CN109053725B - 2- (tetrahydroquinoline-6-yl) -tetrahydro-1, 8-naphthyridine compound and preparation method and application thereof - Google Patents
2- (tetrahydroquinoline-6-yl) -tetrahydro-1, 8-naphthyridine compound and preparation method and application thereof Download PDFInfo
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- CN109053725B CN109053725B CN201810973000.8A CN201810973000A CN109053725B CN 109053725 B CN109053725 B CN 109053725B CN 201810973000 A CN201810973000 A CN 201810973000A CN 109053725 B CN109053725 B CN 109053725B
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- -1 2- (tetrahydroquinoline-6-yl) -tetrahydro-1, 8-naphthyridine compound Chemical class 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- LBUJPTNKIBCYBY-UHFFFAOYSA-N tetrahydroquinoline Natural products C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims abstract description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 25
- 239000001257 hydrogen Substances 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 17
- 239000012043 crude product Substances 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 238000004440 column chromatography Methods 0.000 claims abstract description 10
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 238000001816 cooling Methods 0.000 claims abstract description 8
- 238000002390 rotary evaporation Methods 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 8
- 229910052751 metal Inorganic materials 0.000 claims abstract description 6
- 239000002184 metal Substances 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 125000005059 halophenyl group Chemical group 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- DAKOVVGRYRXCEP-UHFFFAOYSA-N 2-(1,2,3,4-tetrahydroquinolin-6-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine Chemical class N1CCCC2=CC(=CC=C12)C1NC2=NC=CC=C2CC1 DAKOVVGRYRXCEP-UHFFFAOYSA-N 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- 229940011182 cobalt acetate Drugs 0.000 claims description 3
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 claims description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 3
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 150000001555 benzenes Chemical class 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 2
- 229940079721 copper chloride Drugs 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- 229960000355 copper sulfate Drugs 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 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
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- 229940032296 ferric chloride Drugs 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229940071125 manganese acetate Drugs 0.000 claims description 2
- UOGMEBQRZBEZQT-UHFFFAOYSA-L manganese(2+);diacetate Chemical compound [Mn+2].CC([O-])=O.CC([O-])=O UOGMEBQRZBEZQT-UHFFFAOYSA-L 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
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- 239000000047 product Substances 0.000 description 33
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 238000001228 spectrum Methods 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
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- 230000000259 anti-tumor effect Effects 0.000 description 11
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- JZICUKPOZUKZLL-UHFFFAOYSA-N 2-methyl-1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2NC(C)CCC2=C1 JZICUKPOZUKZLL-UHFFFAOYSA-N 0.000 description 5
- YIIPMCFBCZKCFB-UHFFFAOYSA-N 8-methyl-1,2,3,4-tetrahydroquinoline Chemical compound C1CCNC2=C1C=CC=C2C YIIPMCFBCZKCFB-UHFFFAOYSA-N 0.000 description 5
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- MLFRLYOJELUIOR-UHFFFAOYSA-N 3-methyl-2-phenyl-1,8-naphthyridine Chemical class CC1=CC2=CC=CN=C2N=C1C1=CC=CC=C1 MLFRLYOJELUIOR-UHFFFAOYSA-N 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
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- ZCZVGQCBSJLDDS-UHFFFAOYSA-N 1,2,3,4-tetrahydro-1,8-naphthyridine Chemical compound C1=CC=C2CCCNC2=N1 ZCZVGQCBSJLDDS-UHFFFAOYSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
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- 150000005058 1,8-naphthyridines Chemical class 0.000 description 1
- FBRBUGVSEJYVDD-UHFFFAOYSA-N 2-(4-bromophenyl)-1,8-naphthyridine Chemical compound C1=CC(Br)=CC=C1C1=CC=C(C=CC=N2)C2=N1 FBRBUGVSEJYVDD-UHFFFAOYSA-N 0.000 description 1
- STCTVADMIRRKNK-UHFFFAOYSA-N 2-(4-chlorophenyl)-1,8-naphthyridine Chemical compound C1=CC(Cl)=CC=C1C1=CC=C(C=CC=N2)C2=N1 STCTVADMIRRKNK-UHFFFAOYSA-N 0.000 description 1
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- USBYIDDEYLTUIR-UHFFFAOYSA-N [O-][N+](=O)C1=CC=CC(C=2N=C3N=CC=CC3=CC=2)=C1 Chemical compound [O-][N+](=O)C1=CC=CC(C=2N=C3N=CC=CC3=CC=2)=C1 USBYIDDEYLTUIR-UHFFFAOYSA-N 0.000 description 1
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a 2- (tetrahydroquinoline-6-yl) -tetrahydro-1, 8-naphthyridine compound and a preparation method and application thereof, wherein the molecular general formula of the compound is shown as formula I:
wherein R in the formula I1Is phenyl, nitrobenzene or halophenyl; r2Is hydrogen or methyl; r3Is hydrogen or methyl; r4Is hydrogen or methyl. The preparation method comprises the following steps: s1, adding a tetrahydroquinoline compound and a 1,8 naphthyridine compound into a reaction container, adding a metal catalyst accounting for 1-5% of the mass of the tetrahydroquinoline compound, adding an acid and a solvent, and stirring and reacting at 80-160 ℃ for 5-24 hours; and S2, cooling to room temperature after the reaction is finished, filtering, performing reduced pressure rotary evaporation to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemical synthesis, and particularly relates to a 2- (tetrahydroquinoline-6-yl) -tetrahydro-1, 8-naphthyridine compound and a preparation method and application thereof.
Background
In recent years, heterocyclic compounds, especially nitrogen-containing heterocyclic compounds, play a crucial role in modern drug research, and the development of efficient nitrogen-containing heterocyclic compound construction methods attracts more and more attention. The naphthyridine nitrogen heterocyclic compound is an extremely important heterocyclic ring system, is commonly found in drug intermediates and various natural products, and has potential biological activity. The tetrahydronaphthyridine is also an important heterocyclic ring system and has wide application prospect in the fields of organic intermediates, medicines, pesticides, material science and the like. In addition, tetrahydroquinoline organic compounds are relatively common nitrogen heterocyclic compounds, unique molecular structures of the tetrahydroquinoline organic compounds exist in nature in a large quantity, and various derivatives of the tetrahydroquinoline organic compounds mostly have biological and pharmacological activities. Most of the natural products with biological activity in nature contain one or more nitrogen heterocyclic skeletons. When a new bi-heterocyclic or multi-heterocyclic structure is formed by combining single heterocyclic compounds, the original biological activity is always kept, and unexpected new characteristics are generated. Therefore, promoting the coupling between the nitrogen heterocyclic compounds to form the double nitrogen heterocyclic compounds with more excellent functionality is the hot spot of the current research.
With the development of organic chemistry and the development of materials and medical interdisciplinary science, scientists find a great number of new medicines and novel functional materials from nitrogen-containing heterocyclic compounds, and the double nitrogen heterocyclic compounds with two heterocycles combined together in different ways play an important role in biological medicines and functional materials. Tetrahydroquinoline and naphthyridine structures are basic skeletons of nitrogen heterocyclic compounds, and molecular structures of many natural products contain the structures, and some compounds show good biological activity. Carbon-carbon bond coupling between two nitrogen heterocyclic compounds is always a hotspot and a difficulty in research in the organic field, most of double-nitrogen heterocyclic skeleton molecules with complex structures can be synthesized through a plurality of steps of reactions, the operation steps are very complicated, and the economical efficiency of atoms and steps is low, so that in the synthesis of the complex double-nitrogen heterocyclic, the reduction of the synthesis route is an effective way for improving the final yield of the complex nitrogen heterocyclic compounds. Based on the above, if a green, efficient and simple-to-operate synthesis method can be found, the effective combination of the tetrahydroquinoline and the tetrahydronaphthyridine structural units can be carried out, and the construction of a series of dinitrogen heterocyclic skeleton molecules containing potential pharmaceutical activity has important significance.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provides a 2- (1,2,3, 4-tetrahydroquinoline-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compound with an inhibiting effect on tumors and a preparation method and application thereof.
In order to solve the technical problems, the invention adopts the technical scheme that: a2- (1,2,3, 4-tetrahydroquinoline-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compound has a molecular general formula shown in the following formula I:
wherein R in the formula I1Is phenyl, nitrobenzene or halophenyl; r2Is hydrogen or methyl; r3Is hydrogen or methyl; r4Is hydrogen or methyl.
The invention also provides a preparation method of the 2- (1,2,3, 4-tetrahydroquinoline-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compound, which comprises the following steps:
s1, adding tetrahydroquinoline compound and 2-phenyl-3-methyl-1, 8 naphthyridine compound into a reaction container, adding a metal Catalyst (Catalyst, Cat.) accounting for 1-5% of the mass of the tetrahydroquinoline compound, adding an acid and a solvent, stirring and reacting at 80-160 ℃ for 5-24 hours, wherein the molar ratio of the tetrahydroquinoline compound to the 1,8 naphthyridine compound is 1-2: 1, the mass of the acid is 10-100% of that of the tetrahydroquinoline compound, wherein the tetrahydroquinoline compound is preferably 2-methyl-tetrahydroquinoline or 8-methyl-tetrahydroquinoline, the 1,8 naphthyridine compounds are preferably 2-phenyl-3-methyl-1, 8 naphthyridine compounds with phenyl groups substituted by halogen or nitro groups;
and S2, cooling to room temperature after the reaction is finished, filtering, carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain the 2-tetrahydroquinolyl-tetrahydronaphthyridine compound.
Further, the room temperature is 20-30 ℃.
In step S1, the metal catalyst is one or a mixture of two or more of copper acetate, copper trifluoromethanesulfonate, copper sulfate, copper chloride, cuprous chloride, ferric chloride, cobalt acetate, cobalt chloride, and manganese acetate.
From the above description, the beneficial effects of the present invention are: effective catalysis can be realized by adopting a cheap metal catalyst, so that the production cost is greatly reduced.
Further, the solvent in step S1 is one or a mixture of two or more of ethanol, t-amyl alcohol, isopropanol, 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, toluene, p-xylene and water; the molar volume ratio of the added amount of the solvent to the tetrahydroquinoline compound is preferably the tetrahydroquinoline compound: solvent 0.5 mmol: 1-3 ml.
Further, the acid in step S1 is one or a mixture of two or more of formic acid, acetic acid, methanesulfonic acid, benzoic acid, p-toluenesulfonic acid, hydrochloric acid, trifluoromethanesulfonic acid and trifluoroacetic acid; the molar ratio of the acid to the tetrahydroquinoline compound is preferably tetrahydroquinoline compound: acid 0.5 mmol: 0.05 mmol.
Further, the reaction vessel in step S1 is preferably a schlenk tube (schlank tube), and the reaction process is preferably performed under nitrogen.
Further, in the step S2, the volume ratio of an eluent used in the column chromatography purification operation is (0.5-50): (0-20): 1 petroleum ether: dichloromethane: mixed solution of ethyl acetate.
Wherein, the partial reaction equation involved in the preparation method is as follows:
wherein, R is1Is phenyl, nitrobenzene, halogen substituted benzene; r2Is hydrogen or methyl; r3Is hydrogen or methyl; r4Is hydrogen or methyl.
The invention also comprises the application of the 2- (1,2,3, 4-tetrahydroquinoline-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compound in preparing an anti-tumor reagent or a medicine for preventing and treating tumors.
Further, the application is in the reagent or the medicine for resisting human cancer K562, HL-60, HeLa and/or BGC-823 cells.
The invention has the beneficial effects that: the invention provides a 2- (1,2,3, 4-tetrahydroquinoline-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compound with antitumor activity and a preparation method and application thereof, and effectively solves the preparation problem of the 2- (1,2,3, 4-tetrahydroquinoline-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compound with antitumor activity. The preparation method can efficiently synthesize the 2- (1,2,3, 4-tetrahydroquinoline-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dinitrogen heterocyclic compound, and has the advantages of simple synthesis steps, safe operation, nontoxic raw materials, cheap and easily-obtained raw materials and the like; the novel 2- (1,2,3, 4-tetrahydroquinoline-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compound has good inhibition effect on tested human cancers K562, HL-60, HeLa and BGC-823 cells, so the compound is used as an anti-tumor reagent for in vitro anti-tumor activity screening and can also be used in medicaments for preventing and treating tumors.
Drawings
FIG. 1 is a hydrogen spectrum of product 3a obtained in example 1 of the present invention;
FIG. 2 is a carbon spectrum of product 3a obtained in example 1 of the present invention;
FIG. 3 is a hydrogen spectrum of product 3b obtained in example 2 of the present invention;
FIG. 4 is a carbon spectrum of product 3b obtained in example 2 of the present invention;
FIG. 5 is a hydrogen spectrum of product 3c obtained in example 3 of the present invention;
FIG. 6 is a carbon spectrum of product 3c obtained in example 3 of the present invention;
FIG. 7 is a hydrogen spectrum of product 3d obtained in example 4 of the present invention;
FIG. 8 is a carbon spectrum of product 3d obtained in example 4 of the present invention;
FIG. 9 is a hydrogen spectrum of product 3e obtained in example 5 of the present invention;
FIG. 10 is a carbon spectrum of product 3e obtained in example 5 of the present invention.
Detailed Description
In order to explain technical contents, achieved objects, and effects of the present invention in detail, the following description is made with reference to the accompanying drawings in combination with the embodiments.
Embodiment 1 of the present invention is a method for preparing 2- (1,2,3, 4-tetrahydroquinolin-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine having an anti-tumor activity, comprising the steps of: adding 1.0 mmol of tetrahydroquinoline and 0.5mmol of 2-phenyl-3-methyl-1, 8-naphthyridine into a reactor, adding 1% of copper trifluoromethanesulfonate (Catalyst, Cat.), then adding 50% of trifluoromethanesulfonic acid and 1.5ml of toluene, stirring and reacting for 5 hours at 80 ℃, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain 3a, wherein the product is yellow oily.
The hydrogen spectrum and the carbon spectrum of the obtained product 3a are respectively shown in fig. 1 and fig. 2, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)：
δ7.49(d,J＝7.5Hz,2H),7.40(t,J＝7.5Hz,2H),7.32(t,J＝7.2Hz,1H),7.12(s,1H),6.95(d,J＝7.7Hz,2H),6.43(d,J＝7.8Hz,1H),4.98(s,1H),4.44(dd,J＝9.1,2.8Hz,1H),3.33-3.23(m,2H),2.89-2.80(m,1H),2.76-2.66(m,3H),2.18(s,3H),2.11-2.05(m,1H),1.96-1.86(m,3H)；
13C NMR(101MHz,CDCl3)：
δ154.28,144.15,141.15,139.07,132.32,128.95,128.02,127.43,127.35,124.77,121.45,118.86,114.72,114.18,55.79,42.02,30.92,27.04,25.53,22.20,18.77；
the infrared absorption spectrum of the product 3a was measured by an infrared spectrometer (IR (KBr)), and it was found that the compound was present at 2928, 1588, 1452, 1308, 1131, 819, 750, 699cm-1There is a characteristic absorption peak indicating that the scheme of the invention produces a product with the target functional group.
The molecular weight of the compound, C, was determined by High Resolution Mass Spectrometers (HRMS) using an electrospray Ionization source (ESI)24H26N3[M+H]+Theoretical value(normalized value, Calcd.) 356.2121; actual measured value (found): 356.2125.
embodiment 2 of the present invention is a method for preparing 2- (1,2,3, 4-tetrahydroquinolin-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compounds having anti-tumor activity, comprising the following steps: adding 0.8 mmol of 2-methyltetrahydroquinoline and 0.5mmol of 2-phenyl-3-methyl-1, 8-naphthyridine into a reactor, adding ferric chloride accounting for 5% of the mass of the 2-methyltetrahydroquinoline, adding 60% of methanesulfonic acid and 1.0ml of toluene, stirring and reacting for 12 hours at 160 ℃, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3b, wherein the product 3b is yellow oily.
The hydrogen spectrum and the carbon spectrum of the obtained product 3b are respectively shown in fig. 3 and 4, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)δ7.87(d,J＝4.8Hz,1H),7.18(d,J＝7.1Hz,1H),6.95(d,J＝9.8Hz,2H),6.54-6.47(m,1H),6.44(d,J＝7.9Hz,1H),5.04(s,1H),4.43(dd,J＝9.0,2.8Hz,1H),3.55-3.28(m,1H),2.88-2.77(m,2H),2.72-2.64(m,2H),2.11-2.02(m,1H),1.97-1.82(m,2H),1.65-1.53(m,1H),1.21(d,J＝6.2Hz,3H)；
13C NMR(101MHz,CDCl3)δ156.41,145.85,144.28,136.02,132.11,127.20,124.78,121.15,115.94,113.99,112.70,55.72,47.21,30.54,30.10,26.63,25.84,22.59；
IR (KBr) results indicated that product 3b was present at 2936, 2845, 1860, 1819, 1489, 1352, 1330, 1292, 1194, 1170, 771, 739cm-1All have characteristic absorption peaks, and the product has the target functional group.
The molecular weight of the compound, C, was determined by High Resolution Mass Spectrometers (HRMS) using an electrospray Ionization source (ESI)18H22N3[M+H]+Theoretical value (Calcd.) 2801808; actual measured value (found): 280.1804.
embodiment 3 of the present invention is a method for preparing 2- (1,2,3, 4-tetrahydroquinolin-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compounds having anti-tumor activity, comprising the steps of: adding 0.75 mmol of 2-methyltetrahydroquinoline and 0.5mmol of 2- (3-nitrophenyl) -1, 8-naphthyridine into a reactor, adding 2% of cobalt acetate catalyst of 2-methyltetrahydroquinoline, then adding 10% of p-toluenesulfonic acid and 1.2ml of toluene, stirring and reacting for 15 hours at 130 ℃, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3c, wherein the product 3c is yellow oily.
The hydrogen spectrum and the carbon spectrum of the obtained product 3c are respectively shown in fig. 5 and 6, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)δ8.80(s,1H),8.27(d,J＝7.8Hz,1H),8.16(d,J＝8.1Hz,1H),7.56(d,J＝7.9Hz,1H),7.30(d,J＝7.4Hz,1H),7.03(d,J＝7.4Hz,1H),6.96(d,J＝12.5Hz,2H),6.45(d,J＝8.0Hz,1H),5.19(s,1H),4.47(d,J＝7.5Hz,1H),3.72(s,1H),3.44-3.37(m,1H),2.89-2.70(m,4H),2.11(dd,J＝12.9,3.9Hz,1H),2.00-1.91(m,2H),1.64-1.53(m,1H),1.21(d,J＝6.2Hz,3H)；
13C NMR(101MHz,CDCl3)δ156.39,151.04,148.69,144.37,141.66,136.77,132.30,131.79,129.29,127.22,124.82,122.68,121.47,121.19,116.17,114.00,109.58,55.80,47.23,30.42,30.12,26.66,25.70,22.59；
IR (KBr) results showed that the product 3c was found to be 3415, 1638, 1618, 1527, 1442, 1348, 1121, 870, 792, 734cm-1All have characteristic absorption peaks, and the product has the target functional group.
The molecular weight of this compound, Calcd. for, was determined by High Resolution Mass Spectrometers (HRMS) using an electrospray Ionization source (ESI) C24H25N4O2[M+H]+:401.1972；found:401.1975。
Embodiment 4 of the present invention is a method for preparing 2- (1,2,3, 4-tetrahydroquinolin-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compounds having anti-tumor activity, comprising the steps of: adding 0.8 mmol of 8-methyltetrahydroquinoline and 0.4 mmol of 2- (4-chlorphenyl) -1, 8-naphthyridine into a reactor, adding 3 percent of copper acetate catalyst of 8-methyltetrahydroquinoline, then adding 50 percent of trifluoroacetic acid and 1.2ml of tert-amyl alcohol, stirring and reacting for 10 hours at 100 ℃, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3d, wherein the product 3d is a brown solid with a melting point of 140-141 ℃.
The hydrogen spectrum and the carbon spectrum of the obtained product 3d are respectively shown in fig. 7 and 8, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.5Hz,2H),7.36(d,J＝8.5Hz,2H),7.25(t,J＝3.7Hz,1H),6.93(d,J＝7.5Hz,1H),6.88(d,J＝10.2Hz,2H),5.15(s,1H),4.44(dd,J＝9.1,3.1Hz,1H),3.40-3.30(m,2H),2.87-2.71(m,4H),2.12-2.07(m,1H),2.07(s,3H),1.96-1.88(m,3H)；
13C NMR(101MHz,CDCl3)δ156.18,152.54,142.20,138.28,136.76,134.12,131.35,128.61,127.87,125.96,125.34,121.33,120.91,115.09,109.37,55.89,42.36,30.75,27.36,25.81,22.14,17.22；
IR (KBr) results indicated that product 3d was present at 2928, 2857, 1665, 1627, 1594, 1462, 1304, 1088, 806, 752cm-1All have characteristic absorption peaks, and the product has the target functional group.
The molecular weight of the compound, Calcd. for C, was determined by High Resolution Mass Spectrometry (HRMS) using an electrospray Ionization source (ESI)24H25ClN3[M+H]+:390.1731；found:390.1735.
Embodiment 5 of the present invention is a method for preparing 2- (1,2,3, 4-tetrahydroquinolin-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compounds having anti-tumor activity, comprising the steps of: adding 0.4 mmol of 8-methyltetrahydroquinoline and 0.4 mmol of 2- (4-bromophenyl) -1, 8-naphthyridine into a reactor, adding a copper chloride catalyst accounting for 3 percent of the mass of the 8-methyltetrahydroquinoline, adding 80 percent of p-toluenesulfonic acid and 1.2ml of p-xylene, stirring and reacting for 10 hours at 150 ℃, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, performing reduced pressure rotary evaporation to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain 3e, wherein the product 3e is a yellow solid, and the melting point is 173-.
The hydrogen spectrum and the carbon spectrum of the obtained product 3e are respectively shown in fig. 9 and fig. 10, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,2H),7.32-7.27(m,1H),6.97(d,J＝7.5Hz,1H),6.92(d,J＝10.3Hz,2H),5.18(s,1H),4.48(dd,J＝9.2,3.0Hz,1H),3.46-3.36(m,2H),2.90-2.75(m,4H),2.18-2.11(m,1H),2.11(s,3H),1.99-1.88(m,3H)；
13C NMR(101MHz,CDCl3)δ156.21,142.20,136.76,131.56,131.34,128.19,125.96,125.34,122.42,121.33,120.90,115.17,109.34,55.89,42.36,30.75,27.37,25.83,22.14,17.22；
IR (KBr) results indicated that product 3e was present at 2928, 1633, 1591, 1501, 1462, 1321, 807cm-1All have characteristic absorption peaks, and the product has the target functional group.
The molecular weight of the compound, Calcd. for C, was determined by High Resolution Mass Spectrometry (HRMS) using an electrospray Ionization source (ESI)24H25BrN3[M+H]+:434.1226；found:434.1224。
The novel compounds 3a to 3e prepared in the above examples 1 to 5 were subjected to an antitumor activity test: each compound was prepared to 100. mu.g/mL-1The methanol solution, the positive control drugs 5-fluorouracil (5-fluorouracil, 5-FU) and docetaxel (docetaxel) are respectively prepared into 100 mu g/mL-1The Dimethyl sulfoxide (DMSO) solution is prepared by testing the inhibition effect of each compound on K562, HL-60, HeLa and BGC-823 cells by using a tetramethyl azozolium salt (MTT) method by taking methanol and DMSO solvents as blank controls respectively, and specifically operating as follows:
1. preparing a cell culture solution: pouring a bag of RPMI-1640 culture medium powder (net content: 10.4g) into a clean beaker, dissolving with 900mL of ultra-pure water, and adding 100 mg/mL-11mL streptomycin, 0.5mL penicillin and NaHCO32g of the total weight. After magnetic stirring, the mixture was sterilized in a super clean bench by filtration through a 0.22 μm filter using an autoclaved Zeiss filter, and the filtrate was directly stored in a moist heat-sterilized glass bottle (450 mL/bottle). Before the culture medium is used, the frozen and preserved serum is taken, inactivated at 56 ℃ for 30min, added into the prepared RPMI-1640 culture solution (50 mL of serum is added into 450mL of culture medium), and covered, sealed by tinfoil paper and stored in a refrigerator at 4 ℃.
Preparing an MTT solution: 50mg of MTT powder was dissolved in 10mL of PBS solution, filtered through a 0.22 μm filter, and stored in a refrigerator at 4 ℃.
2. Antitumor activity test: respectively taking K562, HL-60, HeLa and BGC-823 cells in logarithmic phase, centrifuging at 4 deg.C and 3000rpm for 3min, removing supernatant, adding fresh RPMI-1640 culture medium, and diluting to 1 × 105Cell suspension per ml. 200. mu.L per well were inoculated in a 96-well plate at 37 ℃ with 5% CO2After culturing for 1h in the cell culture box, 2 μ L of sample solution is added to each well, each sample is provided with 3 parallel wells, two groups of blank controls with three wells are additionally arranged, and after sample addition, the cells are cultured for 24h under the same conditions. And after 24h, observing whether the cells have morphological changes under an optical microscope, preliminarily judging whether the samples have cytotoxic activity, and photographing if necessary. 5 mg/mL of the solution was added to each well-120. mu.L of each MTT solution was cultured in an incubator for 4 hours. The supernatant was removed by centrifugation (20 min at 2000rpm at 4 ℃) using a 96-well plate, 150. mu.L DMSO was added to each well, and the plate was shaken well to dissolve the purple precipitate completely. The optical density OD was measured at 570nm on a microplate reader, and each group of samples was averaged and expressed as Inhibition Rate (IR)% (OD)Blank space-ODSample (I))/ODBlank spaceX 100% formula.
The results of the MTT method for testing the inhibition of the proliferation activity of five 2- (1,2,3, 4-tetrahydroquinoline-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dinitro-heterocyclic compounds on four tumor cells are shown in Table 1:
TABLE 1 results of MTT assay for inhibition of proliferation activity of four tumor cells by the class of compounds
As can be seen from the above table 1, the compound prepared by the scheme of the invention has certain inhibition effect on K562, HL-60, HeLa and BGC-823 cells.
In conclusion, the 2- (tetrahydroquinoline-6-yl) -tetrahydro-1, 8-naphthyridine compound, the preparation method and the application thereof provided by the invention have an inhibition effect on tumors.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all equivalent changes made by using the contents of the present specification and the drawings, or applied directly or indirectly to the related technical fields, are included in the scope of the present invention.
Claims (7)
1. A2- (1,2,3, 4-tetrahydroquinoline-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compound is characterized in that: the molecular general formula of the compound is shown as the following formula I:
wherein R in the formula I1Is phenyl, nitrobenzene or halophenyl; r2Is hydrogen or methyl; r3Is hydrogen or methyl; r4Is hydrogen or methyl; and R is3And R4At least one of which is methyl.
2. A preparation method of 2- (1,2,3, 4-tetrahydroquinoline-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compounds is characterized in that: the method comprises the following steps:
s1, adding a tetrahydroquinoline compound and a 1, 8-naphthyridine compound into a reaction container, adding a metal catalyst accounting for 1-5% of the mass of the tetrahydroquinoline compound, adding an acid and a solvent, and stirring and reacting at 80-160 ℃ for 5-24 hours, wherein the molar ratio of the tetrahydroquinoline compound to the 1, 8-naphthyridine compound is 1-2: 1, and the mass of the acid is 10-100% of the mass of the tetrahydroquinoline compound;
s2, cooling to room temperature after the reaction is finished, filtering, carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain the 2- (1,2,3, 4-tetrahydroquinoline-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compound;
in step S1, the metal catalyst is one or a mixture of two or more of copper acetate, copper trifluoromethanesulfonate, copper sulfate, copper chloride, cuprous chloride, ferric chloride, cobalt acetate, cobalt chloride, and manganese acetate; the solvent is one or a mixture of more than two of ethanol, tertiary amyl alcohol, isopropanol, 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, toluene, p-xylene and water; the acid is one or the mixture of more than two of formic acid, acetic acid, methanesulfonic acid, benzoic acid, p-toluenesulfonic acid, hydrochloric acid, trifluoromethanesulfonic acid and trifluoroacetic acid;
the partial reaction equation involved in the above preparation method is as follows:
wherein the compound 1 is a tetrahydroquinoline compound, the compound 2 is a 1, 8-naphthyridine compound, and the compound 3 is a 2- (1,2,3, 4-tetrahydroquinolin-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compound; said R1Is phenyl, nitrobenzene, halogen substituted benzene; r2Is hydrogen or methyl; r3Is hydrogen or methyl; r4Is hydrogen or methyl; and R is3And R4At least one of which is methyl.
3. The method for preparing 2- (1,2,3, 4-tetrahydroquinolin-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compound according to claim 2, wherein: the molar volume ratio of the added solvent to the tetrahydroquinoline compound is tetrahydroquinoline: solvent 0.5 mmol: 1-3 ml.
4. The method for preparing 2- (1,2,3, 4-tetrahydroquinolin-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compound according to claim 2, wherein: the molar ratio of the acid to the tetrahydroquinoline compound is as follows: acid 0.5 mmol: 0.05 mmol.
5. The method for preparing 2- (1,2,3, 4-tetrahydroquinolin-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine compound according to claim 2, wherein: and step S2, the column chromatography purification operation adopts eluent with the volume ratio of (0.5-50): (0-20): 1 petroleum ether: dichloromethane: mixed solution of ethyl acetate.
6. The use of 2- (1,2,3, 4-tetrahydroquinolin-6-yl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine of claim 1 in the preparation of an anti-tumor agent or a medicament for the prevention or treatment of tumors.
7. The use of claim 6, wherein: the application is in the reagent or the medicine for resisting human cancer K562, HL-60, HeLa and/or BGC-823 cells.
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