CN114671868A - Polysubstituted indolizine compound containing pyridone and preparation method and application thereof - Google Patents
Polysubstituted indolizine compound containing pyridone and preparation method and application thereof Download PDFInfo
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- CN114671868A CN114671868A CN202210305460.XA CN202210305460A CN114671868A CN 114671868 A CN114671868 A CN 114671868A CN 202210305460 A CN202210305460 A CN 202210305460A CN 114671868 A CN114671868 A CN 114671868A
- Authority
- CN
- China
- Prior art keywords
- pyridin
- indolizin
- chloropyridine
- solvent
- benzoyl
- Prior art date
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- -1 Polysubstituted indolizine compound Chemical class 0.000 title claims abstract description 108
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical class ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 16
- 150000004982 aromatic amines Chemical group 0.000 claims abstract description 10
- 125000001424 substituent group Chemical group 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims abstract description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 3
- 125000003406 indolizinyl group Chemical class C=1(C=CN2C=CC=CC12)* 0.000 claims abstract 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 21
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 14
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 14
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000005489 Bromoxynil Substances 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000000259 anti-tumor effect Effects 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 239000003586 protic polar solvent Substances 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000032612 Glial tumor Diseases 0.000 claims description 3
- 206010018338 Glioma Diseases 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims 1
- 206010038038 rectal cancer Diseases 0.000 claims 1
- 201000001275 rectum cancer Diseases 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 88
- 239000007787 solid Substances 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 238000002844 melting Methods 0.000 description 23
- 230000008018 melting Effects 0.000 description 23
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 21
- 239000000843 powder Substances 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 238000000926 separation method Methods 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical compound NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002478 indolizines Chemical class 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- 229940127093 camptothecin Drugs 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- IZZYUABKZYIINT-UHFFFAOYSA-N 2-[3-[(4-cyanophenyl)methyl]indolizin-1-yl]-n-(3-methyl-1,2-thiazol-5-yl)-2-oxoacetamide Chemical compound S1N=C(C)C=C1NC(=O)C(=O)C1=C2C=CC=CN2C(CC=2C=CC(=CC=2)C#N)=C1 IZZYUABKZYIINT-UHFFFAOYSA-N 0.000 description 1
- MGCGMYPNXAFGFA-UHFFFAOYSA-N 2-amino-5-nitrobenzonitrile Chemical compound NC1=CC=C([N+]([O-])=O)C=C1C#N MGCGMYPNXAFGFA-UHFFFAOYSA-N 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- ITAMRBIZWGDOHW-UHFFFAOYSA-N fantofarone Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCOC1=CC=C(S(=O)(=O)C2=C3C=CC=CN3C=C2C(C)C)C=C1 ITAMRBIZWGDOHW-UHFFFAOYSA-N 0.000 description 1
- 229950009236 fantofarone Drugs 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000004247 indolizin-1-yl group Chemical group [H]C1=C([H])C(*)=C2C([H])=C([H])C([H])=C([H])N12 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 229950003261 rosabulin Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a polysubstituted indolizine compound containing pyridone, which has the structural formula as follows:
the R is1Is variously substituted phenyl, naphthyl, heterocyclic aryl and aliphatic hydrocarbon, R2Is hydrogen atom and methyl, X is oxygen atom, aromatic amine with various stituents on benzene ring. The invention also discloses a preparation method of the compounds, which comprises the steps of dissolving the o-chloropyridine salt and the alkali in the solvent, stirring until the o-chloropyridine salt is reacted, carrying out cyclization reaction of the o-chloropyridine salt under the action of the corresponding alkali, and generating the polysubstituted indolizine containing pyridone by the o-chloropyridine salt and the arylamine with various substituents on benzene rings under the action of the corresponding alkaliA compound of the class. The preparation method provided by the invention has the advantages of simple operation, easily obtained raw materials, mild preparation conditions, good functional group tolerance and the like.
Description
Technical Field
The invention belongs to a synthesis method of compounds, and particularly relates to a polysubstituted indolizine compound containing pyridone, and a preparation method and application thereof.
Background
The indolizine derivatives are very important organic small molecules, and particularly, the polysubstituted indolizine compounds are used as an important chemical intermediate, so that the indolizine derivatives have very high application value and a very wide application range in the field of medicines. Many molecules of natural products and synthetic drugs, such as Camptothecin (Camptothecin), Rosabulin and Fantofarone, have a skeleton of indolizine nucleus, and their structural formulas are as follows:
pyridones are heterocycles with unique structures, can serve as hydrogen bond supply receptors, serve as bioisosteres of amides, phenyl or other nitrogen-containing or oxygen-containing heterocycles, and have very good drug-like properties. However, at present, no multi-substituted indolizine compound containing pyridone is reported, conditions for constructing an aromatic ring connected with the pyridone compound are harsh, most of the compounds need metal catalysis, and heavy metal is used to cause serious pollution to the environment. Therefore, the method for developing the polysubstituted indolizine compound direct synthesis method which has mild reaction conditions, is environment-friendly, has strong substrate applicability and can be quickly and efficiently used for the polysubstituted indolizine compound direct synthesis has certain application value.
Disclosure of Invention
The embodiment of the application aims to provide a multi-substituted indolizine compound containing pyridone and a preparation method and application thereof.
According to a first aspect of embodiments of the present application, there is provided a pyridone-containing polysubstituted indolizine compound, characterized by the structural formula:
the R is1Is variously substituted phenyl, naphthyl, heterocyclic aryl and aliphatic hydrocarbon, R2Is a hydrogen atom or a methyl group, X is an oxygen atom,Aromatic amines having various substituents on the benzene ring.
Further, the polysubstituted indolizine compound containing pyridone is any one of the following compounds:
1- (3- (4-methoxybenzoyl) -2- (4-methoxyphenyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (4-methylbenzoyl) -2- (p-tolyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (4-fluorobenzoyl) -2- (4-fluorobenzoyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3-benzoyl-2-phenylindolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (4-chlorobenzoyl) -2- (4-chlorophenyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (4-bromobenzoyl) -2- (4-bromophenyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (4-nitrobenzoyl) -2- (4-nitrophenyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (2- (thiophen-2-yl) -3- (thiophene-2-carbonyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (4- (trifluoromethyl) benzoyl) -2- (4- (trifluoromethyl) phenyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (3-methylbenzoyl) -2- (m-tolyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (3-bromobenzoyl) -2- (3-bromophenyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (furan-2-carbonyl) -2- (furan-2-yl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (2-naphthyl) -2- (naphthalen-2-yl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- ([1,1 '-biphenyl ] -4-carbonyl) -2- ([1,1' -biphenyl ] -4-yl) indolizin-1-yl) pyridin-2 (1H) -one;
4- (3- (4-cyanobenzoyl) -1- (2-oxopyridin-1 (2H) -yl) indolizin-2-yl) benzonitrile;
1- (2- (tert-butyl) -3-pivaloyl indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (2-methylbenzoyl) -2- (o-tolyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (2-bromobenzoyl) -2- (2-bromophenyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3-benzoyl-6-methyl-2-phenylindolizin-1-yl) -5-methylpyridin-2 (1H) -one;
(E) -2- ((1- (3-benzoyl-2-phenylindolizin-1-yl) pyridine-2 (1H) -ethylidene) amino) benzonitrile;
(E) -2- ((1- (3-benzoyl-2-phenylindolizin-1-yl) pyridine-2 (1H) -ethylene) amino) -5-bromoxynil;
(E) -4- ((1- (3-benzoyl-2-phenylindolizin-1-yl) pyridin-2 (1H) -ylidene) amino) benzonitrile;
(E) -2- ((1- (3-benzoyl-2-phenylindolizin-1-yl) pyridine-2 (1H) -ethylidene) amino) -5-nitrobenzonitrile.
According to a second aspect of embodiments of the present application, there is provided a method for producing a pyridone-containing polysubstituted indolizine compound of the first aspect, comprising the steps of:
dissolving the o-chloropyridine salt and alkali in a solvent, and stirring until the reaction of the o-chloropyridine salt is finished;
the structural formula of the o-chloropyridine salt is as follows:
the reaction formula is as follows:
the R is1Various substituted phenyl, naphthyl, heterocyclic aryl and aliphatic hydrocarbon; the R is2Is H or methyl.
Preferably, the reaction temperature of the o-chloropyridine salt is in the range of 0 to 60 ℃ and 0 ℃, 20 ℃, 60 ℃ and preferably 20 ℃.
Preferably, the solvent is an aprotic solvent selected from acetonitrile, tetrahydrofuran, N-dimethylformamide, dichloromethane, toluene, preferably acetonitrile.
Preferably, the solvent is a protic solvent, and the protic solvent is methanol.
Preferably, the base is cesium carbonate, potassium carbonate, sodium hydroxide, sodium hydride, triethylamine, wherein cesium carbonate is preferred.
Preferably, the base is used in an amount of 2.0 to 3.0 equivalents of the o-chloropyridine salt, with an equivalent of 2.0 equivalents being preferred.
The embodiment of the invention also provides a preparation method of the polysubstituted indolizine compound in the first aspect, which comprises the following steps:
dissolving an o-chloropyridine salt, arylamine with different substituents on a benzene ring and alkali in a solvent, and stirring until the o-chloropyridine salt is reacted;
the structural formula of the o-chloropyridine salt is as follows:
the structural formula of the arylamine with different substituent groups on the benzene ring is as follows:
the R is1When it is hydrogen atom, bromine atom, nitro group, R2Is cyano; when R is present1When it is a hydrogen atom, R2Is cyano.
Preferably, the reaction temperature of the o-chloropyridine salt is 20 ℃, the solvent is acetonitrile, the base is cesium carbonate, the dosage is 2.0 equivalents of the o-chloropyridine salt, the concentration of the o-chloropyridine salt is 0.1mol/mL, and the concentration of the arylamine with different substituents on the benzene ring is 0.3 mol/mL.
The technical scheme provided by the embodiment of the application can have the following beneficial effects:
as can be seen from the above examples, the present application does not require any precious metal catalyst; the reaction condition is mild; the reaction yield is high, and the separation yield of most products is over 60 percent; the substrate has wide applicability, and various substrate structures can bear the reaction conditions. Can be used for constructing a polysubstituted indolizine compound library containing pyridone, and can be used for carrying out activity screening of different targets as an effective way for discovering new drugs.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the application.
Detailed Description
The invention will now be further illustrated by the following examples.
Example 11- (3-benzoyl-2-phenylindolizin-1-yl) pyridin-2 (1H) -one
2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide (0.2mmol, 1.0 equiv.) and cesium carbonate (0.4mmol, 2.0 equiv.) were dissolved in 2mL acetonitrile and stirred at 20 ℃ for 24 h. After the reaction was completed, the solvent was distilled off under reduced pressure, and then the product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 1:2) to obtain a yellow powder. The yield thereof was found to be 78%.
Yellow solid, yield 78%. Melting point: 186.3-187.2 ℃.1H NMR(500MHz,CDCl3)δ9.81(d,J＝7.0Hz,1H),7.45–7.42(m,2H),7.38–7.33(m,2H),7.26(d,J＝15.5Hz,1H),7.15–7.11(m,1H),7.03–6.90(m,8H),6.89–6.86(m,1H),6.76(d,J＝9.5Hz,1H),5.99(t,J＝6.5Hz,1H).13C NMR(126MHz,CDCl3)δ187.06,163.67,140.31,140.01,139.44,134.40,133.25,131.61,130.88,130.49,129.44,128.21,127.79,127.39,127.23,125.43,121.46,119.24,116.25,115.28,114.65,106.13.HRMS(ESI):m/z calcd for[M+H]+:391.1441,found:391.1448。
Example 1 comparison of yields under different solvent conditions
Example 1 comparison of yields under different base conditions
Example 1 comparison of yields under different equivalents of base
Example 1 comparison of yields at different temperatures
Comparative example 1: 1- (3-benzoyl-2-phenylindolizin-1-yl) pyridin-2 (1H) -one
2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide (0.2mmol, 1.0 equiv.) and cesium carbonate (0.4mmol, 2.0 equiv.) were dissolved in 2mL of N, N-dimethylformamide and stirred at 20 ℃ for 24 hours. After the reaction was completed, the solvent was distilled off under reduced pressure and then subjected to separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate 1:2) to obtain yellow powder with a yield of 48%
Comparative example 2: 1- (3-benzoyl-2-phenylindolizin-1-yl) pyridin-2 (1H) -one
2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide (0.2mmol, 1.0 equiv.) and cesium carbonate (0.4mmol, 2.0 equiv.) were dissolved in 2mL of dichloromethane and stirred at 20 ℃ for 24 hours. After the reaction was completed, the solvent was distilled off under reduced pressure and then subjected to separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate 1:2) to obtain a yellow powder with a yield of 51%
Comparative example 3: 1- (3-benzoyl-2-phenylindolizin-1-yl) pyridin-2 (1H) -one
2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide (0.2mmol, 1.0 equiv.) and potassium carbonate (0.4mmol, 2.0 equiv.) were dissolved in 2mL acetonitrile and stirred at 20 ℃ for 24 h. After the reaction was completed, the solvent was distilled off under reduced pressure and then subjected to separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate 1:2) to obtain yellow powder with a yield of 55%
Comparative example 4: 1- (3-benzoyl-2-phenylindolizin-1-yl) pyridin-2 (1H) -one
2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide (0.2mmol, 1.0 equiv.) and sodium hydroxide (0.4mmol, 2.0 equiv.) were dissolved in 2mL acetonitrile and stirred at 20 ℃ for 24 h. After the reaction was completed, the solvent was distilled off under reduced pressure and then subjected to separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate 1:2) to obtain yellow powder with a yield of 45%
Comparative example 5: 1- (3-benzoyl-2-phenylindolizin-1-yl) pyridin-2 (1H) -one
2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide (0.2mmol, 1.0 equiv.) and cesium carbonate (0.4mmol, 2.5 equiv.) were dissolved in 2mL acetonitrile and stirred at 20 ℃ for 24 h. After the reaction was completed, the solvent was distilled off under reduced pressure and then subjected to separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate 1:2) to obtain yellow powder with a yield of 56%
Comparative example 6: 1- (3-benzoyl-2-phenylindolizin-1-yl) pyridin-2 (1H) -one
2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide (0.2mmol, 1.0 equiv.) and cesium carbonate (0.4mmol, 3.0 equiv.) were dissolved in 2mL acetonitrile and stirred at 20 ℃ for 24 h. After the reaction was completed, the solvent was distilled off under reduced pressure and then subjected to separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate 1:2) to obtain yellow powder with a yield of 68%
Comparative example 7: 1- (3-benzoyl-2-phenylindolizin-1-yl) pyridin-2 (1H) -one
2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide (0.2mmol, 1.0 equiv.) and cesium carbonate (0.4mmol, 2.0 equiv.) were dissolved in 2mL acetonitrile and stirred at 0 ℃ for 24 h. After the reaction was completed, the solvent was distilled off under reduced pressure and then subjected to separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate 1:2) to obtain a yellow powder with a yield of 69%
Comparative example 8: 1- (3-benzoyl-2-phenylindolizin-1-yl) pyridin-2 (1H) -one
2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide (0.2mmol, 1.0 equiv.) and cesium carbonate (0.4mmol, 2.0 equiv.) were dissolved in 2mL acetonitrile and stirred at 60 ℃ for 24 h. After the reaction was completed, the solvent was distilled off under reduced pressure and then subjected to separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate 1:2) to obtain yellow powder with a yield of 70%
Example 21- (3- (4-methylbenzoyl) -2- (p-tolyl) indolizin-1-yl) pyridin-2 (1H) -one
The synthesis procedure is as in example 1 except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide is replaced with 2-chloro-1- (2-oxo-2- (p-tolyl) ethyl) pyridine-1-ammonium bromide to give a yellow powder. The yield thereof was found to be 61%.
Yellow solid, yield 61%. Melting point: 199.6-200.3 ℃.1H NMR(400MHz,CDCl3)δ9.74(d,J＝7.2Hz,1H),7.35–7.29(m,4H),7.25–7.19(m,1H),6.96(td,J＝7.2,1.2Hz,1H),6.87(dd,J＝6.8,1.6Hz,1H),6.83(d,J＝8.0Hz,2H),6.78(d,J＝7.9Hz,2H),6.75–6.69(m,3H),5.97(td,J＝6.8,0.8Hz,1H),2.19(s,3H),2.15(s,3H).13C NMR(100MHz,CDCl3)δ187.14,163.79,141.43,140.28,140.26,136.97,136.78,134.27,133.14,130.49,129.75,128.76,128.56,128.18,128.10,125.13,121.57,119.52,116.23,115.09,114.43,106.13,21.45,21.14.HRMS(ESI):m/z calcd for[M+H]+:419.1754,found:419.1751。
Example 31- (3- (4-fluorobenzoyl) -2- (4-fluorobenzene) indolizin-1-yl) pyridin-2 (1H) -one
The procedure is as in example 1 except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide is replaced with 2-chloro-1- (2- (4-fluorophenyl) -2-oxyethyl) pyridine-1-ammonium bromide to give a yellow powder. The yield thereof was found to be 69%.
Yellow solid, yield 69%. Melting point: 270.4-271.1 ℃.1H NMR(400MHz,CDCl3)δ9.76(d,J＝7.2Hz,1H),7.45(dd,J＝8.4,5.6Hz,2H),7.39–7.33(m,2H),7.28(d,J＝7.2Hz,1H),7.02(t,J＝6.8Hz,1H),6.96(dd,J＝8.0,5.6Hz,2H),6.89–6.85(m,1H),6.70(q,J＝8.8Hz,5H),6.01(t,J＝6.6Hz,1H).13C NMR(100MHz,CDCl3)δ185.32,163.63,140.35,139.75,135.61(d,J＝3.0Hz),133.40,133.22,132.15(d,J＝8.2Hz),131.82(d,J＝9.0Hz),128.13,127.63(d,J＝3.5Hz),125.67,121.58,119.08,116.10,115.36,115.19,114.97,114.85,114.70,114.49,106.22.HRMS(ESI):m/z calcd for[M+H]+:427.1258,found:427.1264。
Example 41- (3- (4-methoxybenzoyl) -2- (4-methoxyphenyl) indolizin-1-yl) pyridin-2 (1H) -one
The procedure was as in example 1 except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide was changed to 2-chloro-1- (2- (4-methoxyphenyl) -2-oxyethyl) pyridine-1-ammonium bromide to give a yellow powder. The yield thereof was found to be 57%.
Yellow solid, yield 57%. Melting point: 185.5-186.2 ℃.1H NMR(400MHz,CDCl3)δ9.64(d,J＝7.2Hz,1H),7.45(d,J＝8.0Hz,2H),7.38–7.29(m,2H),7.22–7.16(m,1H),6.96–6.86(m,4H),6.72(d,J＝9.2Hz,1H),6.50(d,J＝7.2Hz,4H),5.99(t,J＝6.4Hz,1H),3.69(s,3H),3.66(s,3H).13C NMR(100MHz,CDCl3)δ186.16,163.85,162.13,158.86,140.32,133.44,133.01,131.93,131.88,128.02,124.90,124.13,121.58,119.46,116.18,114.88,114.23,113.63,112.92,106.21,55.42,55.27.HRMS(ESI):m/z calcd for[M+H]+:451.1652,found:471.1650。
Example 51- (3- (4-chlorobenzoyl) -2- (4-chlorophenyl) indolizin-1-yl) pyridin-2 (1H) -one
The procedure was as in example 1 except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide was replaced with 2-chloro-1- (2- (4-chlorophenyl) -2-oxyethyl) pyridine-1-ammonium bromide to give a yellow powder. The yield thereof was found to be 51%.
Yellow solid, yield 51%. Melting point: 196.6-197.2 ℃.1H NMR(400MHz,CDCl3)δ9.80(d,J＝7.2Hz,1H),7.39–7.27(m,5H),7.06–6.96(m,5H),6.90–6.86(m,3H),6.70(d,J＝9.6Hz,1H),6.02(td,J＝6.8,1.2Hz,1H).13C NMR(126MHz,CDCl3)δ185.36,163.62,140.48,139.66,137.74,137.41,133.94,133.56,133.26,131.64,130.70,130.05,128.24,128.20,127.78,125.95,121.59,119.00,116.14,115.36,115.07,106.40.HRMS(ESI):m/z calcd for[M+H]+:459.0662,found:459.0658。
Example 61- (3- (4-bromobenzoyl) -2- (4-bromophenyl) indolizin-1-yl) pyridin-2 (1H) -one
The synthesis procedure was the same as in example 1 except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide was replaced with 1- (2- (4-bromophenyl) -2-oxyethyl) -2-chloropyridine-1-ammonium bromide to give a yellow solid in 65% yield.
Yellow solid, yield 65%. Melting point: 194.5-195.3 ℃.1H NMR(400MHz,CDCl3)δ9.82(d,J＝7.6Hz,1H),7.39–7.29(m,3H),7.28–7.23(m,2H),7.15(dd,J＝18.0,8.4Hz,4H),7.04(td,J＝7.2,1.2Hz,1H),6.88(dd,J＝6.8,2.0Hz,1H),6.82(d,J＝8.4Hz,2H),6.70(d,J＝9.6Hz,1H),6.03(t,J＝6.8Hz,1H).13C NMR(126MHz,CDCl3)δ185.45,163.60,140.48,139.62,138.17,133.60,133.38,131.90,131.16,130.78,130.76,130.52,128.29,126.02,125.88,122.18,121.57,118.92,116.12,115.34,115.13,106.41.HRMS(ESI):m/z calcd for[M+H]+:546.9651,found:546.9658。
Example 71- (3- (4-nitrobenzoyl) -2- (4-nitrophenyl) indolizin-1-yl) pyridin-2 (1H) -one
The synthesis procedure was the same as in example 1 except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide was replaced with 2-chloro-1- (2- (4-nitrophenyl) -2-oxyethyl) pyridine-1-ammonium bromide to give a yellow solid in 80% yield.
Yellow solid, yield 80%. Melting point: 218.7-219.2 ℃.1H NMR(500MHz,CDCl3)δ9.92(d,J＝7.0Hz,1H),7.85(dd,J＝20.0,8.5Hz,4H),7.57(d,J＝8.5Hz,2H),7.45–7.37(m,3H),7.22–7.13(m,3H),6.91(d,J＝6.0Hz,1H),6.72(d,J＝9.0Hz,1H),6.08(t,J＝6.0Hz,1H).13C NMR(126MHz,CDCl3)δ183.71,163.43,148.79,146.99,144.94,140.84,139.07,138.38,134.25,132.60,131.29,130.11,128.51,127.22,123.05,122.82,121.77,118.67,116.29,116.20,116.11,106.85.HRMS(ESI):m/z calcd for[M+H]+:481.1148,found:481.1152。
Example 81- (2- (thien-2-yl) -3- (thien-2-carbonyl) indolizin-1-yl) pyridin-2 (1H) -one
The synthesis procedure is the same as in example 1 except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide is replaced by 2-chloro-1- (2-oxo-2- (thiophen-2-yl) ethyl) pyridine-1-ammonium bromide to give a yellow solid in 48% yield.
Yellow solid, yield 48%. Melting point: 226.7-227.2 ℃.1H NMR(500MHz,CDCl3)δ9.39(d,J＝7.5Hz,1H),7.47(t,J＝7.5Hz,1H),7.36–7.33(m,1H),7.31–7.26(m,1H),7.19–7.13(m,3H),6.91(t,J＝7.0Hz,1H),6.83(dd,J＝3.5,0.5Hz,1H),6.79(d,J＝9.0Hz,1H),6.33–6.30(m,1H),6.25(dd,J＝3.0,1.5Hz,1H),6.23–6.19(m,2H).13C NMR(126MHz,CDCl3)δ173.43,163.27,152.73,145.91,145.36,143.41,140.58,140.09,132.92,127.25,124.87,122.02,121.58,118.03,117.62,116.13,114.46,113.79,111.86,111.45,110.64,106.46.HRMS(ESI):m/z calcd for[M+H]+:403.0575,found:403.0579。
Example 91- (3- (4- (trifluoromethyl) benzoyl) -2- (4- (trifluoromethyl) phenyl) indolizin-1-yl) pyridin-2 (1H) -one
The synthesis procedure was the same as in example 1 except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide was replaced with 2-chloro-1- (2-oxo-2- (4- (trifluoromethyl) phenyl) ethyl) pyridine-1-ammonium bromide to give a yellow solid in 75% yield.
Yellow solid, yield 75%. Melting point: 184.4-185.0 ℃.1H NMR(400MHz,CDCl3)δ9.98(d,J＝7.2Hz,1H),7.45–7.34(m,5H),7.21(dd,J＝18.4,8.0Hz,4H),7.12(td,J＝7.2,2.0Hz,1H),7.06(d,J＝8.0Hz,2H),6.90(dd,J＝6.8,1.6Hz,1H),6.69(d,J＝9.2Hz,1H),6.03(td,J＝6.8,0.8Hz,1H).13C NMR(100MHz,CDCl3)δ185.08,163.48,142.73,140.57,139.37,135.33,133.98,133.67,132.59,132.27,130.71,130.04,129.71,129.27,128.60,126.65,124.68(q,J＝3.6Hz),124.43(q,J＝3.6Hz),121.63,119.00,116.19,115.91,115.67,106.47.HRMS(ESI):m/z calcd for[M+H]+:527.1194,found:527.1191。
Example 101- (3- (3-methylbenzoyl) -2- (m-tolyl) indolizin-1-yl) pyridin-2 (1H) -one
The procedure was as in example 1 except for changing 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide to 2-chloro-1- (2-oxo-2- (m-tolyl) ethyl) pyridine-1-ammonium bromide to give a yellow solid in 53% yield.
Yellow solid, yield 53%. Melting point: 208.4-209.2 ℃.1H NMR(500MHz,CDCl3)δ9.82(d,J＝7.0Hz,1H),7.40–7.36(m,1H),7.36–7.31(m,2H),7.28–7.24(m,1H),7.15(s,1H),7.00(td,J＝7.0,1.2Hz,1H),6.98–6.92(m,2H),6.90(dd,J＝7.0,1.5Hz,1H),6.86(t,J＝7.5Hz,1H),6.84–6.80(m,2H),6.75(d,J＝7.5Hz,1H),6.69(s,1H),6.03(td,J＝7.0,1.3Hz,1H).13C NMR(126MHz,CDCl3)δ187.32,163.68,140.53,140.20,139.44,137.28,136.87,134.50,133.07,131.53,131.46,131.37,130.24,128.23,127.98,127.67,127.41,127.03,126.12,125.36,121.10,119.36,116.17,114.93,114.57,106.58,20.95,20.82.HRMS(ESI):m/z calcd for[M+H]+:419.1760,found:419.1758。
Example 111- (3- (3-bromobenzoyl) -2- (3-bromophenyl) indolizin-1-yl) pyridin-2 (1H) -one
The synthesis procedure was the same as in example 1 except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide was replaced with 1- (2- (3-bromophenyl) -2-oxyethyl) -2-chloropyridine-1-ammonium bromide to give a yellow solid in 64% yield.
Yellow solid, yield 64%. Melting point: 208.5-209.1 ℃.1H NMR(500MHz,CDCl3)δ9.87(d,J＝7.0Hz,1H),7.48–7.45(m,1H),7.43–7.36(m,3H),7.35–7.31(m,1H),7.29(ddd,J＝8.0,2.0,1.0Hz,1H),7.16–7.13(m,1H),7.08(t,J＝7.0Hz,1H),7.05–6.98(m,3H),6.97–6.90(m,2H),6.78(d,J＝8.5Hz,1H),6.07(t,J＝5.8Hz,1H).13C NMR(126MHz,CDCl3)δ184.89,163.52,141.26,140.66,140.56,139.69,133.80,133.63,133.38,133.26,132.09,130.68,129.62,129.29,128.50,128.40,127.34,126.28,122.04,121.80,121.46,118.87,116.29,115.36,106.67,106.53.HRMS(ESI):m/z calcd for[M+H]+:546.9657,found:546.9650。
Example 121- (3- (furan-2-carbonyl) -2- (furan-2-yl) indolizin-1-yl) pyridin-2 (1H) -one
The procedure was as in example 1 except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide was replaced with 2-chloro-1- (2- (furan-2-yl) -2-oxyethyl) pyridine-1-ammonium bromide as a pale yellow solid in 35% yield.
Pale yellow solid, yield 35%. Melting point: 209.3-210.2 ℃.1H NMR(500MHz,CDCl3)δ9.39(d,J＝7.0Hz,1H),7.50–7.46(m,1H),7.35–7.33(m,1H),7.29(d,J＝9.0Hz,1H),7.19–7.14(m,3H),6.93–6.89(m,1H),6.85–6.80(m,2H),6.32(dd,J＝3.8,1.8Hz,1H),6.26–6.20(m,3H).13C NMR(126MHz,CDCl3)δ173.44,163.29,152.72,145.93,145.34,143.42,140.64,140.11,132.91,127.25,124.89,122.01,121.55,118.03,117.64,116.13,114.47,113.75,111.87,111.46,110.65,106.55.HRMS(ESI):m/z calcd for[M+H]+:371.1032,found:371.1029。
Example 131- (3- (2-naphthyl) -2- (naphthalen-2-yl) indolizin-1-yl) pyridin-2 (1H) -one
The synthesis procedure was the same as in example 1 except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide was replaced with 2-chloro-1- (2- (naphthalen-2-yl) -2-oxyethyl) pyridine-1-ammonium bromide to give a yellow solid in 68% yield.
Yellow solid, yield 68%. Melting point 212.5-213.3 deg.C.1H NMR(400MHz,CDCl3)δ9.92(d,J＝7.2Hz,1H),7.87–7.84(m,1H),7.57(dd,J＝8.4,1.6Hz,1H),7.46–7.28(m,9H),7.21–7.15(m,3H),7.15–7.00(m,4H),6.88(dd,J＝6.8,1.6Hz,1H),6.73(d,J＝9.2Hz,1H),5.87(td,J＝6.8,1.3Hz,1H).13C NMR(101MHz,CDCl3)δ187.00,163.67,140.24,139.97,136.41,134.57,134.05,133.36,132.54,131.78,131.55,130.91,130.00,129.17,128.43,128.36,127.46,127.41,127.31,127.26,127.11,126.99,126.96,125.89,125.68,125.64,125.52,124.93,121.46,119.86,116.31,115.57,114.76,106.12.HRMS(ESI):m/z calcd for[M+H]+:491.1760,found:491.1768。
Example 141- (3- ([1,1 '-biphenyl ] -4-carbonyl) -2- ([1,1' -biphenyl ] -4-yl) indolizin-1-yl) pyridin-2 (1H) -one
The synthesis procedure was the same as in example 1 except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide was changed to 1- (2- ([1,1' -biphenyl ] -4-yl) -2-oxyethyl) -2-chloropyridine-1-ammonium bromide to give a yellow solid in 54% yield.
Yellow solid, yield 54%. Melting point: 203.5-203.9 ℃.1H NMR(400MHz,CDCl3)δ9.92(d,J＝7.2Hz,1H),7.49(d,J＝8.0Hz,2H),7.41–7.33(m,2H),7.31–7.24(m,11H),7.19–7.13(m,4H),7.07–7.01(m,3H),6.95(d,J＝5.6Hz,1H),6.74(d,J＝9.2Hz,1H),6.01(t,J＝6.6Hz,1H).13C NMR(101MHz,CDCl3)δ186.53,163.66,143.76,140.30,140.29,140.14,140.05,138.26,134.22,133.45,130.96,130.67,129.90,128.57,128.40,127.61,127.32,127.25,127.03,126.52,126.19,125.56,121.53,119.47,116.19,115.37,114.75,106.20.HRMS(ESI):m/z calcd for[M+H]+:543.2073,found:543.2076。
Example 154- (3- (4-cyanobenzoyl) -1- (2-oxopyridin-1 (2H) -yl) indolizin-2-yl) benzonitrile
The synthesis procedure was the same as in example 1 except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide was replaced with 2-chloro-1- (2- (4-cyanophenyl) -2-oxyethyl) pyridine-1-ammonium bromide to give a yellow solid in 65% yield.
Yellow solid, yield 65%. Melting point: 287.5-288.3 ℃.1H NMR(400MHz,CDCl3)δ9.87(d,J＝7.2Hz,1H),7.48(d,J＝8.4Hz,2H),7.40–7.35(m,3H),7.31(dd,J＝20.0,8.4Hz,4H),7.16–7.09(m,3H),6.87(dd,J＝6.8,1.6Hz,1H),6.68(d,J＝9.2Hz,1H),6.05(td,J＝6.8,1.2Hz,1H).13C NMR(101MHz,CDCl3)δ184.11,163.43,143.29,140.65,139.11,136.48,134.15,132.88,131.60,131.41,131.07,129.70,128.41,126.94,121.76,118.55,117.86,117.64,116.22,115.98,114.47,111.74,106.58.HRMS(ESI):m/z calcd for[M+H]+:441.1352,found:441.1359。
Example 161- (2- (tert-butyl) -3-pivaloyl-indolizin-1-yl) pyridin-2 (1H) -one
The synthesis procedure is the same as in example 1, except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide is replaced with 2-chloro-1- (3, 3-dimethyl-2-oxybutyl) pyridine-1-ammonium bromide to give a pale yellow solid in 57% yield.
Yellow solid, yield 57%. Melting point: 97.6-98.2 ℃.1H NMR(500MHz,CDCl3)δ9.94(dt,J＝7.0,1.0Hz,1H),7.90–7.88(m,1H),7.84(d,J＝9.0Hz,1H),7.77(d,J＝16.5Hz,1H),7.28–7.23(m,1H),6.91(td,J＝7.0,1.5Hz,1H),6.81(d,J＝16.0Hz,1H),6.78–6.74(m,1H),1.47(s,9H),1.35(s,9H).13C NMR(126MHz,CDCl3)δ196.76,161.18,160.29,136.48,129.62,126.81,125.08,121.30,120.20,120.05,116.72,114.50,111.60,109.89,44.06,31.55,29.19,28.73.HRMS(ESI):m/z calcd for[M+H]+:351.2073,found:351.2069。
Example 171- (3- (2-methylbenzoyl) -2- (o-tolyl) indolizin-1-yl) pyridin-2 (1H) -one
The synthesis procedure is as in example 1, except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide is replaced with 2-chloro-1- (2-oxo-2- (o-tolyl) ethyl) pyridine-1-ammonium bromide to give a light yellow solid in 24% yield.
Pale yellow solid, yield 24%. Melting point: 198.3-199.1 deg.C.1H NMR(400MHz,CDCl3)δ10.13(d,J＝7.2Hz,1H),7.43–7.28(m,2H),7.25–7.17(m,1H),7.09–6.97(m,2H),6.95–6.63(m,8H),6.58(t,J＝10.0Hz,1H),5.86(t,J＝6.4Hz,1H),2.32(s,3H),2.01(s,3H).HRMS(ESI):m/z calcd for[M+H]+:419.1760,found:419.1765。
Example 181- (3- (2-bromobenzoyl) -2- (2-bromophenyl) indolizin-1-yl) pyridin-2 (1H) -one
The synthesis procedure was the same as in example 1 except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide was replaced with 1- (2- (2-bromophenyl) -2-oxyethyl) -2-chloropyridine-1-ammonium bromide to give a pale yellow solid in 32% yield.
Pale yellow solid, yield 32%. Melting point: 189.4-190.2 ℃.1H NMR(400MHz,CDCl3)δ10.20(d,J＝6.8Hz,1H),7.41–7.31(m,3H),7.29–7.20(m,3H),7.19–7.07(m,3H),7.02–6.90(m,2H),6.89–6.77(m,2H),6.50(d,J＝9.6Hz,1H),6.01(t,J＝6.8Hz,1H).HRMS(ESI):m/z calcd for[M+H]+:546.9657,found:546.9660。
Example 191- (3-benzoyl-6-methyl-2-phenylindolizin-1-yl) -5-methylpyridin-2 (1H) -one
The synthesis procedure was the same as in example 1 except that 2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide was replaced with 2-chloro-5-methyl-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide to give a yellow solid in 69% yield.
Yellow solid, yield 69%. Melting point: 207.1-207.6 ℃.1H NMR(500MHz,CDCl3)δ9.65(s,1H),7.42(dd,J＝8.0,1.3Hz,2H),7.26–7.21(m,2H),7.14–7.10(m,2H),6.99–6.90(m,7H),6.76(d,J＝9.0Hz,1H),6.67(s,1H),2.41(d,J＝1.0Hz,3H),1.85(s,3H).13C NMR(126MHz,CDCl3)δ186.96,163.04,143.39,139.55,137.33,133.90,132.11,131.78,130.79,130.47,129.46,128.46,127.71,127.34,127.10,126.02,124.55,120.61,118.99,115.72,115.47,115.05,18.72,16.80.HRMS(ESI):m/z calcd for[M+H]+:419.1760,found:419.1767。
Example 20(E) -2- ((1- (3-benzoyl-2-phenylindolizin-1-yl) pyridin-2 (1H) -ethylidene) amino) benzonitrile
2-chloro-1- (2-oxo-2-phenylethyl) pyridine-1-ammonium bromide (0.2mmol, 1.0 equiv.), 2-aminobenzonitrile (0.6mmol, 3.0 equiv.) and cesium carbonate (0.6mmol, 3.0 equiv.) were dissolved in 2mL acetonitrile and stirred at 20 ℃ for 24 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and then the product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 5:1) to obtain a yellow powder. The yield thereof was found to be 25%.
Yellow powder, yield 25%. Melting point: 189.5-190.2 ℃.1H NMR(400MHz,CDCl3)δ9.84(d,J＝6.8Hz,1H),7.73(d,J＝8.8Hz,1H),7.56(dd,J＝8.0,1.6Hz,1H),7.48–7.43(m,3H),7.37–7.30(m,1H),7.17–7.10(m,3H),7.04–6.90(m,9H),6.68(dd,J＝6.8,1.2Hz,1H),6.29(d,J＝9.6Hz,1H),5.69(td,J＝6.8,1.2Hz,1H).13C NMR(126MHz,CDCl3)δ186.81,155.09,154.63,140.26,139.57,137.05,134.59,133.80,133.54,133.46,131.93,131.88,130.69,129.53,128.32,127.82,127.37,127.19,125.47,123.71,121.77,119.07,118.82,117.13,116.74,114.80,114.47,106.22,104.51.HRMS(ESI):m/z calcd for[M+H]+:419.1760,found:419.1769。
Example 21(E) -2- ((1- (3-benzoyl-2-phenylindolizin-1-yl) pyridine-2 (1H) -ethylidene) amino) -5-bromoxynil
The procedure is as in example 19 except that 2-aminobenzonitrile is replaced by 2-amino-5-bromoxynil to give a yellow powder. The yield thereof was found to be 29%.
Yellow powder, yield 25%. Melting point: 208.3-208.9 ℃.1H NMR(400MHz,CDCl3)δ9.84(d,J＝7.2Hz,1H),7.69–7.63(m,2H),7.52(dd,J＝8.4,2.0Hz,1H),7.44(d,J＝7.2Hz,2H),7.35–7.29(m,1H),7.15–7.08(m,3H),7.04–6.96(m,7H),6.78(d,J＝8.6Hz,1H),6.72(d,J＝6.8Hz,1H),6.30(d,J＝9.2Hz,1H),5.74(t,J＝6.4Hz,1H).13C NMR(101MHz,CDCl3)δ186.84,154.72,154.26,140.45,139.53,137.52,136.85,135.58,134.51,133.32,131.86,130.79,130.65,129.51,128.34,127.84,127.39,127.23,125.49,125.34,119.07,117.43,116.91,116.53,114.78,114.21,113.20,107.98,104.97.HRMS(ESI):m/z calcd for[M+H]+:569.0977,found:569.0982。
Example 22(E) -4- ((1- (3-benzoyl-2-phenylindolizin-1-yl) pyridin-2 (1H) -ylidene) amino) benzonitrile
The procedure is as in example 19 except that 2-aminobenzonitrile is replaced by p-aminobenzonitrile to give a yellow powder. The yield thereof was found to be 19%.
Yellow powder, yield 19%. Melting point: 190.3-191.0 ℃.1H NMR(400MHz,CDCl3)δ9.84(d,J＝7.2Hz,1H),7.49(d,J＝8.4Hz,3H),7.42(d,J＝7.6Hz,2H),7.30(d,J＝7.2Hz,1H),7.13(t,J＝7.2Hz,1H),7.06–6.96(m,8H),6.93–6.87(m,1H),6.81(d,J＝6.8Hz,1H),6.74(d,J＝8.4Hz,2H),6.35(d,J＝9.6Hz,1H),5.74(t,J＝6.4Hz,1H).13C NMR(101MHz,CDCl3)δ186.87,155.95,153.73,140.26,139.57,136.72,134.62,133.52,133.24,132.25,130.80,130.49,129.42,128.53,127.75,127.38,127.17,125.21,123.04,120.09,119.24,116.78,116.04,114.70,114.52,104.42,104.00.HRMS(ESI):m/z calcd for[M+H]+:491.1872,found:491.1879。
Example 23(E) -2- ((1- (3-benzoyl-2-phenylindolizin-1-yl) pyridine-2 (1H) -ethylidene) amino) -5-nitrobenzonitrile
The procedure is as in example 19, except that 2-aminobenzonitrile is replaced by 2-amino-5-nitrobenzonitrile to give a yellow powder. The yield thereof was found to be 25%.
Yellow powder, yield 25%. Melting point: 276.1-276.8 ℃.1H NMR(400MHz,CDCl3)δ9.83(d,J＝7.2Hz,1H),8.42(d,J＝2.4Hz,1H),8.23(dd,J＝9.2,2.8Hz,1H),7.57(d,J＝8.8Hz,1H),7.44(d,J＝7.2Hz,2H),7.35–7.30(m,1H),7.22–7.11(m,2H),7.09–6.97(m,8H),6.96–6.92(m,2H),6.54(d,J＝9.2Hz,1H),5.99(t,J＝6.8Hz,1H).13C NMR(101MHz,CDCl3)δ187.00,160.28,154.91,140.98,140.62,139.36,139.00,134.33,133.05,131.67,130.95,130.52,130.08,129.50,128.76,128.32,127.91,127.46,127.38,125.69,122.44,119.18,116.96,116.38,116.03,114.79,114.17,107.06,106.19.HRMS(ESI):m/z calcd for[M+H]+:536.1723,found:536.1728。
In addition to the compounds of the above examples, the present invention performed in vitro screening for anti-tumor cell activity on the compounds of the examples.
Biological test example:
the obtained compounds were tested for proliferation inhibitory activity against human glioma cell U251, colon cancer cell HT29, liver cancer cell HepG2, lung cancer cell H1299 and kidney cancer cell 769P.
The experimental method comprises the following steps:
1) cell lines: selecting a human glioma cell U251, a colon cancer cell HT29, a liver cancer cell HepG2, a lung cancer cell H1299 and a kidney cancer cell 769P;
2) the cells in logarithmic growth phase are digested, counted and prepared to a concentration of 5 × 104Cell suspension/mL, 100. mu.L of cell suspension per well in a 96-well cell culture plate (5X 10 per well)3Individual cells). The 96-well cell culture plate was placed at 37 ℃ in 5% CO2After 24h incubation in the incubator, 100 μ L of compound was added, each compound was set up in a concentration gradient, and each concentration was set up in triplicate wells.
3) Standing at 37 deg.C for 5% CO2After 72 hours of culture in an incubator, the supernatant was discarded, 20. mu.L of 5mg/mL MTT solution and 80. mu.L of culture medium were added to each well, the mixture was incubated at 37 ℃ for 4 hours, the supernatant was discarded, 150. mu.L of DMSO was added to each well, the crystals were sufficiently dissolved by gentle shaking, and the absorbance (OD) was measured at a wavelength of 570nm using a microplate reader (absorbance was measured at a wavelength of 490nm for adherent cells). The inhibition rate was calculated by the following formula using cells cultured in the same conditions and the same concentration of DMSO without the sample as a control:
the cell growth inhibition rate (OD control-OD administration-OD blank)/(OD control-OD blank) × 100%. Median inhibitory concentration IC50Calculated using Graphpad Prism 4.
The experimental results are as follows: the inhibition of cell proliferation by the compounds on U251, HT29, HepG2, H1299 and 769P is shown in Table 1.
Cell proliferation inhibitory Activity of the Compounds of Table 1 against U251, HT29, HepG2, H1299 and 769P
As can be seen from the data in the table, most of the prepared compounds have better in vitro tumor inhibition activity, and the inhibition activity of examples 4, 8 and 12 on different tumor cell lines is less than 10 mu M, so that the compounds related to the application have stronger antitumor activity. In conclusion, the compounds have better anti-tumor application prospect, so that the compounds have good commercial value.
It is to be understood that the present application is not limited to what has been described above, and that various modifications and changes may be made without departing from the scope thereof. The scope of the application is limited only by the appended claims.
Claims (10)
1. A polysubstituted indolizine compound containing pyridone is characterized in that the structural formula is as follows:
the R is1Are various substituted phenyl, naphthyl, heterocyclic aryl and aliphatic hydrocarbons, R2Is hydrogen atom or methyl, X is oxygen atom or arylamine with various substituent groups on benzene ring.
2. The polysubstituted indolizines containing a pyridone of claim 1, being any one of the following:
1- (3- (4-methoxybenzoyl) -2- (4-methoxyphenyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (4-methylbenzoyl) -2- (p-tolyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (4-fluorobenzoyl) -2- (4-fluorobenzoyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3-benzoyl-2-phenylindolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (4-chlorobenzoyl) -2- (4-chlorophenyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (4-bromobenzoyl) -2- (4-bromophenyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (4-nitrobenzoyl) -2- (4-nitrophenyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (2- (thiophen-2-yl) -3- (thiophene-2-carbonyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (4- (trifluoromethyl) benzoyl) -2- (4- (trifluoromethyl) phenyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (3-methylbenzoyl) -2- (m-tolyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (3-bromobenzoyl) -2- (3-bromophenyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (furan-2-carbonyl) -2- (furan-2-yl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (2-naphthyl) -2- (naphthalen-2-yl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- ([1,1 '-biphenyl ] -4-carbonyl) -2- ([1,1' -biphenyl ] -4-yl) indolizin-1-yl) pyridin-2 (1H) -one;
4- (3- (4-cyanobenzoyl) -1- (2-oxopyridin-1 (2H) -yl) indolizin-2-yl) benzonitrile;
1- (2- (tert-butyl) -3-pivaloyl indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (2-methylbenzoyl) -2- (o-tolyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3- (2-bromobenzoyl) -2- (2-bromophenyl) indolizin-1-yl) pyridin-2 (1H) -one;
1- (3-benzoyl-6-methyl-2-phenylindolizin-1-yl) -5-methylpyridin-2 (1H) -one;
(E) -2- ((1- (3-benzoyl-2-phenylindolizin-1-yl) pyridine-2 (1H) -ethylidene) amino) benzonitrile;
(E) -2- ((1- (3-benzoyl-2-phenylindolizin-1-yl) pyridine-2 (1H) -ethylene) amino) -5-bromoxynil;
(E) -4- ((1- (3-benzoyl-2-phenylindolizin-1-yl) pyridin-2 (1H) -ylidene) amino) benzonitrile;
(E) -2- ((1- (3-benzoyl-2-phenylindolizin-1-yl) pyridine-2 (1H) -ethylidene) amino) -5-nitrobenzonitrile.
3. The method for producing a polysubstituted indolizine-based compound containing pyridone according to claim 1, comprising the steps of:
dissolving the o-chloropyridine salt and alkali in a solvent, and stirring until the reaction of the o-chloropyridine salt is finished;
the structural formula of the o-chloropyridine salt is as follows:
the R is1Various substituted phenyl, naphthyl, heterocyclic aryl and aliphatic hydrocarbon; said R is2H and methyl.
4. The process according to claim 3, wherein the reaction temperature of the o-chloropyridine salt is in the range of 0 ℃ to 60 ℃ and is 0 ℃, 20 ℃, 60 ℃, preferably 20 ℃.
5. The method of claim 3, wherein: the solvent is an aprotic solvent, and the aprotic solvent is selected from acetonitrile, tetrahydrofuran, N-dimethylformamide, dichloromethane and toluene, preferably acetonitrile;
the solvent is a protic solvent, and the protic solvent is methanol.
6. The process according to claim 3, wherein the base is cesium carbonate, potassium carbonate, sodium hydroxide, sodium hydride, triethylamine, preferably cesium carbonate; the amount of the base used is 2.0 to 3.0 equivalents of the o-chloropyridine salt, with 2.0 equivalents being preferred.
7. The method for producing a polysubstituted indolizine-based compound containing pyridone according to claim 1, comprising the steps of:
dissolving an o-chloropyridine salt, arylamine with different substituents on a benzene ring and alkali in a solvent, and stirring until the o-chloropyridine salt is reacted;
the structural formula of the o-chloropyridine salt is as follows:
the structural formula of the arylamine with different substituent groups on the benzene ring is as follows:
the R is1When it is hydrogen atom, bromine atom, nitro group, R2Is cyano; when R is present1When it is a hydrogen atom, R2Is cyano.
8. The process according to claim 7, wherein the reaction temperature of the o-chloropyridine salt is 20 ℃, the solvent is acetonitrile, the base is cesium carbonate, the amount is 2.0 equivalents of the o-chloropyridine salt, the concentration of the o-chloropyridine salt is 0.1mol/mL, and the concentration of the aromatic amine having a different substituent on the benzene ring is 0.3 mol/mL.
9. Use of the compound of claim 1 in the preparation of an antitumor medicament.
10. Use according to claim 9, characterized in that said tumor is selected from glioma, lung cancer, kidney cancer, colon cancer, rectal cancer and liver cancer.
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| CN113429409A (en) * | 2021-07-29 | 2021-09-24 | 浙大城市学院 | Sulfur-containing polysubstituted indolizine compound and preparation method thereof |
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