13C NMR(100MHz,CDCl3)δ205.8,162.1,136.7,136.1,134.2,134.0,133.9,130.0,128.9,128.7,128.6,127.7,127.4,124.5,123.6,122.9,119.1,110.5,108.5,50.7,44.7,36.7,28.1,21.6。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C26H23NNaO,388.1672;found 388.1682。
实施例25:(S)-3-((5-氟-2-苯基-1H-吲哚-3-基)甲基)-3-甲基-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、2,2,2-三氟-N-(4-氟-2-(苯乙炔基)苯基)乙酰胺(73.7mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体50.8mg,目标产物的产率为69%。
通过具有Chiralpak As-H柱和Chiralpak IC柱的HPLC测定对映体过量(己烷:2-丙醇=90:10,1.0mL/min,230nm,97:3er);和。主要对映体tr=44.8分钟,次要对映体tr=42.5分钟。
1H NMR(400MHz,CDCl3)δ8.33(d,J=164.4Hz,1H),7.39-7.28(m,7H),7.24(d,J=4.8Hz,1H),7.20-7.16(m,1H),7.12(dd,J=8.8,4.4Hz,1H),6.85-6.77(m,1H),6.75-6.59(m,1H),3.34-3.22(m,2H),2.56(d,J=18.4Hz,1H),2.14(d,J=18.4Hz,1H),1.39(d,J=20.8Hz,3H)。
13C NMR(100MHz,CDCl3)δ205.6,161.6,157.9(d,J=232.8Hz),138.5,136.1,134.4,133.5,132.0,130.2(d,J=9.5Hz),129.0,128.5,128.1,127.6,124.4,122.9,111.6(d,J=9.6Hz),110.2(d,J=26.1Hz),109.0(d,J=4.6Hz),104.1(d,J=23.6Hz),50.6,44.6,36.8,28.0。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C25H20FNNaO,392.1421;found 392.1432。
实施例26:(S)-3-甲基-3-((2-苯基-1-甲苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、4-甲基-N-(2-(苯乙炔基)苯基)苯磺酰胺(90.2mg,0.26mmol)、三(二亚苄基丙酮)二钯(9.2mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾(74.6mg,0.54mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在100℃的油浴锅中反应24h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1进行分离,得到47.8mg白色固体,目标产物的产率为49%。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=95:5,1.0mL/min,254nm,61:39er)。主要对映体tr=21.4分钟,次要对映体tr=16.9分钟。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C32H27NNaO3S,528.1604;found 528.1620。
1H NMR(400MHz,CDCl3)δ8.22(d,J=8.4Hz,1H),7.46(d,J=7.6Hz,1H),7.30(dd,J=14.8,7.6Hz,2H),7.25-7.09(m,6H),7.08-6.93(m,6H),6.91(d,J=7.6Hz,1H),2.91(d,J=14.4Hz,1H),2.84(d,J=14.4Hz,1H),2.42(d,J=18.8Hz,1H),2.21(s,3H),2.11(d,J=18.8Hz,1H),1.14(s,3H)。
13C NMR(100MHz,CDCl3)δ205.0,161.8,144.7,138.8,136.8,135.7,135.5,134.7,132.2,131.5,131.0,131.0,129.4,128.8,127.6,126.7,124.8,124.4,123.6,123.3,119.9,119.7,115.8,51.2,43.6,36.6,28.7,21.6。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C32H27NNaO3S,528.1604;found 528.1620。
实施例27:(S)-3-((5-氯-2-苯基-1H-吲哚-3-基)甲基)-3-甲基-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、2,2,2-三氟-N-(4-氯-2-(苯乙炔基)苯基)乙酰胺(77.7mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体59.7mg,目标产物的产率为78%。
用双Chiralpak OD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=98∶2,1.0mL/min,254nm,96∶4er);m/z(MH+)。主要对映体tr=94.4分钟,次要对映体tr=103.0分钟。
1H NMR(400MHz,CDCl3)δ8.39(s,1H),7.39-7.27(m,7H),7.24(d,J=6.0Hz,1H),7.17(t,J=7.6Hz,1H),7.07(d,J=8.8Hz,1H),6.99-6.89(m,2H),3.26(s,2H),2.50(d,J=18.4Hz,1H),2.11(d,J=18.4Hz,1H),1.40(s,3H)。
13C NMR(100MHz,CDCl3)δ205.5,161.5,138.1,136.1,134.4,133.8,133.2,130.7,129.0,128.6,128.2,127.7,125.2,124.4,122.9,122.1,118.7,111.9,108.5,50.5,44.5,36.8,27.9。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C25H20ClNNaO,408.1126;found 408.1130。
实施例28:(S)-3-乙基-3-((2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-乙基-3-(2-碘苯基)环丁烷-1-酮(60.0mg,0.2mmol)、2,2,2-三氟-N-(2-(苯乙炔基)苯基)乙酰胺(69.4mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到45.0mg白色固体,目标产物的产率为62%。
通过使用Chiralpak IC柱的HPLC测定对映体过量(己烷:2-丙醇=97:3,1.0mL/min,230nm,97.5:2.5er);m/z。主要对映体tr=36.4分钟,次要对映体tr=28.6分钟。
1H NMR(400MHz,CDCl3)δ8.26(d,J=81.2Hz,1H),7.30(d,J=7.2Hz,1H),7.21-7.13(m,6H),7.13-7.04(m,4H),6.99(t,J=7.2Hz,1H),6.86(t,J=7.6Hz,1H),3.35-3.22(m,2H),2.42(d,J=18.4Hz,1H),2.15(d,J=18.4Hz,1H),1.72(q,J=7.2Hz,2H),0.47(t,J=7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ206.1,160.3,137.1,136.7,135.5,134.2,133.8,129.9,128.9,128.6,127.8,127.4,124.7,122.8,122.0,119.7,119.4,110.9,108.7,48.7,46.6,35.3,32.5,9.0。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C26H23NNaO,388.1672;found 388.1682。
实施例29:(S)-3-苯基-3-((2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘苯基)-3-苯基环丁烷-1-酮(69.6mg,0.2mmol)、2,2,2-三氟-N-(2-(苯乙炔基)苯基)乙酰胺(69.4mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体27mg,目标产物的产率为33%。
用Chiralpak IC柱通过HPLC测定对映体过量(己烷:2-丙醇=90∶10,1.0mL/min,230nm,>99∶1);主要对映体tr=12.1min,次要对映体tr=8.4min。
1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.38-7.27(m,9H),7.25-7.21(m,3H),7.20-7.17(m,1H),7.16-7.11(m,2H),7.07(t,J=7.2Hz,1H),7.00(d,J=8.0Hz,1H),6.89(t,J=7.6Hz,1H),4.02(d,J=14.0Hz,1H),3.89(d,J=14.0Hz,1H),3.03(d,J=18.4Hz,1H),2.62(d,J=18.4Hz,1H),1.67(s,3H)。
13C NMR(101MHz,CDCl3)δ204.8,159.2,147.2,137.3,137.1,135.4,133.9,133.7,129.9,129.0,128.8,128.6,128.0,127.8,127.1,126.6,122.6,122.1,119.8,119.1,52.5,52.2,34.7。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C30H23NNaO,436.1672;found 436.1672。
实施例30:(S)-3-甲基-3-((2-苯基-1H-吲哚-3-基)甲基)-5-(噻吩-2-基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘-5-(噻吩-2-基)苯基)-3-甲基环丁烷-1-酮(73.6mg,0.2mmol)、2,2,2-三氟-N-(2-(苯乙炔基)苯基)乙酰胺(69.4mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体60.4mg,目标产物的产率为70%。
用Chiralpak IC柱通过HPLC测定对映体过量(己烷:2-丙醇=95:5,1.0mL/min,230nm,96:4er);m/z 185。主要对映体tr=37.3分钟,次要对映体tr=30.0分钟。
1H NMR(400MHz,CDCl3)δ8.21(s,1H),7.43-7.38(m,2H),7.36-7.29(m,4H),7.29-7.24(m,4H),7.21(dd,J=3.6,1.2Hz,1H),7.18-7.07(m,3H),7.04-6.96(m,1H),3.42(d,J=14.4Hz,1H),3.35(d,J=14.4,1H),2.69(d,J=18.4,1H),2.25(d,J=18.4Hz,1H),1.43(s,3H)。
13C NMR(100MHz,CDCl3)δ204.7,162.5,143.7,140.1,136.7,135.6,135.0,133.6,129.9,128.9,128.4,128.3,127.9,126.5,125.5,124.9,123.6,122.2,121.7,119.9,119.5,110.9,108.8,51.4,44.8,36.8,27.9。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C29H23NNaOS,456.1393;found 456.1402。
实施例31:(S)-3-甲基-3-((2-苯基-1-甲苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘代苯基)-3-甲基环丁烷-1-酮(57.2mg,0.2mmol)、4-甲基-N-(2-(苯乙炔基)苯基)苯磺酰胺(83.3mg,0.24mmol)、三(二亚苄基丙酮)二钯(9.2mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钠(53.0mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2.5mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1进行分离,得到76.1mg白色固体,目标产物的产率为78%。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=95:5,1.0mL/min,254nm,61:39er)。主要对映体tr=21.2分钟,次要对映体tr=16.5分钟。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C32H27NNaO3S,528.1604;found 528.1620。
1H NMR(400MHz,CDCl3)δ8.22(d,J=8.4Hz,1H),7.46(d,J=7.6Hz,1H),7.30(dd,J=14.8,7.6Hz,2H),7.25-7.09(m,6H),7.08-6.93(m,6H),6.91(d,J=7.6Hz,1H),2.91(d,J=14.4Hz,1H),2.84(d,J=14.4Hz,1H),2.42(d,J=18.8Hz,1H),2.21(s,3H),2.11(d,J=18.8Hz,1H),1.14(s,3H)。
13C NMR(100MHz,CDCl3)δ205.0,161.8,144.7,138.8,136.8,135.7,135.5,134.7,132.2,131.5,131.0,131.0,129.4,128.8,127.6,126.7,124.8,124.4,123.6,123.3,119.9,119.7,115.8,51.2,43.6,36.6,28.7,21.6。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C32H27NNaO3S,528.1604;found 528.1620。
实施例32:(S)-5-甲氧基-3-甲基-3-((2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘-5-甲氧基苯基)-3-甲基环丁烷-1-酮(63.2mg,0.2mmol)、2,2,2-三氟-N-(2-(苯乙炔基)苯基)乙酰胺(69.4mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到51.1mg白色固体,目标产物的产率为67%。用Chiralpak IC柱通过HPLC测定对映体过量(己烷:2-丙醇=95:5,1.0mL/min,230nm,97:3er);m/z(MH+)。主要对映体tr=22.1分钟,次要对映体tr=18.4分钟。
1H NMR(400MHz,CDCl3)δ8.31(s,1H),7.40(d,J=8.8Hz,1H),7.32-7.27(m,5H),7.27-7.21(m,2H),7.11(t,J=7.6Hz,1H),7.00(t,J=7.6Hz,1H),6.68(dd,J=8.4,2.0Hz,1H),6.51(d,J=2.0Hz,1H),3.61(s,3H),3.36(d,J=14.4Hz,1H),3.26(d,J=14.4Hz,1H),2.66(d,J=18.4Hz,1H),2.20(d,J=18.4Hz,1H),1.31(s,3H)。
13C NMR(100MHz,CDCl3)δ204.0,164.9,164.9,136.6,135.6,133.8,130.0,129.3,128.8,128.5,127.7,124.7,122.0,119.6,119.5,115.2,110.9,108.9,108.3,55.4,51.3,44.5,36.7,27.7。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C26H23NNaO2,404.1621;found 404.1631。
实施例33:(S)-3,5-二甲基-3-((2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘-5-甲基苯基)-3-甲基环丁烷-1-酮(60.0mg,0.2mmol)、2,2,2-三氟-N-(2-(苯乙炔基)苯基)乙酰胺(69.4mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体42.1mg,目标产物的产率为58%。
用Chiralpak IC柱通过HPLC测定对映体过量(己烷∶2-丙醇=95∶5,1.0mL/min,230nm,98∶2er);m/z(MH+)。主要对映体tr=29.3分钟,次要对映体tr=23.9分钟。
1H NMR(400MHz,CDCl3)δ8.23(s,1H),7.36-7.28(m,6H),7.28-7.23(m,2H),7.13-7.08(m,1H),7.03-6.93(m,3H),3.35(d,J=14.4Hz,1H),3.30(d,J=14.4Hz,1H),2.65(d,J=18.4Hz,1H),2.24(s,3H),2.16(d,J=18.4Hz,1H),1.33(s,3H)。
13C NMR(100MHz,CDCl3)δ205.3,162.5,145.5,136.5,135.6,133.9,133.8,130.0,128.9,128.7,128.6,127.9,125.1,122.9,122.1,119.7,119.5,51.0,44.6,36.5,28.1,22.3。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C26H23NNaO,388.1672;found 388.1681。
实施例34:(S)-5-氯-3-甲基-3-((2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(5-氯-2-碘苯基)-3-甲基环丁烷-1-酮(64.1mg,0.2mmol)、2,2,2-三氟-N-(2-(苯乙炔基)苯基)乙酰胺(69.4mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体42.2mg,目标产物的产率为55%。
用Chiralpak IC柱通过HPLC测定对映体过量(己烷:2-丙醇=97∶3,1.0mL/min,230nm,96∶4er);m/z(MH+)。主要对映体tr=26.2分钟,次要对映体tr=22.7分钟。
1H NMR(400MHz,CDCl3)δ8.15(s,1H),7.34-7.27(m,7H),7.22(d,J=8.4Hz,1H),7.16-7.10(m,2H),7.09-7.01(m,2H),3.35(d,J=14.4Hz,1H),3.30(d,J=14.4Hz,1H),2.66(d,J=18.4Hz,1H),2.19(d,J=18.4Hz,1H),1.38(s,3H)。
13C NMR(100MHz,CDCl3)δ204.0,163.0,140.7,136.6,135.6,134.5,133.5,129.8,128.9,128.4,128.2,128.1,125.1,124.0,122.1,119.8,119.2,111.0,108.2,50.9,44.8,36.6,27.7。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C25H20ClNNaO,408.1126;found 408.1136。
实施例35:(S)-3,5,6-三甲基-3-((2-苯基-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
将25mL的反应管进行无水无氧操作后,向其中依次加入3-(2-碘-4,5-二甲基苯基)-3-甲基环丁烷-1-酮(62.8mg,0.2mmol)、2,2,2-三氟-N-(2-(苯乙炔基)苯基)乙酰胺(69.4mg,0.24mmol)、烯丙基氯化钯二聚体(3.7mg,0.01mmol)、(R,R)-L1(11.3mg,0.02mmol)、碳酸钾69.1mg,0.5mmol),再次进行抽换气三次后在氮气保护下加入2mL,1,4-二氧六环,在90℃的油浴锅中反应12h。反应结束后使用旋转蒸发仪除去溶剂,再将其用少量二氯甲烷溶解后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体63.3mg,目标产物的产率为83%。
用Chiralpak AS-H柱通过HPLC测定对映体过量(己烷:2-丙醇=90:10,1.0mL/min,230nm,95:5er);m/z(MH+)。主要对映体tr=27.2分钟,次要对映体tr=22.0分钟。
1H NMR(400MHz,CDCl3)δ8.24(s,1H),7.35(d,J=8.0Hz,1H),7.30-7.23(m,6H),7.19(s,1H),7.13-7.08(m,1H),7.05-7.00(m,1H),6.96-6.90(m,1H),3.34(d,J=14.4Hz,1H),3.29(d,J=14.4Hz,1H),2.64(d,J=18.4Hz,1H),2.16(s,1H),2.14(s,3H),2.11(s,3H),1.33(s,3H)。
13C NMR(100MHz,CDCl3)δ205.6,160.1,144.3,136.4,136.1,135.6,134.1,133.7,130.0,128.5,128.4,127.5,125.4,123.2,121.9,119.5,119.3,111.0,108.8,50.9,44.3,36.5,28.0,20.9,19.6。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C27H25NNaO,402.1828;found 402.1839。
实施例36:(S)-3-甲基-3-((1-(甲基磺酰基)-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮的合成
25mL的反应管进行无水无氧操作后,向其中加入如上所述制备得到的(S)-3-甲基-3-((1-(甲基磺酰基)-2-(三甲基硅烷基)-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮(106.3mg,0.25mmol)和无水三氯化铝(33.3mg,0.25mmol),在氮气保护下加入5mL二氯甲烷,在60℃下反应15h,反应完成后用水淬灭并用二氯甲烷萃取,减压蒸馏浓缩后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体53.1mg,目标产物的产率为60%。
通过HPLC使用Chiralpak AD-H柱(己烷:2-丙醇=95:5,1.0mL/min,254nm,99:1er)测定对映体过量。主要对映体tr=32.6分钟,次要对映体tr=27.5分钟。
1H NMR(400MHz,CDCl3)δ7.82(d,J=8.8Hz,1H),7.68-7.62(m,1H),7.57(dd,J=17.2,8.0Hz,2H),7.38(t,J=7.6Hz,1H),7.32-7.26(m,2H),7.23-7.15(m,1H),6.57(s,1H),3.12(d,J=14.4Hz,1H),3.05(d,J=14.4Hz,1H),2.91(s,3H),2.71(d,J=18.4Hz,1H),2.44(d,J=18.4Hz,1H),1.64(s,3H)。
13C NMR(100MHz,CDCl3)δ205.1,161.2,136.6,135.1,134.8,131.5,128.2,125.0,124.6,124.2,123.5,123.0,119.5,118.4,113.2,50.4,43.1,40.4,37.6,27.9。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C20H19NNaO3S,376.0978;found 376.0986。
实施例37:(S)-3-((2-溴-1-(甲基磺酰基)-1H-吲哚-3-基)甲基)-3-甲基-2,3-二氢-1H-茚-1-酮的合成
25mL的反应管进行无水无氧操作后,向其中加入如上所述制备得到的(S)-3-甲基-3-((1-(甲基磺酰基)-2-(三甲基硅烷基)-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮(212.6mg,0.5mmol)和NBS(106.8mg,0.6mmol),在氮气保护下加入6mL二氯甲烷,在40℃下反应18h,反应完成后用水和二氯甲烷萃取,减压蒸馏浓缩后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体204.0mg,目标产物的产率为95%。
用Chiralpak As-H柱通过HPLC测定对映体过量(己烷:2-丙醇=90:10,1.0mL/min,254nm,99:1er)。主要对映体tr=50.5分钟,次要对映体tr=38.1分钟。
1H NMR(400MHz,CDCl3)δ8.01(d,J=8.4Hz,1H),7.63-7.56(m,1H),7.51(d,J=8.8Hz,2H),7.35(t,J=7.2Hz,1H),7.23-7.15(m,1H),7.06(t,J=7.6Hz,1H),6.89(d,J=8.0Hz,1H),3.16-3.02(m,5H),2.98(d,J=18.4Hz,1H),2.45(d,J=18.4Hz,1H),1.65(s,3H)。
13C NMR(100MHz,CDCl3)δ204.7,160.9,137.0,136.2,134.9,129.8,128.1,125.0,124.6,123.8,123.3,121.9,119.2,114.9,111.7,51.2,43.9,41.3,38.5,27.7。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C20H18BrNNaO3S,454.0083;found454.0087。
实施例38:(S)-3-((2-碘-1-(甲基磺酰基)-1H-吲哚-3-基)甲基)-3-甲基-2,3-二氢-1H-茚-1-酮的合成
25mL的反应管进行无水无氧操作后,向其中加入如上所述制备得到的(S)-3-甲基-3-((1-(甲基磺酰基)-2-(三甲基硅烷基)-1H-吲哚-3-基)甲基)-2,3-二氢-1H-茚-1-酮(107mg,0.25mmol)和二氯甲烷(2mL),然后加入氯化碘(52mg,0.32mmol)在室温下反应24h,反应完成后用硫代硫酸钠的水溶液淬灭和二氯甲烷萃取,减压蒸馏浓缩后使用硅胶柱以石油醚:乙酸乙酯15:1分离,得到白色固体113mg,目标产物的产率为94%。
用Chiralpak AD-H柱通过HPLC测定对映体过量(己烷:2-丙醇=90:10,1.0mL/min,230nm,99:1er)。主要对映体tr=20.1分钟,次要对映体tr=18.9分钟。
1H NMR(400MHz,CDCl3)δ8.04(d,J=8.4Hz,1H),7.60-7.56(m,1H),7.54(d,J=7.6Hz,1H),7.45(d,J=7.6Hz,1H),7.39-7.34(m,1H),7.18-7.12(m,1H),7.05-6.99(m,1H),6.89(d,J=8.0Hz,1H),3.13(d,J=14.4Hz,1H),3.08(d,J=14.4Hz,1H),3.01(d,J=16.8Hz,4H),2.46(d,J=18.4Hz,1H),1.67(s,3H)。
13C NMR(100MHz,CDCl3)δ204.9,161.1,138.9,136.5,135.0,130.6,128.9,128.2,125.1,124.9,123.7,123.5,119.4,115.4,83.4,51.6,44.1,41.5,40.9,28.1。
HRMS(ESI-TOF)m/z:[M+Na]+Calcd for C20H18INNaO3S,501.9944;found501.9939。
测试例1:参考公开号为CN108552195A的测定方法测定本发明化合物对斜纹夜蛾2龄幼虫的室内毒杀活性。测定结果如表1所示。
表1
表1中“+”代表对斜纹夜蛾2龄幼虫具有室内毒杀活性。
Claims (9)
2.一种如式(I)所示的手性吲哚类化合物的制备方法,其特征在于,在反应介质中,式(II)所示的环丁酮类化合物和式(III)所示的苯乙烯类化合物在催化剂钯盐、手性配体和碱的作用下,进行不对称开环环化-串联反应得到所述的式(I)所示的手性吲哚类化合物;
其中,
R1分别独立地为H、F、Cl、Br、I、C1-3烷基、C1-3烷氧基或噻吩基;
R2为甲基、乙基或苯基;
R3为H、Br、I、正丁基、叔丁基、三甲基硅基、苯基、对氟苯基、对甲基苯基、对三氟甲基苯基、对硝基苯基、噻吩基;
R4为H、对甲苯磺酰基或甲磺酰基;
R5为F、Cl、Br、I或C1-3烷基;
所述的手性配体为如式(R,R)-L1、(R,R)-L2、(R,R)-L3、(R,R)-L4、(R,R)-L5或(R,R)-L6所示的TADDOL衍生的亚磷酰胺类化合物;
所述的催化剂钯盐选自烯丙基氯化钯、三(二亚苄基丙酮)二钯、氯化钯、醋酸钯或三氟乙酸钯中的任意一种;
所述的碱选自碳酸钾、碳酸钠、碳酸银或磷酸钾中的任意一种。
4.根据权利要求2所述的手性吲哚类化合物的制备方法,其特征在于,所述的制备方法具体包括如下步骤:在惰性气体的保护下,将手性配体、催化剂钯盐、碱、式(II)所示的环丁酮类化合物和式(III)所示的苯乙烯类化合物依次加入反应介质中,进行不对称开环环化-串联反应得到式(I)所示的手性吲哚类化合物。
5.根据权利要求2所述的手性吲哚类化合物的制备方法,其特征在于,所述的不对称开环环化-串联反应的反应温度为25~100℃,反应时间为12~24h。
6.根据权利要求2所述的手性吲哚类化合物的制备方法,其特征在于,反应介质选自1,4-二氧六环、二氯甲烷、二氯乙烷、甲苯中的任意一种,式(II)所示的环丁酮类化合物的浓度为0.08~0.12mol/L。
7.根据权利要求2所述的手性吲哚类化合物的制备方法,其特征在于,所述的式(II)所示的环丁酮类化合物、式(III)所示的苯乙烯类化合物的摩尔比为1:1.1~1.3。
8.根据权利要求2所述的手性吲哚类化合物的制备方法,其特征在于,所述的催化剂钯盐的用量为式(II)所示的环丁酮类化合物的3~6mol%;所述的手性配体的用量为式(II)所示的环丁酮类化合物的8~12mol%。
9.根据权利要求1所述的手性吲哚类化合物在制备杀虫剂中的应用。
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