CN118108725A - Chiral aza-bridged ring compound, and preparation method and application thereof - Google Patents
Chiral aza-bridged ring compound, and preparation method and application thereof Download PDFInfo
- Publication number
- CN118108725A CN118108725A CN202211520038.2A CN202211520038A CN118108725A CN 118108725 A CN118108725 A CN 118108725A CN 202211520038 A CN202211520038 A CN 202211520038A CN 118108725 A CN118108725 A CN 118108725A
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- CN
- China
- Prior art keywords
- substituted
- chiral
- benzyl
- bridged ring
- ring compound
- Prior art date
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- Pending
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 82
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 229910052751 metal Inorganic materials 0.000 claims abstract description 11
- 239000002184 metal Substances 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- 150000004714 phosphonium salts Chemical group 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 6
- 229940126062 Compound A Drugs 0.000 claims abstract description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- -1 diastereomers Chemical group 0.000 claims description 21
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical class C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical class C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 150000002431 hydrogen Chemical class 0.000 claims description 17
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical class C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 16
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 16
- 125000001624 naphthyl group Chemical class 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 12
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical class COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- 125000003107 substituted aryl group Chemical group 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 10
- 229930192474 thiophene Chemical class 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical class C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N Benzylformate Chemical compound O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 206010028980 Neoplasm Diseases 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 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 6
- 125000002915 carbonyl group Chemical class [*:2]C([*:1])=O 0.000 claims description 6
- 150000002475 indoles Chemical class 0.000 claims description 6
- 150000003233 pyrroles Chemical class 0.000 claims description 6
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 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
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical class CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-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
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 4
- 239000013078 crystal Chemical group 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 150000002240 furans Chemical class 0.000 claims description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 150000003222 pyridines Chemical class 0.000 claims description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 4
- 150000003577 thiophenes Chemical class 0.000 claims description 4
- NCXADAULCYRZML-UHFFFAOYSA-N (carbamothioylamino)urea Chemical compound NC(=O)NNC(N)=S NCXADAULCYRZML-UHFFFAOYSA-N 0.000 claims description 3
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910015898 BF4 Inorganic materials 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910021293 PO 4 Inorganic materials 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 3
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 3
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 150000003585 thioureas Chemical class 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 125000006651 (C3-C20) cycloalkyl group Chemical group 0.000 claims description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- HCGYMSSYSAKGPK-UHFFFAOYSA-N 2-nitro-1h-indole Chemical compound C1=CC=C2NC([N+](=O)[O-])=CC2=C1 HCGYMSSYSAKGPK-UHFFFAOYSA-N 0.000 claims description 2
- 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 group C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000005599 alkyl carboxylate group Chemical class 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 2
- LJDZFAPLPVPTBD-UHFFFAOYSA-N nitroformic acid Chemical compound OC(=O)[N+]([O-])=O LJDZFAPLPVPTBD-UHFFFAOYSA-N 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940071536 silver acetate Drugs 0.000 claims description 2
- KKKDGYXNGYJJRX-UHFFFAOYSA-M silver nitrite Chemical group [Ag+].[O-]N=O KKKDGYXNGYJJRX-UHFFFAOYSA-M 0.000 claims description 2
- 229910001923 silver oxide Inorganic materials 0.000 claims description 2
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 claims description 2
- 229910000367 silver sulfate Inorganic materials 0.000 claims description 2
- 229910001494 silver tetrafluoroborate Inorganic materials 0.000 claims description 2
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
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- 125000000547 substituted alkyl group Chemical class 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- CBNBGETWKBUTEL-UHFFFAOYSA-K tripotassium;phosphate;heptahydrate Chemical compound O.O.O.O.O.O.O.[K+].[K+].[K+].[O-]P([O-])([O-])=O CBNBGETWKBUTEL-UHFFFAOYSA-K 0.000 claims description 2
- KPZYAGQLBFUTMA-UHFFFAOYSA-K tripotassium;phosphate;trihydrate Chemical compound O.O.O.[K+].[K+].[K+].[O-]P([O-])([O-])=O KPZYAGQLBFUTMA-UHFFFAOYSA-K 0.000 claims description 2
- AGXLJXZOBXXTBA-UHFFFAOYSA-K trisodium phosphate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[O-]P([O-])([O-])=O AGXLJXZOBXXTBA-UHFFFAOYSA-K 0.000 claims description 2
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- 238000006555 catalytic reaction Methods 0.000 abstract description 2
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- 238000000926 separation method Methods 0.000 abstract description 2
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 abstract 1
- 229910052731 fluorine Inorganic materials 0.000 abstract 1
- 239000011737 fluorine Substances 0.000 abstract 1
- 125000000524 functional group Chemical group 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 210000004027 cell Anatomy 0.000 description 33
- 238000006467 substitution reaction Methods 0.000 description 25
- KESNYCKCLIGEBX-UHFFFAOYSA-N 2h-chromene-8-carboxylic acid Chemical compound C1=CCOC2=C1C=CC=C2C(=O)O KESNYCKCLIGEBX-UHFFFAOYSA-N 0.000 description 19
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 238000012512 characterization method Methods 0.000 description 9
- 238000001819 mass spectrum Methods 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 230000005311 nuclear magnetism Effects 0.000 description 9
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- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
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- 238000012360 testing method Methods 0.000 description 5
- VNWYCQAUXWEBHU-UHFFFAOYSA-N 2h-chromene-8-carboxamide Chemical compound C1=CCOC2=C1C=CC=C2C(=O)N VNWYCQAUXWEBHU-UHFFFAOYSA-N 0.000 description 4
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
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Landscapes
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Abstract
The invention discloses a chiral aza-bridged ring compound, a preparation method and application thereof, wherein the preparation method comprises the following steps: dissolving a compound A and a compound B in an organic solvent, adding a chiral quaternary phosphonium salt catalyst, and reacting an alkali with a metal salt to obtain the chiral fluorine-containing tropane derivative. The chiral aza-bridged ring compound synthesized by the method has high stereoselectivity and excellent separation yield through novel efficient asymmetric catalytic reaction, the synthetic method has good functional group compatibility, simple and convenient operation, easily obtained raw materials, tolerance to water and oxygen and capability of synthesizing a series of polysubstituted chiral aza-bridged ring compounds in a diversified way. The chiral aza-bridged ring compound provided by the invention has great application potential and development prospect in preparing medicines for preventing and/or treating melanoma and cervical cancer.
Description
Technical Field
The invention relates to the technical fields of chemical industry and medicine, in particular to a chiral aza-bridged ring compound, a preparation method and application thereof.
Background
Chiral aza-bridged ring compounds are widely used in natural products and pharmaceutical molecular structures, and have important biological and pharmacological activities. The compounds are often used for screening and researching pharmacological, biosynthesis, biological activity and medicinal properties, and play important roles in resisting cancers and tumors and treating Alzheimer's disease and parkinsonism. However, these compounds often contain multiple sequential chiral centers and asymmetric synthesis is challenging and difficult due to their unfavorable trans-cyclic interactions and large ring tensions. At present, the asymmetric synthesis of chiral aza-bridged ring compounds has the following problems: 1) The synthesis line is redundant, and the total yield is low; 2) The report of asymmetric catalytic synthesis is less, and an efficient synthesis method is lacked; 3) The catalytic system is single, and the diversity synthesis is limited; 4) Chiral aza-octanine-membered bridged rings have not been reported so far. Therefore, the synthesis of the chiral aza-bridged ring skeleton molecule has high research value, not only can enrich chiral aza-bridged ring compound families, but also is beneficial to the development and application of the compound in the aspects of biological activity exploration and drug research and development.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide a chiral aza-bridged ring compound, a preparation method and application thereof, enrich chiral aza-bridged ring compound families and construct the chiral aza-bridged ring compound through a novel efficient asymmetric catalytic reaction by a one-pot method.
The technical scheme for solving the technical problems is as follows: provided is a chiral aza-bridged ring compound, comprising: a structural general formula I and corresponding enantiomers, diastereomers, salts or crystal forms thereof:
Wherein R 1 is hydrogen, C 1-20 straight or branched alkyl, C 3-20 cycloalkyl, alkoxy, aryl or substituted aryl, benzyl or substituted benzyl, halogen, ketocarbonyl, ester, sulfonyl, trifluoromethyl, nitro;
r 2 is hydrogen, formyl or substituted formyl, C 1-20 straight or branched alkyl or substituted C 1-20 straight or branched alkyl, alkyl alcohol, phenyl alcohol or substituted phenyl alcohol, nitro, alkyl carboxylate or substituted alkyl carboxylate, sulfonyl, aryl or substituted aryl, heterocycle or substituted heterocycle;
R 3 is hydrogen, C 1-20 straight or branched alkyl or substituted C 1-20 straight or branched alkyl, alkyl alcohol, nitro, indole or substituted indole, benzofuran or substituted benzofuran, benzothiophene or substituted benzothiophene, pyrrole or substituted pyrrole, thiophene or substituted thiophene, furan or substituted furan, pyridine or substituted pyridine, naphthyl or substituted naphthyl, phenyl or substituted phenyl, sulfonyl, aryl or substituted aryl, heterocycle or substituted heterocycle;
r 4 is hydrogen, C 1-20 straight or branched alkyl, alkyl alcohol, nitro, ester group or substituted ester group, carboxyl or substituted carboxyl, amide group;
R 5 is hydrogen, C 1-20 straight or branched alkyl, t-butoxycarbonyl, benzoyl or substituted benzoyl, benzyl or substituted benzyl, ester or substituted ester, carboxyl or substituted carboxyl;
ar is aryl or substituted aryl, heterocycle or substituted heterocycle;
n is 1 or 2.
Based on the technical scheme, the invention can also be improved as follows:
Further, R 1 is hydrogen, C 1-20 straight or branched alkyl, cyclopropyl, benzyl;
R 2 is benzoyl or substituted benzoyl (e.g., methyl substitution, halogen substitution, methoxy substitution, natural bioactive macromolecule substitution such as gemfibrozil (1-36), fenofibric acid (1-37), retinoic acid (1-38), etc.), benzothiophenyl, furoyl, thenoyl, naphthoyl, pyrroloyl, pyridine formyl, benzyl alcohol, indole formyl or substituted indole formyl (e.g., methyl substitution, etc.), cycloalkyl formyl (e.g., cyclopropane formyl, cyclohexane formyl, cyclobutane formyl, etc.), C 1-20 straight chain alkyl formyl or C 1-20 branched alkyl formyl, nitro, trifluoromethyl, benzenesulfonyl, alkyl dicarboxylic acid ester (e.g., diethyl malonate, etc.);
R 3 is indole or substituted indole (e.g., methyl substitution, halogen substitution, methoxy substitution, benzyl substitution, boc substitution, etc.), benzofuran or substituted benzofuran, benzothiophene or substituted benzothiophene (e.g., halogen substitution, etc.), pyrrole or substituted pyrrole (e.g., methyl substitution, etc.), thiophene or substituted thiophene, furan or substituted furan, pyridine or substituted pyridine, naphthyl or substituted naphthyl, phenyl or substituted phenyl (e.g., methyl substitution, halogen substitution, methoxy substitution, trifluoromethyl substitution, etc.);
R 4 is methyl formate, ethyl formate, propyl formate, benzyl formate, nitro, formate, methanol, amide;
r 5 is hydrogen, C 1-20 straight or branched alkyl, t-butoxycarbonyl, benzoyl or substituted benzoyl (such as trifluoromethyl substitution, etc.), acetyl, benzyloxycarbonyl, methyl formate;
Ar is phenyl or substituted phenyl (methyl substitution, methoxy substitution, halogen substitution, cyano substitution, nitro substitution, trifluoromethyl substitution, etc.), pyridine, benzofuran, naphthyl or substituted naphthyl, pyrrole or substituted pyrrole (methyl substitution, etc.), furan, thiophene, indole or substituted indole (methyl substitution, etc.), benzothiophene;
n is 1 or 2.
Further, the specific structural formula of the chiral aza-bridged ring compound is as follows:
The preparation method of the chiral aza-bridged ring compound comprises the following steps: dissolving a compound A and a compound B in an organic solvent, adding a chiral quaternary phosphonium salt catalyst, an alkaline substance and a metal salt, and reacting to obtain a chiral aza-bridged ring compound, namely a compound of the formula I;
The synthetic route is as follows:
Further, the organic solvent is dichloromethane, chloroform, 1, 2-dichloroethane, n-hexane, cyclohexane, petroleum ether, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, anisole, isopropyl ether, n-butyl ether, ethyl acetate, methanol, ethanol, acetonitrile, toluene, xylene, trimethylbenzene, chlorobenzene, fluorobenzene, bromobenzene, anisole or benzotrifluoride.
Further, the basic substance is triethylamine, diisopropylethylamine, DABCO, potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate trihydrate, potassium phosphate heptahydrate, sodium phosphate decahydrate, cesium fluoride, sodium phenolate, potassium t-butoxide, sodium hydroxide, potassium hydroxide or lithium hydroxide.
Further, the metal salt is silver nitrite, silver nitrate, silver acetate, silver tetrafluoroborate, silver carbonate, silver sulfate, silver oxide, silver triflate, copper acetate, copper sulfate, copper iodide, copper chloride, copper bromide, and copper tetrafluoroborate.
Further, the chiral quaternary phosphonium salt catalyst is:
Wherein, in the compound P, R 6 is hydrogen, C 1-20 alkyl, aryl or substituted aryl, benzyl or substituted benzyl, heterocycle or substituted heterocycle; r 7 is Boc, ts, acyl, ureido, thiourea or substituted thiourea, carbonyl or substituted carbonyl; r 8 is phenyl or substituted phenyl, benzyl or substituted benzyl, naphthyl or substituted naphthyl; x is halogen, PO 4,NO2,NO3,BF4, OTf, OAc or OBoc.
Further, the chiral quaternary phosphonium salt catalyst has the specific structure:
Further, the preparation method of the chiral quaternary phosphonium salt catalyst P comprises the following steps:
The chiral phosphine obtained by condensing amino phosphine and natural amino acid is subjected to wittig reaction to prepare the chiral bifunctional quaternary phosphonium salt catalyst in one step, and the synthetic route is as follows:
Slowly dripping methyl iodide into DCM solution of the phosphinous, stirring at room temperature until the reaction is complete (spot plate monitoring), washing with water, extracting and concentrating to obtain a target compound; or adding benzyl bromide into toluene solution of the trivalent phosphine, refluxing for 5 hours, cooling, spin drying and recrystallizing to obtain a product;
Wherein R 6 is hydrogen, C 1-20 alkyl, aryl or substituted aryl, benzyl or substituted benzyl, heterocycle or substituted heterocycle; r 7 is Boc, ts, acyl, ureido, thiourea or substituted thiourea, carbonyl or substituted carbonyl; r 8 is phenyl or substituted phenyl, benzyl or substituted benzyl, naphthyl or substituted naphthyl; x is halogen, PO 4,NO2,NO3,BF4, OTf, OAc or OBoc.
The preparation process of the trivalent phosphine and the benzyl bromide compound is carried out by adopting the prior art.
Further, the reaction temperature is between-78 and 40 ℃ and the reaction time is between 48 and 72 hours.
The chiral aza-bridged ring compound is applied to preparing medicines for preventing and/or treating tumors.
Further, the tumor is colon cancer, melanoma, cervical cancer or gastric cancer.
The invention has the following beneficial effects:
(1) The chiral nitrogen-containing heterocyclic compound synthesized by the method has high stereoselectivity and excellent separation yield, is simple and convenient to operate, has easily-obtained raw materials, and can be used for synthesizing a series of polysubstituted chiral nitrogen-containing heterocyclic compounds in a diversified manner.
(2) The novel chiral polypeptide quaternary phosphonium salt used in the invention has high structural adjustability, and can efficiently realize asymmetric transformation of reaction. The quaternary phosphonium salt is stable to water and oxygen, can be stored for a long time under the condition of room temperature, has easily available and cheap synthetic raw materials, and can be prepared and synthesized in a large amount.
(3) The chiral aza-bridged ring compound provided by the invention has certain activity in the test of inhibiting the growth of tumor cells, such as colon cancer, melanoma, cervical cancer and gastric cancer, has good inhibition effect in the biological activity test of gastric cancer and colon cancer cells, has insignificant inhibition effect on normal human cells, and has great application potential and development prospect in preparing medicines for preventing and/or treating melanoma and cervical cancer.
Drawings
FIG. 1 is a single crystal structure of Compound I-48 in example 5.
FIG. 2 is a HPLC chromatogram of the racemate of Compound I-1 in example 1.
FIG. 3 is a chiral product HPLC profile of Compound I-1 of example 1.
FIG. 4 is a HPLC chromatogram of the racemate of compound I-8 in example 2.
FIG. 5 is a HPLC chart of chiral product of compound I-8 of example 2.
FIG. 6 is a HPLC chromatogram of the racemate of compound I-37 of example 3.
FIG. 7 is a chiral product HPLC profile of Compound I-37 of example 3.
FIG. 8 is a HPLC chromatogram of the racemate of compound I-44 in example 4.
FIG. 9 is a chiral product HPLC chromatogram of compound I-44 in example 4.
FIG. 10 is a HPLC chromatogram of the racemate of compound I-48 in example 5.
FIG. 11 is a chiral product HPLC chromatogram of compound I-48 in example 5.
FIG. 12 is a HPLC chromatogram of the racemate of compound I-64 in example 6.
FIG. 13 is a chiral product HPLC chromatogram of compound I-64 in example 6.
FIG. 14 is a HPLC chromatogram of the racemate of compound I-70 of example 7.
FIG. 15 is a chiral product HPLC chromatogram of compound I-70 of example 7.
FIG. 16 is a HPLC chromatogram of the racemate of compound I-78 of example 8.
FIG. 17 is a chiral product HPLC chromatogram of compound I-78 of example 8.
FIG. 18 is a HPLC chromatogram of the racemate of compound I-79 of example 9.
FIG. 19 is a chiral product HPLC chromatogram of compound I-79 in example 9.
Detailed Description
The examples given below are only intended to illustrate the invention and are not intended to limit the scope thereof. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1
Preparation of methyl (5 r,6s,7r,8 s) -6-benzoyl-5-methyl-7- (1-methyl-2-indole) -6,7,9,10-tetrahydro-5, 8-cyclic iminobenzo [8] chromene-8-carboxylate (I-1):
26.0mg of Compound 1a (0.12 mmol) and 26.1mg of Compound 1b (0.10 mmol), 97.8mg (0.3 mmol) of cesium carbonate, cuprous tetrafluoroborate (0.02 mmol), catalyst P-44 (0.01 mmol) and 1mL of toluene were added to a round bottom flask and reacted at 25℃with stirring at a constant speed for 48 hours, TLC plate detection showed complete consumption of raw material 1b, addition of salt water quench, dichloromethane extraction, drying, removal of solvent under reduced pressure, flash column chromatography (petroleum ether/ethyl acetate, v/v=5/1), yielding 39.7mg of product I-1.
Characterization data: 83% yield, white solid, melting point: 62.9-63.1 ℃;
1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.0Hz,2H),7.53(t,J＝7.4Hz,1H),7.43(d,J＝7.8Hz,1H),7.35(t,J＝7.7Hz,2H),7.30–7.25(m,3H),7.17(t,J＝7.6Hz,2H),7.03(dd,J＝8.0,7.9Hz,2H),6.37(s,1H),4.85(d,J＝10.8Hz,1H),4.73(d,J＝10.8Hz,1H),3.81(s,3H),3.74(s,3H),3.45–3.32(m,2H),2.51–2.42(m,1H),2.33–2.24(m,1H),1.52(s,3H);13C NMR(101MHz,CDCl3)δ198.61,174.64,147.18,139.49,137.63,137.29,136.07,133.67,132.37,128.93,128.71,127.48,127.23,126.17,125.53,121.47,120.06,119.59,109.47,100.84,70.67,66.23,64.32,52.97,51.26,33.60,31.09,29.78,25.39.
HRMS(ESI)m/z calcd for C31H30N2O3[M+H]+＝479.2334,found＝479.2333;
The ee value was 91％,tR(major)＝9.8min,tR(minor)＝13.4min(Chiralcel IF,λ＝254nm,10％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
From the above nuclear magnetism and mass spectrum data, the obtained product had the correct structure.
Example 2
Preparation of methyl (5 r,6s,7r,8 s) -5-methyl-7- (1-methyl-2-indole) -6- (4-methyl-benzoyl) -6,7,9,10-tetrahydro-5, 8-cyclic iminobenzo [8] chromene-8-carboxylate (I-8):
The preparation of this example was similar to that of example 1, except that the starting materials and the reaction conditions were changed during the reaction, the organic solvent used in the preparation was P-xylene, the catalyst was P-44, and the reaction time was 72 hours.
Characterization data: 97% yield, white solid, melting point: 63.6-64.0 ℃;
1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.2Hz,2H),7.42(d,J＝7.8Hz,1H),7.30–7.26(m,1H),7.26–7.21(m,2H),7.20–7.12(m,4H),7.06–7.01(m,2H),6.35(s,1H),4.81(d,J＝10.8Hz,1H),4.71(d,J＝10.8Hz,1H),3.80(s,3H),3.72(s,3H),3.47–3.28(m,3H),2.44(ddd,J＝14.7,8.2,3.6Hz,1H),2.37(s,3H),2.30–2.23(m,1H),1.51(s,3H);13C NMR(101MHz,CDCl3)δ198.10,174.68,147.26,144.63,139.51,137.64,136.15,134.89,132.36,129.41,129.08,127.51,127.19,126.15,125.59,121.43,120.06,119.56,109.46,100.84,70.68,66.19,64.13,52.96,51.26,33.62,31.09,29.79,25.35,21.75.
HRMS(ESI)m/z calcd for C32H32N2O3[M+H]+＝493.2491,found＝493.2493.
The ee value was 94％,tR(major)＝10.7min,tR(minor)＝14.5min(Chiralcel IF,λ＝254nm,10％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
From the above nuclear magnetism and mass spectrum data, the obtained product had the correct structure.
Example 3
Preparation of methyl (5 r,6s,7r,8 s) -6- (4- (((2 e,4e,6e,8 e) -3, 7-dimethyl-9- (2, 6-trimethyl-1-cyclohexenyl) -2,4,6, 8-tetramethylnonenoyl) benzoyl) -5-methyl-7- (1-methyl-2-indole) -6,7,9,10, 8-cyclic iminobenzo [8] rota-ne-8-carboxylate (I-37):
The preparation of this example was similar to that of example 1, except that the starting materials and the reaction conditions were changed during the reaction, the organic solvent used in the preparation was P-xylene, the catalyst was P-44, the reaction temperature was 25 ℃, and the reaction time was 48 hours.
Characterization data: 96% yield, yellow solid, melting point: 103.7-103.9 ℃;
1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.8Hz,2H),7.44(d,J＝7.8Hz,1H),7.32–7.27(m,2H),7.23–7.00(m,8H),6.41–6.31(m,3H),6.23–6.15(m,2H),5.96(s,1H),4.83(d,J＝10.9Hz,1H),4.71(d,J＝10.9Hz,1H),3.80(s,3H),3.72(s,3H),3.39(t,J＝6.1Hz,2H),2.50–2.43(m,1H),2.41(s,3H),2.30–2.23(m,1H),2.07–2.05(m,1H),2.04(s,3H),2.03–2.00(m,1H),1.74(s,3H),1.68–1.60(m,2H),1.54(s,3H),1.51–1.46(m,2H),1.06(s,6H);13C NMR(101MHz,CDCl3)δ197.36,174.60,164.66,156.76,155.19,147.14,140.98,139.41,137.77,137.65,137.23,135.93,134.58,134.40,132.64,132.44,130.46,129.53,129.41,127.48,127.30,126.28,125.49,121.99,121.47,120.13,119.60,116.54,109.44,100.86,70.72,66.15,64.28,52.96,51.30,39.73,34.40,33.65,33.26,31.04,29.78,29.10,25.28,21.89,19.33,14.29,13.12.
HRMS(ESI)m/z calcd for C51H56N2O5[M+H]+＝777.4267,found＝777.4269.
The ee value was 90％,tR(major)＝22.5min,tR(minor)＝38.7min(Chiralcel OD-H,λ＝254nm,2％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
From the above nuclear magnetism and mass spectrum data, the obtained product had the correct structure.
Example 4
Preparation of methyl (5 r,6s,7r,8 s) -6-benzoyl-7- (5-chloro-1-methyl-2-indole) -5-methyl-6,7,9,10-tetrahydro-5, 8-cycloiminobenzo [8] chromene-8-carboxylate (I-44):
the preparation method of this example is similar to that of example 1, except that the raw materials and the reaction conditions are changed during the reaction, the organic solvent used in the preparation process is chloroform, the catalyst is P-49, the metal salt is copper acetate, the reaction temperature is 25 ℃, and the reaction time is 42 hours.
Characterization data: 67% yield, white solid, melting point: 94.3-94.9 ℃;
1H NMR(400MHz,CDCl3)δ7.69(dd,J＝8.3,1.1Hz,2H),7.55–7.51(m,1H),7.38–7.33(m,3H),7.30–7.26(m,1H),7.25–7.22(m,1H),7.19–7.14(m,2H),7.09(dd,J＝8.7,2.0Hz,1H),7.02–6.99(m,1H),6.25(s,1H),4.80(d,J＝10.6Hz,1H),4.67(d,J＝10.6Hz,1H),3.80(s,3H),3.71(s,3H),3.43(ddd,J＝15.6,8.6,4.0Hz,1H),3.29(ddd,J＝15.6,8.7,3.2Hz,1H),2.41(ddd,J＝14.7,8.6,3.2Hz,1H),2.27(ddd,J＝14.7,8.7,4.0Hz,1H),1.51(s,3H);13C NMR(101MHz,CDCl3)δ198.62,174.51,147.03,139.39,137.64,137.20,136.01,133.79,132.39,128.91,128.77,128.38,127.30,126.25,125.60,125.30,121.69,119.39,110.45,100.40,70.67,66.42,64.33,53.01,51.10,33.55,31.26,29.99,25.42.
HRMS(ESI)m/z calcd for C31H29ClN2O3[M+H]+＝513.1945,found＝513.1944.
The ee value was 86％,tR(minor)＝10.0min,tR(major)＝20.3min(Chiralcel IE,λ＝254nm,30％i-PrOH/hexane,flow rate＝0.8mL/min).dr>20:1.
From the above nuclear magnetism and mass spectrum data, the obtained product had the correct structure.
Example 5
Preparation of methyl (5 r,6s,7r,8 s) -6-benzoyl-7- (1-benzyl-2-indole) -5-methyl-6,7,9,10-tetrahydro-5, 8-cyclic iminobenzo [8] chromene-8-carboxylate (I-48):
The preparation of this example was similar to that of example 1, except that the starting materials and the reaction conditions were changed during the reaction, the solvent used in the preparation was xylene, the catalyst was P-48, the metal salt was copper acetate, the reaction temperature was 25 ℃, and the reaction time was 36 hours.
Characterization data: 89% yield, white solid, melting point: 141.8-142.4 ℃;
1H NMR(400MHz,CDCl3)δ7.71(d,J＝7.4Hz,2H),7.54(t,J＝7.4Hz,1H),7.43(dd,J＝6.2,2.1Hz,1H),7.37(t,J＝7.8Hz,2H),7.26–7.14(m,6H),7.06–6.97(m,4H),6.91(d,J＝6.8Hz,2H),6.26(s,1H),5.46(d,J＝17.1Hz,1H),5.33(d,J＝17.1Hz,1H),4.80(d,J＝9.8Hz,1H),4.66(d,J＝9.8Hz,1H),3.58(s,3H),3.53–3.46(m,1H),3.17(ddd,J＝15.3,7.8,2.8Hz,1H),2.52(ddd,J＝14.7,9.7,2.8Hz,1H),2.32(ddd,J＝14.7,7.8,3.7Hz,1H),1.47(s,3H);13C NMR(101MHz,CDCl3)δ198.84,174.54,146.81,139.71,137.70,137.50,137.25,136.58,133.60,132.24,128.89,128.72,128.70,127.86,127.27,127.17,126.29,125.93,121.72,120.12,119.88,110.69,102.02,70.93,67.29,65.24,52.86,51.83,46.83,33.30,31.58,25.64.
HRMS(ESI)m/z calcd for C37H34N2O3[M+H]+＝555.2647,found＝555.2644;
The ee value was 89％,tR(major)＝13.5min,tR(minor)＝15.4min(Chiralcel ID,λ＝254nm,10％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
From the above nuclear magnetism and mass spectrum data, the crystal structure data shows that the obtained product structure is correct.
Example 6
Preparation of ethyl (5 r,6s,7r,8 s) -6-benzoyl-7- (2-indole) -5-methyl-6,7,9,10-tetrahydro-5, 8-cyclic iminobenzo [8] chromene-8-carboxylate (I-64):
The preparation method of this example is similar to that of example 1, except that the raw materials and the reaction conditions are changed during the reaction, the organic solvent used in the preparation process is dichloromethane, the catalyst is P-48, the metal salt is cuprous iodide, the reaction temperature is 0 ℃, and the reaction time is 48 hours.
Characterization data: 92% yield, white solid, melting point: 63.7-64.2 ℃;
1H NMR(400MHz,CDCl3)δ9.68(s,1H),7.78(d,J＝7.3Hz,2H),7.58(t,J＝7.3Hz,1H),7.41(t,J＝7.8Hz,2H),7.38–7.32(m,2H),7.25–7.15(m,4H),7.12(t,J＝7.5Hz,1H),7.00(t,J＝7.5Hz,1H),5.95(s,1H),4.95(d,J＝10.2Hz,1H),4.86(d,J＝10.2Hz,1H),4.49–4.26(m,2H),3.50–3.38(m,1H),2.97(ddd,J＝16.3,5.6,4.0Hz,1H),2.78(s,1H),2.18(ddd,J＝14.0,5.6,3.8Hz,1H),2.04–1.96(m,1H),1.50(s,3H),1.38(t,J＝7.1Hz,3H);13C NMR(101MHz,CDCl3)δ198.13,175.87,148.58,139.17,137.30,136.50,135.85,133.72,132.73,128.96,128.82,127.96,127.45,126.33,125.24,121.60,119.94,119.52,110.98,100.83,71.61,65.36,62.37,60.27,48.64,33.86,33.61,25.81,14.26.
HRMS(ESI)m/z calcd for C31H30N2O3[M+H]+＝479.2334,found＝479.2330;
The ee value was 94％,tR(major)＝11.8min,tR(minor)＝18.4min(Chiralcel IC,λ＝254nm,10％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
From the above nuclear magnetism and mass spectrum data, the obtained product had the correct structure.
Example 7
Preparation of (5 r,6s,7r,8 s) -6-benzoyl-5-methyl-7- (1-methyl-2-indole) -N-phenyl 6,7,9,10-tetrahydro-5, 8-cyclic iminobenzo [8] chromene-8-amide (I-70):
The preparation of this example was similar to example 1 except that the starting materials and reaction conditions were changed during the reaction, the base used in the preparation was potassium hydroxide, the catalyst was P-49, the metal salt was silver carbonate, the reaction temperature was 20 ℃, and the reaction time was 72 hours.
Characterization data: 85% yield, white solid, melting point: 167.2-167.7 ℃;
1H NMR(400MHz,CDCl3)δ9.75(s,1H),7.66(d,J＝7.8Hz,2H),7.63(d,J＝7.4Hz,2H),7.51(t,J＝7.4Hz,1H),7.43–7.35(m,4H),7.31(t,J＝7.6Hz,3H),7.26–7.19(m,3H),7.15(t,J＝7.4Hz,2H),7.01(t,J＝7.3Hz,1H),6.47(s,1H),5.02(d,J＝11.3Hz,1H),4.80(d,J＝11.3Hz,1H),3.98–3.88(m,1H),3.68(s,3H),3.23(dt,J＝16.6,4.8Hz,1H),2.75(dt,J＝14.9,4.6Hz,1H),2.00–1.90(m,1H),1.57(s,3H);13C NMR(101MHz,CDCl3)δ197.68,172.61,148.62,138.74,137.97,137.85,137.09,135.68,133.73,133.31,129.29,128.78,128.77,127.94,127.39,126.44,125.51,124.25,121.49,119.96,119.45,119.32,109.75,100.46,70.18,63.86,60.57,47.49,34.15,30.68,30.02,26.78.
HRMS(ESI)m/z calcd for C36H33N3O2[M+H]+＝540.2651,found＝540.2649;
The ee value was 90％,tR(major)＝24.2min,tR(minor)＝32.0min(Chiralcel IF,λ＝254nm,10％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
From the above nuclear magnetism and mass spectrum data, the obtained product had the correct structure.
Example 8
Preparation of methyl (5 r,6s,7r,8 s) -6-benzoyl-5-ethyl-7- (2-indole) -6,7,9,10-tetrahydro-5, 8-cyclic iminobenzo [8] chromene-8-carboxylate (I-78):
the preparation method of this example is similar to that of example 1, except that the raw materials and the reaction conditions are changed during the reaction, the alkali used in the preparation process is sodium carbonate, the organic solvent is chloroform, the catalyst is P-49, the metal salt is cuprous iodide, the reaction temperature is 25 ℃, and the reaction time is 42 hours.
Characterization data: 93% yield, white solid, melting point: 72.2-72.9 ℃;
1H NMR(400MHz,CDCl3)δ8.90(s,1H),7.94–7.88(m,2H),7.62(t,J＝7.4Hz,1H),7.48(t,J＝7.7Hz,2H),7.34(d,J＝7.8Hz,1H),7.26–7.18(m,3H),7.14–7.06(m,3H),7.01–6.95(m,1H),5.84(s,1H),4.68(d,J＝8.4Hz,1H),4.64(d,J＝8.4Hz,1H),3.95(s,3H),3.50–3.40(m,1H),2.73(ddd,J＝15.1,6.3,2.6Hz,1H),2.11(ddd,J＝14.7,6.3,3.8Hz,1H),2.05–1.98(m,1H),1.94(dq,J＝14.4,7.2Hz,1H),1.68(dq,J＝14.4,7.2Hz,1H),0.83(t,J＝7.2Hz,3H);13C NMR(101MHz,CDCl3)δ199.32,176.64,144.79,140.81,137.73,136.45,136.31,133.77,132.54,128.97,127.97,127.04,127.00,126.50,121.62,119.94,119.54,110.86,101.51,71.96,70.34,62.33,53.19,50.67,34.25,32.63,31.52,9.38.
HRMS(ESI)m/z calcd for C31H30N2O3[M+H]+＝479.2334,found＝479.2336;
The ee value was 90％,tR(minor)＝14.1min,tR(major)＝30.4min(Chiralcel IE,λ＝254nm,30％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
From the above nuclear magnetism and mass spectrum data, the obtained product had the correct structure.
Example 9
Preparation of methyl (5 r,6s,7r,8 s) -6-benzoyl-5, 11-dimethyl-7- (1-methyl-2-indole) -6,7,9,10-tetrahydro-5, 8-cyclic iminobenzo [8] chromene-8-carboxylate (I-79):
The preparation method of this example is similar to that of example 1, except that the raw materials and the reaction conditions are changed during the reaction, the organic solvent used in the preparation process is diethyl ether, the catalyst is P-48, the metal salt is silver nitrate, the additive is methyl iodide, the reaction temperature is 10 ℃, and the reaction time is 42 hours.
Characterization data: 83% yield, white solid, melting point: 96.7-97.1 ℃;
1H NMR(400MHz,CDCl3)δ7.58(d,J＝7.3Hz,2H),7.44(d,J＝7.5Hz,2H),7.38(d,J＝7.1Hz,1H),7.32–7.26(m,3H),7.26–7.21(m,2H),7.20–7.13(m,2H),7.06–7.01(m,1H),6.57(s,1H),5.07(d,J＝11.8Hz,1H),5.02(d,J＝11.8Hz,1H),4.12–4.01(m,1H),3.82(s,3H),3.78(s,3H),3.11(ddd,J＝16.8,4.7,3.1Hz,1H),2.30(td,J＝14.2,4.7Hz,1H),2.16(ddd,J＝15.0,4.9,3.1Hz,1H),1.86(s,3H),1.46(s,3H);13C NMR(101MHz,CDCl3)δ197.75,174.88,144.37,138.70,137.77,137.18,136.37,133.41,132.20,128.72,128.63,127.62,127.60,126.98,126.61,121.45,120.01,119.54,109.59,100.60,73.91,66.62,60.22,52.56,44.86,34.75,30.09,29.86,22.92,22.69.
HRMS(ESI)m/z calcd for C32H32N2O3[M+H]+＝493.2491,found＝493.2486;
The ee value was 90％,tR(major)＝26.2min,tR(minor)＝31.6min(Chiralcel ID-ID,λ＝254nm,10％i-PrOH/hexane,flow rate＝0.8mL/min).dr>20:1.
From the above nuclear magnetism and mass spectrum data, the obtained product had the correct structure.
Test examples inhibition experiments of the Compounds of the invention on tumor cells
1. Experimental method
Experimental cells: a375 (melanoma cells), HELA (cervical cancer cells), HCT116 (colon cancer cells) and NCIN87 (gastric cancer cells).
Cells in the logarithmic growth phase were inoculated into 96-well plates at 100. Mu.L per well. After overnight incubation, cells were attached, and 100. Mu.L (final concentration 20. Mu. Mmol/L) of medium containing the compound was added to each well of the dosing group; the control group had 100. Mu.L of the corresponding medium added per well. The culture was continued for 72 hours, the old medium was removed, 100. Mu.L of fresh medium containing 10% by volume of CCK-8 reagent was added to each well, and medium containing 10% of CCK-8 was added to the wells of the uncultured cells as a blank. Incubating at 37 ℃ for 2 hours, detecting OD values at 450nm and 600nm of each hole by using an enzyme-labeled instrument, and subtracting the OD values when calculating by taking 600nm as a reference wavelength.
The calculation method comprises the following steps: cell viability at 20 μmmol/L concentration was calculated as = [1- (control OD-dosing OD)/(control OD-blank OD) ]x100%.
2. Experimental results
The survival of HCT116 cells at 20. Mu.M concentration of the compounds of the invention is shown in Table 1. The viability of a375 cells at 20 μm concentration is shown in table 2. The viability of HELA cells at 20. Mu.M concentrations is shown in Table 3. The viability of NCIN87 cells at 20. Mu.M concentration is shown in Table 4. As can be seen from tables 1-4, the compounds of the present invention have different degrees of inhibition on the growth of A375 (melanoma cells), HELA (cervical cancer cells), HCT116 (colon cancer cells) and NCIN87 (gastric cancer cells), and the lower the cell survival rate, the better the inhibition effect of the compounds on the growth of tumor cells, namely, the potential anti-tumor activity. Notably, the compounds I-40, I-55, I-65 and I-70 were very apparent at 20. Mu. Mmol/L in inhibiting the growth of the above cancer cells, with potential for further development and use.
Based on the above results of the bioactivity test, compounds I-40, I-55, I-65 and I-70 were subjected to further intensive research and test, and Table 5 shows IC 50 values of the above compounds in four tumor cells (melanoma cells, cervical cancer cells, colon cancer cells and stomach cancer cells). Through the results shown in Table 5, the compounds I-40 and I55 show ideal IC 50 values in HCT116 (colon cancer cells) and NCIN87 (stomach cancer cells), and reflect that the compounds have better anti-tumor activity and potential for drug development.
TABLE 1 survival of HCT116 cells at 20. Mu.M concentration of the compounds of the invention
| Numbering of compounds | Cell viability% | Numbering of compounds | Cell viability% |
| I-1 | 62.1％ | I-23 | 55.7％ |
| I-6 | 88.4％ | I-26 | 56.3％ |
| I-14 | 10.5％ | I-36 | 78.5％ |
| I-33 | 56.8％ | I-38 | 48.1％ |
| I-48 | 43.2％ | I-40 | 1.3％ |
| I-65 | 0.5％ | I-46 | 28.4％ |
| I-70 | 1.1％ | I-49 | 44.7％ |
| I-82 | 12.5％ | I-52 | 22.6％ |
| I-109 | 67.4％ | I-55 | 1.6％ |
TABLE 2 survival of A375 cells at 20. Mu.M concentration of the compounds of the invention
| Numbering of compounds | Cell viability% | Numbering of compounds | Cell viability% |
| I-1 | 56.3％ | I-23 | 47.2％ |
| I-6 | 66.2％ | I-26 | 51.0％ |
| I-14 | 24.6％ | I-36 | 79.4％ |
| I-33 | 34.5％ | I-38 | 56.2％ |
| I-48 | 77.3％ | I-40 | 3.2％ |
| I-65 | 7.9％ | I-46 | 33.7％ |
| I-70 | 12.9％ | I-49 | 51.9％ |
| I-82 | 21.8％ | I-52 | 32.3％ |
| I-109 | 73.6％ | I-55 | 4.3％ |
TABLE 3 survival of HELA cells with the compounds of the invention at 20. Mu.M concentration
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TABLE 4 survival of NCIN87 cells at 20. Mu.M concentration of the compounds of the invention
| Numbering of compounds | Cell viability% | Numbering of compounds | Cell viability% |
| I-1 | 34.2％ | I-23 | 88.4％ |
| I-6 | 67.1％ | I-26 | 76.9％ |
| I-14 | 12.3％ | I-36 | 83.4％ |
| I-33 | 45.3％ | I-38 | 44.2％ |
| I-48 | 59.7％ | I-40 | 0.8％ |
| I-65 | 3.9％ | I-46 | 36.2％ |
| I-70 | 0.4％ | I-49 | 23.7％ |
| I-82 | 18.8％ | I-52 | 18.6％ |
| I-109 | 72.0％ | I-55 | 1.2％ |
TABLE 5 IC 50 (μmmol/L) of partial compounds of the invention on A375 (melanoma cells), HELA (cervical cancer cells), HCT116 (colon cancer cells) and NCIN87 cells
| Numbering of compounds | A375 | HELA | HCT116 | NCIN87 |
| I-40 | 16.26 | 32.48 | 5.22 | 4.98 |
| I-55 | 16.59 | 21.84 | 4.55 | 4.27 |
| I-65 | 26.88 | 32.04 | 15.23 | 19.01 |
| I-70 | 79.86 | 159.42 | 23.06 | 17.44 |
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.
Claims (10)
1. A chiral aza-bridged ring compound, comprising: a structural general formula I and corresponding enantiomers, diastereomers, salts or crystal forms thereof:
Wherein R 1 is hydrogen, C 1-20 straight or branched alkyl, C 3-20 cycloalkyl, alkoxy, aryl or substituted aryl, benzyl or substituted benzyl, halogen, ketocarbonyl, ester, sulfonyl, trifluoromethyl, nitro;
r 2 is hydrogen, formyl or substituted formyl, C 1-20 straight or branched alkyl or substituted C 1-20 straight or branched alkyl, alkyl alcohol, phenyl alcohol or substituted phenyl alcohol, nitro, alkyl carboxylate or substituted alkyl carboxylate, sulfonyl, aryl or substituted aryl, heterocycle or substituted heterocycle;
R 3 is hydrogen, C 1-20 straight or branched alkyl or substituted C 1-20 straight or branched alkyl, alkyl alcohol, nitro, indole or substituted indole, benzofuran or substituted benzofuran, benzothiophene or substituted benzothiophene, pyrrole or substituted pyrrole, thiophene or substituted thiophene, furan or substituted furan, pyridine or substituted pyridine, naphthyl or substituted naphthyl, phenyl or substituted phenyl, sulfonyl, aryl or substituted aryl, heterocycle or substituted heterocycle;
r 4 is hydrogen, C 1-20 straight or branched alkyl, alkyl alcohol, nitro, ester group or substituted ester group, carboxyl or substituted carboxyl, amide group;
R 5 is hydrogen, C 1-20 straight or branched alkyl, t-butoxycarbonyl, benzoyl or substituted benzoyl, benzyl or substituted benzyl, ester or substituted ester, carboxyl or substituted carboxyl;
ar is aryl or substituted aryl, heterocycle or substituted heterocycle;
n is 1 or 2.
2. The chiral aza-bridged ring compound according to claim 1, wherein R 1 is hydrogen, C 1-20 straight or branched alkyl, cyclopropyl, benzyl;
R 2 is benzoyl or substituted benzoyl, benzothiophenyl, furanyl, thiophenyl, naphthoyl, pyrrolyl, pyridineformyl, benzyl alcohol, indolyl or substituted indolyl, cycloalkylformyl, C 1-20 straight chain alkylcarbonyl or C 1-20 branched alkylcarbonyl, nitro, trifluoromethyl, benzenesulfonyl, alkyldicarboxylic acid ester;
r 3 is indole or substituted indole, benzofuran or substituted benzofuran, benzothiophene or substituted benzothiophene, pyrrole or substituted pyrrole, thiophene or substituted thiophene, furan or substituted furan, pyridine or substituted pyridine, naphthyl or substituted naphthyl, phenyl or substituted phenyl;
R 4 is methyl formate, ethyl formate, propyl formate, benzyl formate, nitro, formate, methanol, amide;
R 5 is hydrogen, C 1-20 straight or branched alkyl, t-butoxycarbonyl, benzoyl or substituted benzoyl, acetyl, benzyloxycarbonyl, methyl formate;
Ar is phenyl or substituted phenyl, pyridine, benzofuran, naphthyl or substituted naphthyl, pyrrole or substituted pyrrole, furan, thiophene, indole or substituted indole, benzothiophene;
n is 1 or 2.
3. The chiral aza-bridged ring compound according to claim 2, characterized by the following specific structural formula:
4. A process for the preparation of chiral aza-bridged compounds as claimed in any one of claims 1 to 3, comprising the steps of: dissolving a compound A and a compound B in an organic solvent, adding a chiral quaternary phosphonium salt catalyst, an alkaline substance and a metal salt, and reacting to obtain a chiral aza-bridged ring compound, namely a compound of the formula I; the synthetic route is as follows:
5. The process for preparing a chiral azabridged ring compound as claimed in claim 4, wherein the organic solvent is methylene chloride, chloroform, 1, 2-dichloroethane, n-hexane, cyclohexane, petroleum ether, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, anisole, isopropyl ether, n-butyl ether, ethyl acetate, methanol, ethanol, acetonitrile, toluene, xylene, trimethylbenzene, chlorobenzene, fluorobenzene, bromobenzene, anisole or benzotrifluoride.
6. The method for producing a chiral azabridged ring compound according to claim 4, wherein the basic substance is triethylamine, diisopropylethylamine, DABCO, potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate trihydrate, potassium phosphate heptahydrate, sodium phosphate decahydrate, cesium fluoride, sodium phenolate, potassium t-butoxide, sodium hydroxide, potassium hydroxide or lithium hydroxide.
7. The method for preparing chiral azabridged ring compound as recited in claim 4, wherein the metal salt is silver nitrite, silver nitrate, silver acetate, silver tetrafluoroborate, silver carbonate, silver sulfate, silver oxide, silver triflate, copper acetate, copper sulfate, copper iodide, copper chloride, copper bromide, copper tetrafluoroborate.
8. The method for preparing chiral aza-bridged ring compound according to claim 4, wherein the chiral quaternary phosphonium salt catalyst is:
Wherein, in the compound P, R 6 is hydrogen, C 1-20 alkyl, aryl or substituted aryl, benzyl or substituted benzyl, heterocycle or substituted heterocycle; r 7 is Boc, ts, acyl, ureido, thiourea or substituted thiourea, carbonyl or substituted carbonyl; r 8 is phenyl or substituted phenyl, benzyl or substituted benzyl, naphthyl or substituted naphthyl; x is halogen, PO 4,NO2,NO3,BF4, OTf, OAc or OBoc.
9. The process for preparing chiral aza-bridged ring compounds as claimed in claim 4, wherein the reaction temperature is from-78 to 40℃and the reaction time is from 48 to 72 hours.
10. Use of a chiral aza-bridged ring compound according to any one of claims 1 to 3 for the preparation of a medicament for the prevention and/or treatment of tumors.
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