CN115232140A - Tetrahydroquinoline chroman polycyclic compound and preparation method and application thereof - Google Patents
Tetrahydroquinoline chroman polycyclic compound and preparation method and application thereof Download PDFInfo
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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, and a preparation method and application thereof. The structural formula of the tetrahydroquinoline chroman polycyclic compound is shown in the specification
Wherein R is 1 Is any one of H, halogen atom or alkyl; r 2 Is H or methyl; r 3 Is an alkyl group. The preparation method comprises the following steps: various substituted quinoline salts, 2, 3-ethyl butadienoate and 8-hydroxyisoquinoline react in an organic solvent at 25-100 ℃ for 0.5-2h in the presence of alkali, and the tetrahydroquinoline chroman polycyclic compound is prepared by one-pot series reaction. The preparation method has the advantages of cheap and easily obtained raw materials, wide substrate range and bondingThe cyclization efficiency is high, the selectivity is good, the intermediate product does not need to be separated and purified, and the target product is easy to separate; simple operation and mild reaction condition. And the prepared tetrahydroquinoline chroman polycyclic compound has the potential of being developed into antitumor drugs.
Description
Technical Field
The invention belongs to the technical field of organic synthesis and pharmacy, and relates to a tetrahydroquinoline chroman polycyclic compound, and a preparation method and application thereof.
Background
Statistically, during 2015-2020, 144 of 164 FDA-approved small organic molecule drugs contain nitrogen heterocycles. Among these azacycles, polysubstituted six-membered azacycles are the most common (j.med. Chem.2021,64, 2339.). As a representative of six-membered nitrogen heterocycles, polysubstituted tetrahydroquinoline polycyclic compounds are core frameworks of many natural products and medicines and have important physiological activities. Therefore, the development of the efficient method for synthesizing tetrahydroquinoline has very important theoretical significance and practical value, can provide a compound source for biological activity screening, and has important application value for screening of medicines and pharmaceutical industry.
Because of its natural cyclic structure, dearomatization of quinoline salts is undoubtedly one of the most direct and efficient means for preparing multi-substituted tetrahydroquinoline polycyclic compounds (chem. Rev.2012,112,2557; chem. Rev.2011,111, 7157.). However, quinoline salts have more reactive sites and less reactivity differences, often facing the challenge of poor regioselectivity and stereoselectivity (chem. Rev.2012,112,2642; org. Chem. Front.2018,5,453 catalysis 2018,8, 632.. Therefore, it is of great significance to design and develop a new tandem reaction strategy for synthesizing the polysubstituted tetrahydroquinoline polycyclic compound with a novel structure.
Disclosure of Invention
Aiming at the technical problems, the invention provides a tetrahydroquinoline chroman polycyclic compound and a preparation method and application thereof. The preparation method provided by the invention has the advantages of high bonding 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 does not need 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 antitumor drugs.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
a tetrahydroquinoline chroman polycyclic compound with the structural formula
Wherein R is 1 Is any one of H, halogen atom or alkyl; r 2 Is H or methyl; r 3 Is an alkyl group.
The preparation method of the tetrahydroquinoline chroman polycyclic compound comprises the following steps: various substituted quinoline salts, 2, 3-ethyl butadienoate and 8-hydroxyisoquinoline react in an organic solvent in the presence of alkali, and the tetrahydroquinoline chroman polycyclic compound is obtained after the thin-layer chromatography tracking reaction is completed and the separation and purification are carried out by column chromatography.
Further, the structural formula of the various substituted quinoline salts is shown in the specification
Wherein R is 1 Is any one of H, halogen atom or alkyl; r 2 Is H or methyl; r 3 Is an alkyl group.
Further, the structural formula of the 2, 3-ethyl butadienoate is shown in the specification
Further, the structural formula of the 8-hydroxyisoquinoline is shown in the specification
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.
Preferably, the base is N-methylmorpholine.
Further, the molar ratio of the various substituted quinoline salts, ethyl 2, 3-butadienoate, and 8-hydroxyisoquinoline was (1-3): 1, and the molar ratio of the base to 8-hydroxyisoquinoline was (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 tetrahydroquinochroman polycyclic compound is as follows:
further, the tetrahydroquinoline chroman polycyclic compound is applied to the preparation of the drugs for preventing and treating tumor diseases.
The invention has the following beneficial effects:
1. the polysubstituted tetrahydroquinoline chromane polycyclic compound is prepared by adding substituted quinoline salt, 2, 3-ethyl butadienoate and 8-hydroxyisoquinoline into a chloroform solvent, taking N-methylmorpholine as an acid-binding agent, and carrying out multicomponent tandem cyclization reaction at the temperature of 60 ℃. The preparation method of the tetrahydroquinoline chroman polycyclic compound provided by the invention has the advantages of high bonding cyclization efficiency and good selectivity. The raw materials are cheap and easy to obtain, the operation is simple, the reaction conditions are mild and efficient, the intermediate products in the preparation process do not need to be separated and purified, and the target products are easy to separate.
2. On the basis of polysubstituted tetrahydroquinoline polycyclic compounds, the invention introduces chroman, a physiologically active framework, and simultaneously 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 IC of the compound 4a to A549 tumor cells 50 26.432 mu mol/L; IC of Compound 4c on A549 tumor cells 50 Is 73.194 mu mol/L; IC of Compound 4j on A549 tumor cells 50 9.667. Mu. Mol/L, and the IC of the positive control cisplatin for A549 tumor cells 50 15.208 mu mol/L; the compounds 4a,4b,4c and 4j have cytotoxicity on human chronic myelogenous leukemia cells (K562), and the IC of the compound 4c on K562 tumor cells 50 67.720. Mu. Mol/L; IC of Compound 4j on K562 tumor cells 50 11.799. Mu. Mol/L; IC of positive control cisplatin on K562 tumor cells 50 It was 16.966. Mu. Mol/L. IC of the above prepared Compound 50 The compound has the same order of magnitude as cisplatin which is a first-line medicament for treating tumors, can be possibly developed into a new medicament with an anti-tumor effect, and has potential application prospects.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a schematic representation of tetrahydroquinochroman polycyclic compound 4a, prepared in example 1 of this invention 1 H NMR chart.
FIG. 2 is a diagram of tetrahydroquinochroman polycyclic compound 4a prepared in example 1 of this invention 13 C NMR chart.
FIG. 3 is an X-ray single crystal diffractogram of tetrahydroquinochroman polycyclic compound 4a prepared in example 1 of this invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive effort based on the embodiments of the present invention, are within the scope of the present invention.
Example 1
This example is a process for the preparation of tetrahydroquinochroman polycyclic compound 4a, the steps of which are as follows:
preparation of polysubstituted tetrahydroquinolinochromic polycyclic compound 4 a: to a 10mL hard glass reaction tube, 1mL of chloroform, N-benzylquinolinate 1a (0.60mmol, 180.1mg), ethyl 2, 3-butadienoate 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.20mmol, 29.0mg), and N-methylmorpholine (0.60mmol, 60.6mg) were added in this order. The mixture was stirred at 60 ℃ for 30min. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30.
The nuclear magnetic resonance 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 in the material feeding ratio 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 selected from 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 in 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 and yield of polysubstituted tetrahydroquinolinochromapolycyclic compounds
Example 2
This example is a process for the preparation of tetrahydroquinochroman polycyclic compound 4b, the steps of which are as follows:
preparation of polysubstituted tetrahydroquinochroman polycyclic Compound 4 b: to a 10mL hard glass reaction tube, 1mL of chloroform, a substituted quinolinate 1b (0.60 mmol), ethyl 2, 3-butadienoate 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.2mmol, 29.0mg), and N-methylmorpholine (0.60mmol, 60.6mg) were added in this order. The mixture was stirred at 60 ℃ for 30min. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30.
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
This example is a process for the preparation of tetrahydroquinochroman polycyclic compound 4c, the steps of which are as follows:
preparation of polysubstituted tetrahydroquinochroman polycyclic Compound 4 c: into a 10mL hard glass reaction tube, 1mL of chloroform, substituted quinolinate 1c (0.60 mmol), ethyl 2, 3-butadienoate 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.20mmol, 29.0mg), and N-methylmorpholine (0.60mmol, 60.6mg) were added in this order. The mixture was stirred at 60 ℃ for 30min. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30.
Compound 4c (yellow solid, melting point: 207.7-208.5 ℃,30% yield): 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
This example is a process for the preparation of tetrahydroquinochroman polycyclic compound 4d, the steps of which are as follows:
preparation of polysubstituted tetrahydroquinochroman polycyclic Compound 4 d: to a 10mL hard glass reaction tube, 1mL of chloroform, a substituted quinolinate 1d (0.60 mmol), 2, 3-ethyl butadienoate 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.20mmol, 29.0mg), and N-methylmorpholine (0.60mmol, 60.6mg) were added in this order. The mixture was stirred at 60 ℃ for 30min. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30.
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
This example is a process for preparing tetrahydroquinolinochromapolycyclic compound 4e, comprising the following steps:
preparation of polysubstituted tetrahydroquinochroman polycyclic compound 4 e: into a 10mL hard glass reaction tube, 1mL of chloroform, instead of quinolinate 1e (0.60 mmol), 2, 3-butadienoic acid ethyl ester 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.20mmol, 29.0mg), and N-methylmorpholine (0.60mmol, 60.6mg) were added in this order. The mixture was stirred at 60 ℃ for 30min. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30).
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
This example is a process for the preparation of tetrahydroquinochroman polycyclic compound 4f, the steps of which are as follows:
preparation of polysubstituted tetrahydroquinochroman polycyclic Compound 4 f: to a 10mL hard glass reaction tube, 1mL of chloroform, substituted quinolinate 1f (0.60 mmol), 2, 3-butadienoic acid ethyl ester 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.20mmol, 29.0mg), and N-methylmorpholine (0.60mmol, 60.6mg) were added in this order. The mixture was stirred at 60 ℃ for 30min. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30.
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 process for the preparation of 4g of tetrahydroquinochroman polycyclic compound by the following steps:
preparation of 4g of polysubstituted tetrahydroquinolinochromapolycyclic Compound: into a 10mL hard glass reaction tube, 1mL of chloroform, 1g (0.60 mmol) of a substituted quinolinate, 2, 3-butadienoic acid ethyl ester 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.20mmol, 29.0mg), and N-methylmorpholine (0.60mmol, 60.6mg) were added in this order. The mixture was stirred at 60 ℃ for 30min. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30.
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
This example is a 4h process for the preparation of tetrahydroquinochroman polycyclic compounds, the steps of which are as follows:
preparation of polysubstituted tetrahydroquinochroman polycyclic compound for 4 h: to a 10mL hard glass reaction tube, 1mL of chloroform, a substituted quinolinate 1h (0.60 mmol), 2, 3-ethyl butadienoate 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.20mmol, 29.0mg), and N-methylmorpholine (0.60mmol, 60.6mg) were added in this order. The mixture was stirred at 60 ℃ for 30min. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30.
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
This example is a process for the preparation of tetrahydroquinochroman polycyclic compound 4i, the steps of which are as follows:
preparation of polysubstituted tetrahydroquinochroman polycyclic Compound 4 i: to a 10mL hard glass reaction tube, 1mL of chloroform, a substituted quinolinate 1i (0.60 mmol), 2, 3-ethyl butadienoate 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.20mmol, 29.0mg), and N-methylmorpholine (0.60mmol, 60.6mg) were added in this order. The mixture was stirred at 60 ℃ for 30min. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30.
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
This example is a process for the preparation of tetrahydroquinochroman polycyclic compound 4j, the steps of which are as follows:
preparation of polysubstituted tetrahydroquinochroman polycyclic compound 4 j: to a 10mL hard glass reaction tube, 1mL of chloroform was added in this order in place of quinolinate 1j (0.60 mmol), 2, 3-butadienoic acid ethyl ester 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.20mmol, 29.0mg), and N-methylmorpholine (0.60mmol, 60.6mg). The mixture was stirred at 60 ℃ for 30min. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30.
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
This example is a method for preparing tetrahydroquinolinochromapolycyclic compound 4k, comprising the following steps:
preparation of polysubstituted tetrahydroquinochroman polycyclic Compound 4 k: to a 10mL hard glass reaction tube, 1mL of chloroform, a substituted quinolinate 1k (0.60 mmol), 2, 3-ethyl butadienoate 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.20mmol, 29.0mg), and N-methylmorpholine (0.60mmol, 60.6mg) were added in this order. The mixture was stirred at 60 ℃ for 30min. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30.
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 tetrahydroquinochroman polycyclic compound 4l, the steps of which are as follows:
preparation of polysubstituted tetrahydroquinolinochromapolycyclic Compound 4 l: to a 10mL hard glass reaction tube, 1mL of chloroform, 1l (0.60 mmol) of a substituted quinolinate, 2, 3-butadienoic acid ethyl ester 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.20mmol, 29.0mg), and N-methylmorpholine (0.60mmol, 60.6mg) were added in this order. The mixture was stirred at 60 ℃ for 30min. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30).
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
This example is a process for the preparation of tetrahydroquinochroman polycyclic compound 4a, the steps of which are as follows:
preparation of polysubstituted tetrahydroquinochroman polycyclic Compound 4 a: to a 10mL hard glass reaction tube, 1mL of acetonitrile, N-benzylquinolinate 1a (0.20mmol, 60mg), ethyl 2, 3-butadienoate 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.20mmol, 29.0mg), and diisopropylethylamine (0.20 mmol) were added in this order. The mixture was stirred at 60 ℃ for 30min. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30).
Example 14
This example is a process for the preparation of tetrahydroquinochroman polycyclic compound 4e, the steps of which are as follows:
preparation of polysubstituted tetrahydroquinochroman polycyclic compound 4 e: to a 10mL hard glass reaction tube, 1mL of toluene, substituted quinolinate 1e (0.25 mmol), ethyl 2, 3-butadienoate 2 (0.20mmol, 22.4 mg), 8-hydroxyisoquinoline 3 (0.2mmol, 29.0mg), and tetramethylguanidine (0.25 mmol) were added in this order. The mixture was stirred at 25 ℃ for 2h. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30.
Example 15
This example is a process for the preparation of tetrahydroquinochroman polycyclic compound 4f, the steps of which are as follows:
preparation of polysubstituted tetrahydroquinochroman polycyclic Compound 4 f: into a 10mL hard glass reaction tube, 1mL of methanol, substituted quinolinate 1f (0.30 mmol), ethyl 2, 3-butadienoate 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.2mmol, 29.0mg), and sodium carbonate (0.30 mmol) were added in this order. The mixture was stirred at 30 ℃ for 1.8h. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30).
Example 16
This example is a process for the preparation of 4g of tetrahydroquinochroman polycyclic compound by the following steps:
preparation of 4g of polysubstituted tetrahydroquinochroman polycyclic Compound: into a 10mL hard glass reaction tube, 1mL of methylene chloride, 1g (0.35 mmol) of a substituted quinolinate, 2, 3-butadienoic acid ethyl ester 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.2mmol, 29.0mg), 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) = (30).
Example 17
This example is a process for the preparation of tetrahydroquinochroman polycyclic compound 4i, the steps of which are as follows:
preparation of polysubstituted tetrahydroquinolinochromic polycyclic compound 4 i: to a 10mL hard glass reaction tube, 1mL1, 2-dichloroethane, substituted quinolinate 1i (0.40 mmol), ethyl 2, 3-butadienoate 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.20mmol, 29.0mg), and piperidine (0.40 mmol) were added in this order. The mixture was stirred at 50 ℃ for 1.5h. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30.
Example 18
This example is a method for preparing tetrahydroquinolinochromapolycyclic compound 4k, comprising the following steps:
preparation of polysubstituted tetrahydroquinolinochromic polycyclic compound 4 k: to a 10mL hard glass reaction tube, 1mL of tetrahydrofuran, substituted quinolinate 1k (0.45 mmol), ethyl 2, 3-butadienoate 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.2mmol, 29.0mg), and potassium carbonate (0.45 mmol) were added in this order. The mixture was stirred at 60 ℃ for 30min. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30).
Example 19
This example is a process for the preparation of tetrahydroquinochroman polycyclic compound 4l, the steps of which are as follows:
preparation of polysubstituted tetrahydroquinochroman polycyclic Compound 4 l: to a 10mL hard glass reaction tube, 1mL1, 4-dioxane, 1l (0.50 mmol) of a substituted quinolinate, ethyl 2, 3-butadienoate (0.20mmol, 22.4 mg), 8-hydroxyisoquinoline 3 (0.20mmol, 29.0 mg), and sodium ethoxide (0.50 mmol) were added in this order. The mixture was stirred at 70 ℃ for 1h. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30).
Example 20
This example is a process for the preparation of tetrahydroquinochroman polycyclic compound 4j, the steps of which are as follows:
preparation of polysubstituted tetrahydroquinochroman polycyclic Compound 4 j: to a 10mL hard glass reaction tube, 1mL of ethyl acetate, substituted quinolinate 1j (0.55 mmol), ethyl 2, 3-butadienoate 2 (0.20mmol, 22.4mg), 8-hydroxyisoquinoline 3 (0.2mmol, 29.0mg), and disodium hydrogenphosphate (0.55 mmol) were added in this order. The mixture was stirred at 100 ℃ for 30min. After completion of the reaction, column chromatography (eluent: V (petroleum ether) = (30.
Application example
The compounds listed in table 1 of the present invention have important biological activities, and cytotoxicity tests of two tumor cells, human lung cancer cell (a 549) and human leukemia cell (K562), show that: the polysubstituted tetrahydroquinoline chroman polycyclic compound shown in the table 1 has an inhibitory effect on the growth of tumor cells and is likely to be developed into a new tumor prevention and treatment drug. It is emphasized, however, that the compounds of the invention are not limited to the cytotoxicity indicated by human lung cancer cells (A549) and human leukemia cells (K562).
Pharmacological example 1: cytotoxicity of Compounds 4a,4c and 4j against A549 cells
A549 (human lung small cell lung carcinoma) 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, containing 5% CO at 37 ℃ 2 The culture was carried out in an incubator with humid air for 24h.
The cell viability was determined by the modified MTT method. After 24h incubation of the cells, the newly formulated dimethylsulfoxide solutions of compounds 4a,4c and 4j were added to each well in a concentration gradient such that the final concentration of compounds in the wells was 5 μmol/L,10. Mu. Mol/L, 20. Mu. Mol/L, 40. Mu. Mol/L and 80. Mu. Mol/L. After 48h, 10. Mu.L of MTT (5 mg/mL) in phosphate buffer was added to each well, and after further incubation at 37 ℃ for 4h, the unconverted MTT was removed by centrifugation for 5min and 150. Mu.L of dimethyl sulfoxide was added to each well. The OD value was measured at 490nm wavelength with a microplate reader by dissolving reduced MTT crystal formazan (formazan). Wherein the semi-inhibitory concentration IC of the compounds 4a,4c and 4j on A549 cells 50 Analyzed by the sps 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 on A549 tumor cells 50 9.667 mu mol/L; while the IC of positive control cisplatin on A549 tumor cells 50 It was 15.208. Mu. Mol/L.
And (4) experimental conclusion: the experiment shows that the polysubstituted tetrahydroquinoline chroman polycyclic compound shown in the table 1 has stronger cytotoxicity on A549 cells, has the same order of magnitude as cisplatin used as a first-line medicament for tumor treatment, and is likely to be developed 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. The cells were added to 96 wells at a concentration of 5000 cells per well, containing 5% CO at 37% 2 The culture was carried out in an incubator with humid air for 24h.
The cell viability was determined by 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 on K562 tumor cells 50 11.799. Mu. Mol/L; IC of positive control cisplatin on K562 tumor cells 50 It was 16.966. Mu. Mol/L.
And (4) experimental conclusion: the experiment shows that the polysubstituted tetrahydroquinoline chroman polycyclic compound shown in the table 1 has stronger cytotoxicity on K562 cells, has the same order of magnitude as cisplatin used as a first-line medicament for tumor treatment, and can be possibly developed into a new medicament with an anti-tumor effect.
From the pharmacological examples, we can see that the compounds have certain cytotoxicity on the two tumor cells, have the potential of being developed into antitumor drugs, and deserve further research.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. A tetrahydroquinochroman polycyclic compound characterized by: the structural formula of the tetrahydroquinoline chroman polycyclic compound is shown in the specification
Wherein R is 1 Is any one of H, halogen atom or alkyl; r is 2 Is H or methyl; r 3 Is an alkyl group.
2. The process for the preparation of tetrahydroquinochroman polycyclic compounds of claim 1 wherein: various substituted quinoline salts, 2, 3-ethyl butadienoate and 8-hydroxyisoquinoline react in an organic solvent in the presence of alkali, and the tetrahydroquinoline chroman polycyclic compound is obtained after the thin-layer chromatography tracking reaction is completed and the separation and purification are carried out by column chromatography.
3. The process for the preparation of tetrahydroquinochroman polycyclic compounds according to claim 2, characterized in that: the structural formula of the various substituted quinoline salts is shown in the specification
Wherein R is 1 Is any one of H, halogen atom or alkyl; r 2 Is H or methyl; r is 3 Is an alkyl group.
4. Root of herbaceous plantThe process for preparing tetrahydroquinochroman polycyclic compounds according to claim 3, characterized by: the structural formula of the 2, 3-ethyl butadienoate is shown in the specification
5. The process for preparing tetrahydroquinochroman polycyclic compounds according to claim 4, characterized in that: the structural formula of the 8-hydroxyisoquinoline is
6. The process for the preparation of tetrahydroquinochroman polycyclic compounds according to claim 5, characterized in that: the organic solvent is any one or more of acetonitrile, toluene, methanol, chloroform, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane or ethyl acetate.
7. The process for the preparation of tetrahydroquinochroman polycyclic compounds according to claim 6, characterized in that: 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.
8. The process for preparing tetrahydroquinochroman polycyclic compounds according to claim 7, characterized in that: the molar ratio of the various substituted quinoline salts, ethyl 2, 3-butadienoate and 8-hydroxyisoquinoline is (1-3): 1 and the molar ratio of the base to 8-hydroxyisoquinoline is (1-3): 1.
9. The process for the preparation of tetrahydroquinochroman polycyclic compounds according to any one of claims 2 to 8, characterized in that: the reaction temperature is 25-100 ℃, and the reaction time is 0.5-2h.
10. The use of the tetrahydroquinome chroman polycyclic compound of claim 1 in the manufacture of a medicament for the prevention or treatment of neoplastic disease.
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| US20070010544A1 (en) * | 2005-06-28 | 2007-01-11 | Matthew Abelman | ABCA1 elevating compounds |
| CN102603692A (en) * | 2011-03-04 | 2012-07-25 | 中国海洋大学 | Chroman and chromene derivatives as tumor multidrug resistance inhibitor as well as preparation method and application of chroman and chromene derivatives |
| CN102731495A (en) * | 2011-04-14 | 2012-10-17 | 中国农业大学 | Synthetic method of tetrahydroisoquinoline compound |
| CN110437227A (en) * | 2019-08-15 | 2019-11-12 | 河南大学 | A kind of polysubstituted tetrahydroisoquinoline and preparation method thereof with polycyclic bridge ring skeleton |
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|---|---|---|---|---|
| US20070010544A1 (en) * | 2005-06-28 | 2007-01-11 | Matthew Abelman | ABCA1 elevating compounds |
| CN102603692A (en) * | 2011-03-04 | 2012-07-25 | 中国海洋大学 | Chroman and chromene derivatives as tumor multidrug resistance inhibitor as well as preparation method and application of chroman and chromene derivatives |
| CN102731495A (en) * | 2011-04-14 | 2012-10-17 | 中国农业大学 | Synthetic method of tetrahydroisoquinoline compound |
| CN110437227A (en) * | 2019-08-15 | 2019-11-12 | 河南大学 | A kind of polysubstituted tetrahydroisoquinoline and preparation method thereof with polycyclic bridge ring skeleton |
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