CN115232140B - Tetrahydroquinoline chroman polycyclic compound and preparation method and application thereof - Google Patents
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Abstract
The invention belongs to the technical field of organic synthesis and pharmacy, and relates to a tetrahydroquinoline chroman polycyclic compound, a preparation method and application thereof. The structural formula of the tetrahydroquinoline chroman polycyclic compound is
Wherein R is 1 Is any one of H, halogen atom or alkyl; r is R 2 Is H or methyl; r is R 3 Is alkyl. The preparation method comprises the following steps: various substituted quinoline salts, 2, 3-ethyl butadienoate and 8-hydroxyisoquinoline are reacted for 0.5 to 2 hours at the temperature of 25 to 100 ℃ in an organic solvent in the presence of alkali, and the tetrahydroquinoline chroman polycyclic compound is prepared by one-pot tandem reaction. The preparation method has the advantages of cheap and easily obtained raw materials, wide substrate range, high bonding and cyclization efficiency, good selectivity, no need of separation and purification of intermediate products and easy separation of target products; simple operation and mild reaction condition. And the prepared tetrahydroquinoline chroman polycyclic compound has the potential of being developed into an anti-tumor drug.
Description
Technical Field
The invention belongs to the technical field of organic synthesis and pharmacy, and relates to a tetrahydroquinoline chroman polycyclic compound, a preparation method and application thereof.
Background
It was counted that 144 out of the 164 small organic molecule drugs approved by the FDA contained nitrogen heterocycles during 2015-2020. Among these azacycles, polysubstituted six-membered azacycles are most common (j.med.chem.2021, 64,2339.). As a representative of six-membered nitrogen heterocycles, polysubstituted tetrahydroquinoline polycyclic compounds are core backbones of many natural products and drugs, having important physiological activities. Therefore, the method for developing the high-efficiency synthetic tetrahydroquinoline has very important theoretical significance and practical value, can provide a compound source for bioactive screening, and has important application value for the screening of medicines and the pharmaceutical industry.
Because of the natural cyclic structure of quinoline salts, dearomatization of quinoline salts to produce polysubstituted tetrahydroquinoline polycyclic compounds is certainly one of the most straightforward and effective means (chem. Rev.2012,112,2557; chem. Rev.2011,111, 7157.). However, quinoline salts have a large number of reaction sites and a small difference in reactivity, and often suffer from poor regioselectivity and stereoselectivity (chem. Rev.2012,112,2642; org. Chem. Front.2018,5,453;Catalysts 2018,8,632.). Therefore, the design and development of a new series reaction strategy for synthesizing the multi-substituted tetrahydroquinoline polycyclic compound with a novel structure have important significance.
Disclosure of Invention
Aiming at the technical problems, the invention provides a tetrahydroquinoline chroman polycyclic compound, a preparation method and application thereof. The preparation method provided by the invention has the advantages of high bond forming and ring forming efficiency and good selectivity, the used raw materials are cheap and easy to obtain, the operation is simple, the reaction condition is mild, the intermediate product is not required to be separated and purified in the preparation process, and the target product is easy to separate. The prepared tetrahydroquinoline chroman polycyclic compound has the potential of being developed into an anti-tumor drug.
In order to achieve the above purpose, the technical scheme of the invention is realized as follows:
tetrahydroquinoline chroman polycyclic compounds having the structural formula
Wherein R is 1 Is any one of H, halogen atom or alkyl; r is R 2 Is H or methyl; r is R 3 Is alkyl.
The preparation method of the tetrahydroquinoline chroman polycyclic compound comprises the following steps: various substituted quinoline salts, ethyl 2, 3-butadiene and 8-hydroxyisoquinoline are reacted in the presence of alkali in an organic solvent, after the thin layer chromatography tracking reaction is completed, the tetrahydroquinoline chroman polycyclic compound is obtained through separation and purification by column chromatography.
Further, the structural formula of the various substituted quinoline salts is
Wherein R is 1 Is any one of H, halogen atom or alkyl; r is R 2 Is H or methyl; r is R 3 Is alkyl.
Further, the structural formula of the 2, 3-ethyl butadienoate is
Further, the structural formula of the 8-hydroxyisoquinoline is
Further, the organic solvent is acetonitrile, toluene, methanol, chloroform, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, ethyl acetate or the like.
Preferably, the organic solvent is chloroform.
Further, the alkali is organic alkali or inorganic alkali, and the inorganic alkali is sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium hydroxide or disodium hydrogen phosphate and the like; the organic base is diisopropylethylamine, tetramethylguanidine, triethylamine, piperidine or N-methylmorpholine, etc.
Preferably, the base is N-methylmorpholine.
Further, the molar ratio of the various substituted quinoline salts, ethyl 2, 3-butadienoate and 8-hydroxyisoquinoline is (1-3): 1:1, and the molar ratio of the base to 8-hydroxyisoquinoline is (1-3): 1.
Further, the reaction temperature is 25-100 ℃, and the reaction time is 0.5-2h.
Preferably, the temperature of the reaction is 60 ℃.
Further, the reaction formula of the tetrahydroquinoline chroman polycyclic compound is shown as follows:
further, the tetrahydroquinoline chroman polycyclic compound is applied to the preparation of medicines for preventing and treating tumor diseases.
The invention has the following beneficial effects:
1. the invention prepares the polysubstituted tetrahydroquinoline chroman polycyclic compound by adding substituted quinoline salt, 2, 3-ethyl butadienoate and 8-hydroxyisoquinoline into chloroform solvent, taking N-methylmorpholine as acid binding agent and carrying out multicomponent serial cyclization reaction at 60 ℃. The preparation method of the tetrahydroquinoline chroman polycyclic compound provided by the invention has the advantages of high bond forming efficiency and good selectivity. The raw materials are cheap and easy to obtain, the operation is simple, the reaction condition is mild and efficient, the intermediate product in the preparation process does not need to be separated and purified, and the target product is easy to separate.
2. The invention introduces the physiologically active skeleton of chroman on the basis of polysubstituted tetrahydroquinoline polycyclic compounds, and also constructs a polycyclic system, thereby having the potential of being developed into antitumor drugs. Wherein the prepared compounds 4a,4c and 4j have cytotoxicity to human lung cancer cells (A549), and the compound 4a has IC to A549 tumor cells 50 26.432. Mu. Mol/L; IC of Compound 4c on A549 tumor cells 50 73.194. Mu. Mol/L; IC of Compound 4j against A549 tumor cells 50 9.667. Mu. Mol/L, and the positive control cisplatin versus A549 tumor cell IC 50 15.208. Mu. Mol/L; compounds 4a,4b,4c, 4j are cytotoxic to human chronic myelogenous leukemia cells (K562), and compound 4c is an IC to K562 tumor cells 50 67.720. Mu. Mol/L; IC of Compound 4j against K562 tumor cells 50 11.799. Mu. Mol/L; while positive control cisplatin versus K562 tumor cell IC 50 16.966. Mu. Mol/L. IC of the above-prepared Compound 50 The cisplatin is in the same order as cisplatin used in the first line of tumor treatment, and can be possibly developed into a new medicine with an anti-tumor effect, thereby having potential application prospect.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a tetrahydroquinoline chroman polycyclic compound 4a prepared in example 1 of the present invention 1 H NMR chart.
FIG. 2 is a tetrahydroquinoline chroman polycyclic compound 4a prepared in example 1 of the present invention 13 C NMR chart.
FIG. 3 is an X-ray single crystal diffraction pattern of tetrahydroquinoline chroman polycyclic compound 4a prepared in example 1 of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without any inventive effort, are intended to be within the scope of the invention.
Example 1
The present example is a process for the preparation of tetrahydroquinoline chroman polycyclic compounds 4a, comprising the steps of:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 a: to a 10mL hard glass reaction tube were added, in order, 1mL chloroform, N-benzylquinoline salt 1a (0.60 mmol,180.1 mg), ethyl 2, 3-butadiene 2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.2 mmol,29.0 mg), and N-methylmorpholine (0.60 mmol,60.6 mg). The mixture was stirred at 60℃for 30min. After the reaction was completed, the objective compound 4a (pale yellow solid, melting point: 212.5-214.1 ℃ C., yield 42%) was obtained by column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)).
The nmr hydrogen spectrum, carbon spectrum, infrared and high resolution mass spectrum data of the obtained compound 4a are as follows:
1 H NMR(300MHz,CDCl 3 )δ7.18-7.10(m,5H),6.99(t,J＝9.0Hz,2H),6.92(d,J＝6.0Hz,1H),6.74(t,J＝6.0Hz,1H),6.57(q,J＝6.0Hz,3H),6.47(d,J＝9.0Hz,1H),5.67(dd,J 1 ＝12.0Hz,J 1 ＝6.0Hz,2H),4.88(d,J＝9.0Hz,1H),4.83(d,J＝3.0Hz,1H),4.54(dd,J 1 ＝9.0Hz,J 1 ＝6.0Hz,2H),4.37-4.20(m,2H),2.85-2.78(m,1H),2.49(s,3H),1.32(t,J＝6.0Hz,3H)。
13 C NMR(75MHz,CDCl 3 )δ169.2,150.0,148.5,141.8,139.1,130.9,129.4,129.1,128.3,127.6,127.5,127.0,126.6,126.6,119.2,116.5,115.0,114.1,113.7,106.5,102.9,84.6,60.0,52.8,46.8,33.3,33.1,16.6,14.5。
IR(KBr)ν2970,1687,1545,1237,1110,747cm -1 。
HRMS(ESI)m/z:[M+H] + Calcd for C 31 H 29 N 2 O 3 477.2173；Found:477.2182.
the preparation method of the compound 4b-l is the same as that of the compound 4a, the material feeding ratio of each substance is the same as that of the compound 4a, meanwhile, the alkali can be inorganic alkali or organic alkali, and the inorganic alkali can be sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium hydroxide, disodium hydrogen phosphate and the like; the organic base can be diisopropylethylamine, tetramethylguanidine, triethylamine, piperidine, N-methylmorpholine, etc., and the organic solvent can be acetonitrile, toluene, methanol, chloroform, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane or ethyl acetate. Thus, compounds 4b-4l were obtained with the reaction yields shown in Table 1, but it should be emphasized that the compounds of the present invention are not limited to the compounds shown in Table 1. The specific method is as follows:
TABLE 1 structural formula of polysubstituted tetrahydroquinoline chroman polycyclic compound and yield thereof
Example 2
The present example is a process for preparing tetrahydroquinoline chroman polycyclic compound 4b, comprising the steps of:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 b: to a 10mL hard glass reaction tube were added, in order, 1mL chloroform, substituted quinoline salt 1b (0.60 mmol), ethyl 2, 3-butadiene 2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.2 mmol,29.0 mg), and N-methylmorpholine (0.60 mmol,60.6 mg). The mixture was stirred at 60℃for 30min. After the reaction was completed, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) gave the objective compound 4b.
Compound 4b (white solid, melting point: 193.6-195.4 ℃,27% yield): 1 H NMR(400MHz,CDCl 3 )δ7.19(d,J＝4.0Hz,3H),7.13(d,J＝8.0Hz,2H),7.01(t,J＝8.0Hz,1H),6.68(t,J＝8.0Hz,2H),6.62(d,J＝8.0Hz,1H),6.56(d,J＝8.0Hz,1H),6.51(d,J＝8.0Hz,2H),5.70(d,J＝8.0Hz,1H),5.61(d,J＝4.0Hz,1H),4.84(d,J＝16.0Hz,1H),4.78(d,J＝12.0Hz,1H),4.51-4.47(m,2H),4.35-4.21(m,2H),2.85-2.80(m,1H),2.51(s,3H),1.32(t,J＝8.0Hz,3H)。
13 C NMR(100MHz,CDCl 3 )δ168.8,156.7(d,J＝237.0Hz,1C),150.1,149.1,138.8,138.1,130.7,129.3,129.2,128.4,127.3,126.8,126.7,116.6,116.0(d,J＝23.0Hz,1C),115.2,115.1,114.0,113.8(d,J＝22.0Hz,1C),106.6,102.0,84.8,60.1,53.1,46.9,33.8,33.5,16.6,14.4。
19 F NMR(375MHz,CDCl 3 )δ-125.1。
IR(KBr)ν2973,1685,1552,1237,1115,796cm -1 。
HRMS(ESI)m/z:[M+H] + Calcd for C 31 H 28 FN 2 O 3 495.2078；Found:495.2084。
example 3
The present example is a process for preparing tetrahydroquinoline chroman polycyclic compounds 4c, comprising the steps of:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 c: to a 10mL hard glass reaction tube were added, in order, 1mL chloroform, substituted quinoline salt 1c (0.60 mmol), ethyl 2, 3-butadiene 2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.20 mmol,29.0 mg), and N-methylmorpholine (0.60 mmol,60.6 mg). The mixture was stirred at 60℃for 30min. After the reaction was completed, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) gave the objective compound 4c.
Compound 4c (yellow solid, melting point: 207.7-208.5 ℃,30% recovery)Rate): 1 H NMR(400MHz,CDCl 3 )δ7.18(d,J＝4.0Hz,3H),7.10-6.99(m,5H),6.62(d,J＝8.0Hz,1H),6.57(d,J＝8.0Hz,1H),6.49(d,J＝8.0Hz,1H),6.44(d,J＝8.0Hz,1H),5.72(d,J＝8.0Hz,1H),5.63(d,J＝8.0Hz,1H),4.84(d,J＝16.0Hz,1H),4.80(d,J＝12.0Hz,1H),4.51(d,J＝8.0Hz,1H),4.48(s,1H),4.41-4.33(m,1H),4.26-4.18(m,1H),2.83-2.78(m,1H),2.52(s,3H),1.34(t,J＝8.0Hz,3H)。
13 C NMR(125MHz,CDCl 3 )δ168.7,149.8,149.2,140.9,138.4,132.2,130.8,130.3,129.3,129.2,128.4,127.4,126.8,126.5,116.7,115.8,115.1,113.6,111.3,106.8,101.9,84.2,60.0,52.4,46.7,33.3,32.9,16.6,14.5。
IR(KBr)ν2974,1686,1591,1554,1239,1117,796cm -1 。
HRMS(ESI)m/z:[M+H] + Calcd for C 31 H 28 BrN 2 O 3 555.1278；Found:555.1278。
example 4
The embodiment is a preparation method of tetrahydroquinoline chroman polycyclic compound 4d, which comprises the following steps:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 d: to a 10mL hard glass reaction tube, 1mL chloroform, substituted quinoline salt 1d (0.60 mmol), ethyl 2, 3-butadiene 2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.20 mmol,29.0 mg), and N-methylmorpholine (0.60 mmol,60.6 mg) were added sequentially. The mixture was stirred at 60℃for 30min. After the reaction was completed, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) gave the objective compound 4d.
Compound 4d (white solid, melting point: 203.6-205.2 ℃,27% yield): 1 H NMR(300MHz,CDCl 3 )δ7.18-7.11(m,5H),6.99(t,J＝9.0Hz,1H),6.78(d,J＝9.0Hz,1H),6.72(s,1H),6.61(d,J＝9.0Hz,1H),6.54(d,J＝9.0Hz,1H),6.48(dd,J 1 ＝9.0Hz,J 1 ＝6.0Hz,2H),5.68(d,J＝9.0Hz,1H),5.62(d,J＝6.0Hz,1H),4.87(s,1H),4.82(d,J＝6.0Hz,1H),4.51(s,1H),4.48(d,J＝9.0Hz,1H),4.40-4.18(m,2H),2.83-2.76(m,1H),2.50(s,3H),2.18(s,3H),1.32(t,J＝6.0Hz,3H)。
13 C NMR(75MHz,CDCl 3 )δ169.2,150.1,148.5,139.5,139.3,130.9,130.0,129.1,128.4,128.3,128.0,127.5,127.0,126.7,126.6,116.4,115.1,114.2,113.9,106.5,102.9,84.8,59.9,52.9,46.9,33.4,33.3,20.5,16.6,14。
IR(KBr)ν2968,1685,1550,1239,1114,798cm -1 。
HRMS(ESI)m/z:[M+H] + Calcd for C 32 H 31 N 2 O 3 491.2329；Found:491.2315。
example 5
The present example is a process for preparing tetrahydroquinoline chroman polycyclic compounds 4e, comprising the steps of:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 e: to a 10mL hard glass reaction tube were added, in order, 1mL chloroform, substituted quinoline salt 1e (0.60 mmol), ethyl 2, 3-butadiene 2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.20 mmol,29.0 mg), and N-methylmorpholine (0.60 mmol,60.6 mg). The mixture was stirred at 60℃for 30min. After the reaction was completed, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) gave the target compound 4e.
Compound 4e (yellow solid, melting point: 187.4-189.1 ℃,60% yield): 1 H NMR(400MHz,CDCl 3 )δ7.19(s,3H),7.12(s,2H),6.99(t,J＝4.0Hz,1H),6.86(d,J＝8.0Hz,1H),6.74(d,J＝12.0Hz,2H),6.60(d,J＝8.0Hz,1H),6.55(d,J＝4.0Hz,1H),6.45(d,J＝8.0Hz,1H),5.70(d,J＝8.0Hz,1H),5.63(s,1H),4.79(t,J＝12.0Hz,2H),4.53(d,J＝16.0Hz,1H),4.41(s,1H),4.28(d,J＝4.0Hz,1H),4.24(d,J＝4.0Hz,1H),2.81-2.79(m,1H),2.49(s,3H),1.30(t,J＝4.0Hz,3H)。
13 C NMR(100MHz,CDCl 3 )δ168.9,149.8,148.9,143.2,138.1,131.0,130.7,129.2,128.5,127.3,126.9,126.7,126.1,126.1,122.0,121.3,116.7,115.0,113.6,106.7,102.2,84.1,60.1,52.3,46.7,33.0,32.9,16.6,14.5。
IR(KBr)ν2962,1689,1591,1555,1236,1115,796cm -1 。
HRMS(ESI)m/z:[M+H] + Calcd for C 31 H 28 BrN 2 O 3 555.1278；Found:555.1272。
example 6
The embodiment is a preparation method of tetrahydroquinoline chroman polycyclic compound 4f, which comprises the following steps:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 f: to a 10mL hard glass reaction tube, 1mL chloroform, substituted quinoline salt 1f (0.60 mmol), ethyl 2, 3-butadiene 2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.20 mmol,29.0 mg), and N-methylmorpholine (0.60 mmol,60.6 mg) were added sequentially. The mixture was stirred at 60℃for 30min. After the reaction was completed, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) gave the objective compound 4f.
Compound 4f (white solid, melting point: 202.1-203.7 ℃,52% yield): 1 H NMR(300MHz,CDCl 3 )δ7.19-7.11(m,5H),6.97(t,J＝6.0Hz,1H),6.81(d,J＝9.0Hz,1H),6.60-6.53(m,3H),6.41(d,J＝9.0Hz,2H),5.67(d,J＝9.0Hz,1H),5.63(d,J＝6.0Hz,1H),4.88(s,1H),4.83(d,J＝9.0Hz,1H),4.54(d,J＝18.0Hz,1H),4.49(d,J＝3.0Hz,1H),4.34-4.20(m,2H),2.82-2.75(m,1H),2.49(s,3H),2.15(s,3H),1.32(t,J＝6.0Hz,3H)。
13 C NMR(125MHz,CDCl 3 )δ169.2,150.0,148.4,141.8,139.2,137.3,130.9,129.3,129.1,128.3,127.5,126.6,126.5,124.2,120.0,116.4,115.0,114.6,113.7,106.4,103.0,84.7,60.0,52.8,46.7,33.1,32.9,21.4,16.6,14.5。
IR(KBr)ν2973,1684,1555,1240,1117,791cm -1 。
HRMS(ESI)m/z:[M+H] + Calcd for C 32 H 31 N 2 O 3 491.2329；Found:491.2343。
example 7
This example is a preparation method of tetrahydroquinoline chroman polycyclic compound 4g, comprising the following steps:
preparation of polysubstituted tetrahydroquinoline-chroman polycyclic compound 4 g: to a 10mL hard glass reaction tube were added 1mL of chloroform, 1g (0.60 mmol) of substituted quinoline salt, 2, 3-ethyl-butadiene-2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.20 mmol,29.0 mg), and N-methylmorpholine (0.60 mmol,60.6 mg) in this order. The mixture was stirred at 60℃for 30min. After the completion of the reaction, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) gave 4g of the target compound.
Compound 4g (white solid, melting point: 206.7-208.2 ℃,53% yield): 1 H NMR(400MHz,CDCl 3 )δ7.03(t,J＝8.0Hz,4H),6.95(t,J＝8.0Hz,4H),6.71(t,J＝8.0Hz,1H),6.61(d,J＝8.0Hz,1H),6.56(d,J＝8.0Hz,1H),6.47(d,J＝8.0Hz,1H),6.42(d,J＝8.0Hz,1H),5.74(d,J＝8.0Hz,1H),5.15(d,J＝20.0Hz,1H),4.91(d,J＝12.0Hz,1H),4.71(s,1H),4.41-4.28(m,2H),4.18(d,J＝16.0Hz,1H),2.60(dd,J 1 ＝12.0Hz,J 2 ＝4.0Hz,1H),2.46(s,3H),1.79(s,3H),1.37(t,J＝8.0Hz,3H)。
13 C NMR(100MHz,CDCl 3 )δ169.5,150.3,148.1,141.3,139.9,131.0,129.6,129.1,128.3,127.9,127.5,126.3,125.8,125.2,118.4,116.4,114.8,114.2,113.1,106.8,103.5,87.7,60.1,48.1,47.7,36.3,33.1,24.2,16.9,14.5。
IR(KBr)ν2979,1687,1549,1239,1117,794cm -1 。
HRMS(ESI)m/z:[M+H] + Calcd for C 32 H 31 N 2 O 3 491.2329；Found:491.2340。
example 8
The embodiment is a preparation method of tetrahydroquinoline chroman polycyclic compound for 4h, which comprises the following steps:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound for 4 h: to a 10mL hard glass reaction tube, 1mL chloroform, substituted quinoline salt (0.60 mmol), ethyl 2, 3-butadiene (2, 0.20mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.20 mmol,29.0 mg), and N-methylmorpholine (0.60 mmol,60.6 mg) were added sequentially. The mixture was stirred at 60℃for 30min. After the reaction was completed, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) gave the objective compound for 4h.
Compound 4h (yellow solid, melting point: 167.9-168.7 ℃,21% yield): 1 H NMR(400MHz,CDCl 3 )δ7.12-7.07(m,2H),6.90(d,J＝8.0Hz,1H),6.77-6.69(m,3H),5.57(t,J＝8.0Hz,2H),5.66(d,J＝8.0Hz,1H),5.49(d,J＝4.0Hz,1H),4.69(d,J＝12.0Hz,1H),4.47(d,J＝4.0Hz,1H),4.33-4.19(m,2H),3.04(s,3H),2.81-2.76(m,1H),2.47(s,3H),1.30(t,J＝8.0Hz,3H)。
13 C NMR(125MHz,CDCl 3 )δ169.2,149.9,148.4,142.2,131.1,129.2,129.1,127.6,127.5,127.0,118.9,116.4,114.9,114.1,113.6,106.3,102.8,85.1,60.0,46.7,34.6,33.2,33.1,16.6,14.4。
IR(KBr)ν2973,1680,1550,1239,1124,786cm -1 。
HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 25 N 2 O 3 401.1860；Found:401.1866。
example 9
The embodiment is a preparation method of tetrahydroquinoline chroman polycyclic compound 4i, which comprises the following steps:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 i: to a 10mL hard glass reaction tube were added, in order, 1mL chloroform, substituted quinoline salt 1i (0.60 mmol), ethyl 2, 3-butadiene 2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.20 mmol,29.0 mg), and N-methylmorpholine (0.60 mmol,60.6 mg). The mixture was stirred at 60℃for 30min. After the reaction was completed, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) gave the target compound 4i.
Compound 4i (white solid, melting point: 184.5-185.6 ℃,42% yield): 1 H NMR(500MHz,CDCl 3 )δ7.10-7.04(m,2H),6.90(d,J＝5.0Hz,1H),6.73(t,J＝10.0Hz,1H),6.70-6.67(m,2H),6.57(t,J＝10.0Hz,2H),5.83-5.79(m,1H),5.67(d,J＝5.0Hz,1H),5.61(d,J＝5.0Hz,1H),5.11-5.05(m,2H),4.75(d,J＝10.0Hz,1H),4.49(d,J＝5.0Hz,1H),4.33-4.19(m,3H),3.98(dd,J 1 ＝15.0Hz,J 2 ＝5.0Hz,1H),2.78-2.74(m,1H),2.47(s,3H),1.31(t,J＝6.0Hz,3H)。
13 C NMR(125MHz,CDCl 3 )δ169.1,149.9,148.5,141.3,134.4,131.0,129.4,129.2,127.7,127.5,126.6,118.9,116.4,116.4,115.0,113.9,113.5,106.6,103.0,83.9,60.0,50.8,46.6,33.1,32.4,16.6,14.5。
IR(KBr)ν2982,1681,1541,1236,1108,794cm -1 。
HRMS(ESI)m/z:[M+H] + Calcd for C 27 H 27 N 2 O 3 427.2016；Found:427.2027。
example 10
The embodiment is a preparation method of tetrahydroquinoline chroman polycyclic compound 4j, which comprises the following steps:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 j: to a 10mL hard glass reaction tube, 1mL chloroform, substituted quinoline salt 1j (0.60 mmol), ethyl 2, 3-butadiene 2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.20 mmol,29.0 mg), and N-methylmorpholine (0.60 mmol,60.6 mg) were added sequentially. The mixture was stirred at 60℃for 30min. After the reaction was completed, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) was performed to obtain the target compound 4j.
Compound 4j (yellow solid, melting point: 223.1-224.7 ℃,38% yield): 1 H NMR(300MHz,CDCl 3 )δ7.14(d,J＝9.0Hz,2H),7.04-6.92(m,5H),6.76(t,J＝6.0Hz,1H),6.60(d,J＝6.0Hz,1H),6.56(d,J＝6.0Hz,1H),6.48(d,J＝9.0Hz,1H),6.45(d,J＝9.0Hz,1H),5.70(d,J＝6.0Hz,1H),5.64(d,J＝6.0Hz,1H),4.86(d,J＝6.0Hz,1H),4.81(d,J＝9.0Hz,1H),4.54(d,J＝3.0Hz,1H),4.48(d,J＝18.0Hz,1H),4.38-4.18(m,2H),2.84-2.78(m,1H),2.49(s,3H),1.32(t,J＝6.0Hz,3H)。
13 C NMR(125MHz,CDCl 3 )δ169.1,149.8,148.5,141.6,137.8,132.2,130.9,129.5,129.2,128.4,127.8,127.6,127.6,126.9,119.4,116.6,114.9,113.9,113.4,106.6,102.9,84.6,60.0,52.5,46.6,33.2,32.8,16.6,14.5。
IR(KBr)ν2978,1684,1590,1551,1238,1116,794cm -1 。
HRMS(ESI)m/z:[M+H] + Calcd for C 31 H 28 ClN 2 O 3 511.1783；Found:511.1797。
example 11
The embodiment is a preparation method of tetrahydroquinoline chroman polycyclic compound 4k, which comprises the following steps:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 k: to a 10mL hard glass reaction tube, 1mL chloroform, substituted quinoline salt 1k (0.60 mmol), ethyl 2, 3-butadiene 2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.20 mmol,29.0 mg), and N-methylmorpholine (0.60 mmol,60.6 mg) were added sequentially. The mixture was stirred at 60℃for 30min. After the reaction was completed, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) gave the target compound 4k.
Compound 4k (pale yellow solid, melting point: 221.1-222.7 ℃,50% yield): 1 H NMR(500MHz,CDCl 3 )δ7.92(d,J＝10.0Hz,2H),7.13(d,J＝5.0Hz,2H),6.91-6.88(m,3H),6.70(t,J＝10.0Hz,1H),6.53(d,J＝5.0Hz,1H),6.48(d,J＝10.0Hz,1H),6.29(d,J＝10.0Hz,1H),6.24(d,J＝10.0Hz,1H),5.64(d,J＝10.0Hz,1H),5.59(d,J＝5.0Hz,1H),4.84(d,J＝20.0Hz,1H),4.80(d,J＝15.0Hz,1H),4.54(d,J＝10.0Hz,1H),4.51(s,1H),4.26-4.18(m,2H),2.76-2.74(m,1H),2.41(s,3H),1.24(t,J＝10.0Hz,3H)。
13 C NMR(125MHz,CDCl 3 )δ169.0,149.5,148.6,147.5,146.8,141.2,131.0,129.7,129.4,127.7,127.7,126.9,126.7,123.6,119.8,116.8,114.6,113.5,113.0,106.7,102.9,84.8,60.1,53.2,46.5,33.2,32.3,16.6,14.5。
IR(KBr)ν2977,1684,1552,1238,1115,792cm -1 。
HRMS(ESI)m/z:[M+H] + Calcd for C 31 H 28 N 3 O 5 522.2023；Found:522.2026。
example 12
This example is a process for the preparation of tetrahydroquinoline chroman polycyclic compounds 4l, comprising the steps of:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 l: to a 10mL hard glass reaction tube were added 1mL of chloroform, 1l of substituted quinoline salt (0.60 mmol), 2, 3-ethyl-butadiene-2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.20 mmol,29.0 mg), and N-methylmorpholine (0.60 mmol,60.6 mg) in this order. The mixture was stirred at 60℃for 30min. After the reaction was completed, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) gave the objective compound 4l.
Compound 4l (white solid, melting point: 161.3-162.6 ℃,40% yield): 1 H NMR(500MHz,CDCl 3 )δ7.20(d,J＝5.0Hz,2H),7.07(d,J＝10.0Hz,2H),7.02-6.98(m,2H),6.92(d,J＝10.0Hz,1H),6.74(t,J＝10.0Hz,1H),6.65(d,J＝10.0Hz,1H),6.60(d,J＝5.0Hz,1H),6.55(d,J＝10.0Hz,1H),6.48(d,J＝5.0Hz,1H),5.68(d,J＝10.0Hz,1H),5.64(d,J＝5.0Hz,1H),4.83(s,1H),4.80(d,J＝5.0Hz,1H),4.52(d,J＝5.0Hz,1H),4.50(d,J＝5.0Hz,1H),4.34-4.21(m,2H),2.83-2.79(m,1H),2.49(s,3H),1.32(t,J＝10.0Hz,3H),1.27(s,9H)。
13 C NMR(125MHz,CDCl 3 )δ169.2,150.0,149.5,148.5,142.0,136.0,130.8,129.4,129.1,127.6,127.5,127.0,126.5,125.2,119.1,116.4,115.1,114.1,113.9,106.4,102.9,84.4,60.0,52.2,46.8,34.4,33.3,33.2,31.3,16.6,14.5。
IR(KBr)ν2964,1686,1553,1238,1116,790cm -1 。
HRMS(ESI)m/z:[M+H] + Calcd for C 35 H 37 N 2 O 3 533.2799；Found:533.2801。
example 13
The present example is a process for the preparation of tetrahydroquinoline chroman polycyclic compounds 4a, comprising the steps of:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 a: to a 10mL hard glass reaction tube were added, in order, 1mL acetonitrile, N-benzylquinoline salt 1a (0.20 mmol,60 mg), ethyl 2, 3-butadienoate 2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.20 mmol,29.0 mg), and diisopropylethylamine (0.20 mmol). The mixture was stirred at 60℃for 30min. After the reaction was completed, the target compound 4a was obtained by column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)).
Example 14
The present example is a process for preparing tetrahydroquinoline chroman polycyclic compounds 4e, comprising the steps of:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 e: to a 10mL hard glass reaction tube, 1mL toluene, substituted quinoline salt 1e (0.25 mmol), ethyl 2, 3-butadiene 2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.2 mmol,29.0 mg), and tetramethylguanidine (0.25 mmol) were added sequentially. The mixture was stirred at 25℃for 2h. After the reaction was completed, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) gave the target compound 4e.
Example 15
The embodiment is a preparation method of tetrahydroquinoline chroman polycyclic compound 4f, which comprises the following steps:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 f: to a 10mL hard glass reaction tube, 1mL of methanol, substituted quinoline salt 1f (0.30 mmol), 2, 3-ethyl-butadiene-2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.2 mmol,29.0 mg), and sodium carbonate (0.30 mmol) were added sequentially. The mixture was stirred at 30℃for 1.8h. After the reaction was completed, the target compound 4f was obtained by column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)).
Example 16
This example is a preparation method of tetrahydroquinoline chroman polycyclic compound 4g, comprising the following steps:
preparation of polysubstituted tetrahydroquinoline-chroman polycyclic compound 4 g: to a 10mL hard glass reaction tube, 1mL of methylene chloride, 1g (0.35 mmol) of a substituted quinoline salt, 2, 3-ethyl-butadiene-2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.2 mmol,29.0 mg), and triethylamine (0.35 mmol) were successively added. The mixture was stirred at 40℃for 2h. After completion of the reaction, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) gave 4g of the target compound.
Example 17
The embodiment is a preparation method of tetrahydroquinoline chroman polycyclic compound 4i, which comprises the following steps:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 i: to a 10mL hard glass reaction tube, 1mL of 1, 2-dichloroethane, substituted quinoline salt 1i (0.40 mmol), ethyl 2, 3-butadiene 2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.2 mmol,29.0 mg), and piperidine (0.40 mmol) were added sequentially. The mixture was stirred at 50℃for 1.5h. After the reaction was completed, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) gave the target compound 4i.
Example 18
The embodiment is a preparation method of tetrahydroquinoline chroman polycyclic compound 4k, which comprises the following steps:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 k: to a 10mL hard glass reaction tube, 1mL tetrahydrofuran, substituted quinoline salt 1k (0.45 mmol), ethyl 2, 3-butadiene 2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.2 mmol,29.0 mg), and potassium carbonate (0.45 mmol) were added sequentially. The mixture was stirred at 60℃for 30min. After the reaction was completed, the target compound 4k was obtained by column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)).
Example 19
This example is a process for the preparation of tetrahydroquinoline chroman polycyclic compounds 4l, comprising the steps of:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 l: to a 10mL hard glass reaction tube, 1mL of 1, 4-dioxane, 1L of substituted quinoline salt (0.50 mmol), 2, 3-ethyl-2-butadienoate (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.2 mmol,29.0 mg), and sodium ethoxide (0.50 mmol) were added sequentially. The mixture was stirred at 70℃for 1h. After the reaction was completed, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) gave the objective compound 4l.
Example 20
The embodiment is a preparation method of tetrahydroquinoline chroman polycyclic compound 4j, which comprises the following steps:
preparation of polysubstituted tetrahydroquinoline chroman polycyclic compound 4 j: to a 10mL hard glass reaction tube, 1mL ethyl acetate, substituted quinoline salt 1j (0.55 mmol), ethyl 2, 3-butadiene 2 (0.20 mmol,22.4 mg), 8-hydroxyisoquinoline 3 (0.2 mmol,29.0 mg), and disodium hydrogen phosphate (0.55 mmol) were added sequentially. The mixture was stirred at 100deg.C for 30min. After the reaction was completed, column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = (30:1) - (25:1)) was performed to obtain the target compound 4j.
Application example
The compounds listed in the table 1 of the invention have important biological activity, and cytotoxicity tests of two tumor cells, namely human lung cancer cells (A549) and human leukemia cells (K562), show that: the polysubstituted tetrahydroquinoline chroman polycyclic compounds shown in the table 1 have an inhibiting effect on the growth of tumor cells, and can be possibly developed into novel medicines for preventing and treating tumors. It is emphasized that the compounds of the present invention are not limited to cytotoxicity expressed by human lung cancer cells (a 549) and human leukemia cells (K562).
Pharmacological example 1: cytotoxicity of Compounds 4a,4c and 4j on A549 cells
A549 (human lung small cell lung cancer) was cultured in DMEM medium containing 10% fetal bovine serum, 100U/mL penicillin and 100U/mL streptomycin. Cells were added to 96 wells at a concentration of 4000 cells per well at 37℃with 5% CO 2 Culturing in a humid air incubator for 24 hours.
Cell viability was determined using the modified MTT method. After 24h incubation of the cells, the newly prepared dimethyl sulfoxide solutions of the compounds 4a,4c and 4j were added to each well in a concentration gradient such that the final concentrations of the compounds in the wells were 5. Mu. Mol/L, 10. Mu. Mol/L, 20. Mu. Mol/L, 40. Mu. Mol/L and 80. Mu. Mol/L, respectively. After 48h, 10. Mu.L of MTT (5 mg/mL) phosphate buffer was added to each well, and after further incubation at 37℃for 4h, centrifugation was performed for 5min to remove unconverted MTT, and 150. Mu.L of dimethyl sulfoxide was added to each well. OD was measured at 490nm using a microplate reader by dissolving reduced MTT crystal formazan (formazan). Wherein compounds 4a,4c and 4j have semi-inhibitory concentration IC for A549 cells 50 Analysis was performed by spss software (version 19). IC of Compound 4a on A549 tumor cells 50 26.432. Mu. Mol/L; IC of Compound 4c on A549 tumor cells 50 73.194. Mu. Mol/L; IC of Compound 4j against A549 tumor cells 50 9.667. Mu. Mol/L; while positive control cisplatin versus A549 tumor cell IC 50 15.208. Mu. Mol/L.
Conclusion of experiment: the experiment shows that the polysubstituted tetrahydroquinoline chroman polycyclic compound shown in the table 1 has stronger cytotoxicity to A549 cells, and has the same order of magnitude as that of cisplatin used for first-line tumor treatment, and can possibly develop into a new medicament with an anti-tumor effect.
Pharmacological example 2: cytotoxicity of Compounds 4a,4b,4c and 4j on K562 cells
K562 (human chronic myelogenous leukemia cells) were cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100U/mL penicillin and 100U/mL streptomycin. Cells were added to 96 wells at a concentration of 5000 cells per well at 37℃with 5% CO 2 Culturing in a humid air incubator for 24 hours.
Cell viability was determined using the modified MTT method. The specific method is as in pharmacological example 1. IC of Compound 4a on K562 tumor cells 50 30.918. Mu. Mol/L; IC of Compound 4b on K562 tumor cells 50 65.123. Mu. Mol/L; IC of Compound 4c on K562 tumor cells 50 67.720. Mu. Mol/L; IC of Compound 4j against K562 tumor cells 50 11.799. Mu. Mol/L; while positive control cisplatin versus K562 tumor cell IC 50 16.966. Mu. Mol/L.
Conclusion of experiment: the experiment shows that the polysubstituted tetrahydroquinoline chroman polycyclic compounds shown in the table 1 have stronger cytotoxicity to K562 cells, and have the same order of magnitude as cisplatin used for first-line tumor treatment, and can possibly develop into new medicines with anti-tumor effect.
From the pharmacological examples, the compounds show a certain cytotoxicity to both tumor cells, have the potential of being developed into antitumor drugs, and deserve to be studied more intensively.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (9)
1. A tetrahydroquinoline chroman polycyclic compound, characterized in that: the structural formula of the tetrahydroquinoline chroman polycyclic compound is
Wherein R is 1 Is any one of H, halogen atom or alkyl; r is R 2 Is H or methyl; r is R 3 Is alkyl.
2. A process for the preparation of tetrahydroquinoline chroman polycyclic compounds according to claim 1, wherein: various substituted quinoline salts, 2, 3-ethyl butadienoate and 8-hydroxyisoquinoline are reacted in an organic solvent in the presence of alkali, after the thin layer chromatography tracking reaction is completed, the tetrahydroquinoline chroman polycyclic compound is obtained through column chromatography separation and purification; the structural formula of the various substituted quinoline salts is
Wherein R is 1 Is any one of H, halogen atom or alkyl; r is R 2 Is H or methyl; r is R 3 Is alkyl.
3. The method for producing a tetrahydroquinoline chroman polycyclic compound according to claim 2, wherein: the structural formula of the 2, 3-ethyl butadiene is
。
4. A process for the preparation of tetrahydroquinoline chroman polycyclic compounds according to claim 3, wherein: the structural formula of the 8-hydroxyisoquinoline is
。
5. The method for producing a tetrahydroquinoline chroman polycyclic compound according to claim 4, wherein: the organic solvent is any one or more of acetonitrile, toluene, methanol, chloroform, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane or ethyl acetate.
6. The method for producing a tetrahydroquinoline chroman polycyclic compound according to claim 5, wherein: the alkali is organic alkali or inorganic alkali, and the inorganic alkali is any one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium hydroxide or disodium hydrogen phosphate; the organic base is any one or more of diisopropylethylamine, tetramethylguanidine, triethylamine, piperidine or N-methylmorpholine.
7. The method for producing a tetrahydroquinoline chroman polycyclic compound according to claim 6, wherein: the molar ratio of the various substituted quinoline salts, the 2, 3-ethyl butadienoate and the 8-hydroxyisoquinoline is (1-3): 1:1, and the molar ratio of the alkali to the 8-hydroxyisoquinoline is (1-3): 1.
8. The method for producing a tetrahydroquinoline chroman polycyclic compound according to any one of claims 2 to 7, characterized in that: the reaction temperature is 25-100 ℃, and the reaction time is 0.5-2h.
9. Use of a tetrahydroquinoline chroman polycyclic compound according to claim 1 for the preparation of a medicament for the prophylaxis and treatment of tumour diseases.
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