CN115261896A - Synthesis method of 4' -alkylaminobenzyl-3-imidazo [1,2-a ] pyridine derivative - Google Patents

Synthesis method of 4' -alkylaminobenzyl-3-imidazo [1,2-a ] pyridine derivative Download PDF

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CN115261896A
CN115261896A CN202210978281.2A CN202210978281A CN115261896A CN 115261896 A CN115261896 A CN 115261896A CN 202210978281 A CN202210978281 A CN 202210978281A CN 115261896 A CN115261896 A CN 115261896A
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imidazo
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tetrabutylammonium
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汪太民
李嗣锋
程斌
李蓬
李兴宸
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Abstract

The invention relates to the field of chemical synthesis, in particular to a synthesis method of a 4' -alkylamino benzyl-3-imidazo [1,2-a ] pyridine derivative; the invention uses imidazo [1,2-a ] pyridine derivatives and N-methyl N-alkylaniline to efficiently synthesize 3-arylmethylimidazo [1,2-a ] pyridine derivatives under electrochemical oxidation, and the reaction is realized by connecting the imidazo [1,2-a ] pyridine derivatives and N-methyl N-alkylaniline through methylene provided by N-methyl. The reaction is simple, convenient and safe to operate, mild in reaction conditions, simple and efficient in method, easy to obtain raw materials, free of by-products, high in tolerance of compound functional groups, convenient to post-treat, generally high in yield, free of inert gas protection in the preparation process of products, wide in substrate applicability, simple to operate and suitable for mass synthesis. The molecular docking technology of Discovery Studio can assist in fast and virtually screening products with potential anticancer activity, and cell experiments prove that a plurality of products have better breast cancer and colorectal cancer resistant activity.

Description

Synthesis method of 4' -alkylaminobenzyl-3-imidazo [1,2-a ] pyridine derivative
Technical Field
The invention relates to the field of chemical synthesis, in particular to a synthesis method of a 4' -alkylamino benzyl-3-imidazo [1,2-a ] pyridine derivative.
Background
Imidazo [1,2-a ] pyridine is an azabicyclic compound fused by five-membered ring imidazole and six-membered ring pyridine (Comprehensive Heterocyclic Chemistry III), and functionalized imidazo [1,2-a ] pyridine exhibits good biological activity, such as various pharmacological activities of antifungal, antiviral, anticancer, anti-inflammatory, anticonvulsant, antiepileptic, antitubercular, antiulcer, and antipyretic, and is also useful for treating hepatitis c and aids, and plays an important role in fields of neurology, virology, etc. (j.med.chem.2015, 23, 6087. Various marketed drugs have been developed based on the imidazo [1,2-a ] pyridine core backbone, such as the hypnotics Zolpidem (Zolpidem) and aprepitant (Alpidem), the vasodilators Olprinone (Olprinone), the anti-ulcer drugs zolemidine (zolemidine) and Soraprazan, the anxiolytics albendan (Alpidem) and thalidomide (Saripidem), and the like. Therefore, the synthesis of imidazo [1,2-a ] pyridine derivatives is beneficial to further expand the pool of potential bioactive molecules.
Since the C-3 position of imidazo [1,2-a ] pyridine is easy to generate electrophilic substitution and radical substitution reaction due to electron enrichment, various functional groups are successfully introduced into the reaction site, however, the electrochemical C-3 position arylmethylation reaction is not reported. At present, only two examples of literature report that the C-3 arylmethylation reaction of imidazo [1,2-a ] pyridine and N, N-dimethylaniline is realized by adding an exogenous carbon source and under the action of a peroxide compound. The Hajra subject group of International University of India (Visva-Bharati University) in 2016 uses N, N-dimethylformamide as a solvent and an additional carbon source to realize aryl methylation reaction of N, N-dimethylaniline to 2-arylimidazo [1,2-a ] pyridine at C3 position, however, the reaction needs equivalent potassium persulfate as an oxidant and can be realized under a high temperature condition of 80 ℃ (Adv.Synth.Catal.2016, 358, 3633-3641); in addition, the reaction also needs 10mol% of cuprous iodide as a catalyst, which is not beneficial to the removal of metal residue in the later period. In 2020, central sea and salts Institute of India (CSIR-Central Salt & Marine Chemicals Research Institute) Adimulthy et al obtained arylmethylated products of N, N-dimethylaniline-p-2-arylimidazo [1,2-a ] pyridine at C3 position using polyethylene glycol 400 as solvent and an additional carbon source and excess iodobenzene diacetate as oxidant, however the reaction required a reaction at a high temperature of 100 ℃ for 24 hours (Eur.J.org.Chem.2020, 2020, 3499-3507). Based on the method, an efficient and green electrochemical synthesis route is developed to realize C-3 arylmethylation reaction of various N, N-dimethylaniline p-imidazo [1,2-a ] pyridine derivatives, and an azabicyclo compound with potential biological activity is obtained.
Disclosure of Invention
The invention mainly aims to provide a synthesis method of a 4' -alkylaminobenzyl-3-imidazo [1,2-a ] pyridine derivative.
The technical scheme adopted by the invention is as follows:
a synthetic method of 4 '-alkylaminobenzyl-3-imidazo [1,2-a ] pyridine derivatives, 4' -N-methyl-N-alkyl benzyl-3-imidazo [1,2-a ] pyridine derivatives with structural formula shown as I
Figure BDA0003799320870000021
Wherein: r 1 Or R 2 Is any one of hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 perfluoroalkyl, halogen, C2-C6 alkylcarbonyl, C6-C12 aryl, benzyl, C2-C6 ester group, C2-C8 alkenyl-containing substituent, C2-C8 alkynyl-containing substituent, C2-C10 heterocyclic group, silicon base and amino;
R 3 or R 4 Is any one of C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkylcarbonyl, C6-C12 aryl, benzyl, C2-C8 alkenyl-containing substituent, C2-C8 alkynyl-containing substituent and C2-C10 heterocyclic radical;
the synthesis method is shown as the following formula:
Figure BDA0003799320870000031
in the formula, the preparation method of the compound I comprises the following steps:
s1, placing a compound II, a compound III, an electrolyte and an additive in an organic solvent, placing the organic solvent into an anode and a cathode, and introducing constant direct current for reaction;
s2, after the compound II disappears completely, removing the organic solvent from the reaction mixture under the reduced pressure condition;
and S3, eluting by using silica gel column chromatography to obtain the compound I.
The molar ratio of the compound II to the compound III is II: III = 1.0.
The anode is an electrode made of graphite flakes, graphite rods, reticular glassy carbon, foam carbon, platinum sheets or platinum wires.
The cathode is an electrode made of graphite flakes, graphite rods, various carbon papers, various carbon cloths, reticular glassy carbon, various graphite felts, foamed carbon, platinum sheets, platinum wires, nickel, iron, stainless steel, aluminum, zinc, tin, titanium, lead, molybdenum, niobium or tantalum.
The electrolyte comprises tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium perchlorate, tetrabutylammonium iodide, tetraethylammonium tetrafluoroborate, tetraethylammonium hexafluorophosphate, tetraethylammonium p-toluenesulfonate, sodium benzoate, lithium perchlorate, lithium bromide, tetraethylammonium chloride, tetrabutylammonium tetrafluoroborate, ammonium hexafluorophosphate, tetramethylammonium acetate, tetrabutylammonium hydrogen sulfate, tetraethylammonium perchlorate, tetrabutylammonium chloride hydrate and the like, and one or more of the substances are selected to be mixed and used as the electrolyte.
The organic solvent comprises any one or more of benzene, xylene, carbon tetrachloride, ethyl acetate, acetonitrile, ethyl chloride, dichloroethane, 1,2-dichloropropane, 1,4-dioxane, dimethylformamide or dimethylacetamide.
The eluent used for column chromatography is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the eluent to the mixed solution is V Petroleum ether :V Ethyl acetate ＝5:1～1:1。
The invention has the beneficial effects that: (1) The invention provides a 4' -N-methyl-N-alkyl benzyl-3-imidazo [1,2-a ] pyridine derivative, which finds a product with a good binding effect with some target proteins by using a molecular docking module of Discovery Studio, and then rapidly screens out small molecules with potential bioactivity. Finally, cell experiments show that several compounds have good biological activity for resisting breast cancer and colorectal cancer.
(2) The preparation method of the invention selects the current as the traceless oxidant, the reaction does not need the protection of catalyst and inert gas, the reaction steps are less, the raw materials are easy to obtain, the reaction conditions are mild, the operation is simple, convenient and safe, the substrate expansion range is wide, the tolerance of the compound functional group is high, and the product yield can reach more than 80%.
(3) The efficient and green synthesis method of the invention uses N-methyl as an additional methylene source, so that the generated products are tertiary amine, and the 4' -N-methyl-N-alkyl benzyl-3-imidazo [1,2-a ] pyridine derivatives can be prepared in gram-scale.
Drawings
FIG. 1 shows a nuclear magnetic spectrum (hydrogen spectrum) of a product I-1 obtained in an example of the present invention;
FIG. 2 shows a nuclear magnetic spectrum (carbon spectrum) of a product I-1 obtained in an example of the present invention;
FIG. 3 shows the nuclear magnetic spectrum (hydrogen spectrum) of the product I-3 obtained in the example of the present invention;
FIG. 4 shows a nuclear magnetic spectrum (carbon spectrum) of a product I-3 obtained in an example of the present invention;
FIG. 5 shows a nuclear magnetic spectrum (hydrogen spectrum) of a product I-9 obtained in an example of the present invention;
FIG. 6 shows a nuclear magnetic spectrum (carbon spectrum) of a product I-9 obtained in an example of the present invention;
FIG. 7 shows the effect of I-1, I-2, I-3, I-6, I-9, I-13, I-17 on the survival rate of breast and colorectal cancer cells at a concentration of 20. Mu.M, obtained in accordance with an embodiment of the present invention.
Detailed Description
The technical scheme of the invention is further explained by specific embodiments in the following with the accompanying drawings:
the following are preferred examples of the compounds of the present invention. In all of the following examples, nuclear magnetic spectroscopy was performed by Bruker400, JEOL400 instrument in CDCl 3 Is obtained in (1). Delta values are relative values of the internal standard (CHCl) 3 Scaling delta 7.26 1 H NMR and 77.16 13 C NMR. High Resolution Mass Spectrometry (HRMS) was obtained using a 4G quartetuole time-of-flight (QTof) mass spectrometer instrument.
Example 1
The reaction scheme of example 1, specifically using compounds II-1, III-1 and product i-1 having the following structure, shows that the preferred anode of the present invention is platinum plate, the preferred cathode is graphite plate, the preferred electrolyte is lithium bromide, the preferred additive is acetic acid, the preferred direct current is 6 milliamps, the preferred organic solvent is acetonitrile, the highest yield of reaction product is 80%, and the best raw material molar ratio is the molar ratio of compound II to compound III: III =1:5 where compound II should be of equivalent value, reaction optimum concentration is 0.04M.
Figure BDA0003799320870000051
The specific experimental steps are as follows: 39mg (0.20mmol, 1.0 equivalent) of Compound II-1, 121mg (1.0mmol, 5.0 equivalent) of Compound III-1, 9mg (0.1mmol, 0.5 equivalent) of lithium bromide, and 0.5mL of acetic acid were dissolved in 4.5mL of acetonitrile, and the resulting solution was charged into a platinum-plate anode and a graphite cathode, followed by reaction at room temperature under a direct current of 6 mA for 6 hours. After the reaction was completed, the reaction mixture was rotary evaporated under reduced pressure by a water pump to remove acetonitrile as a solvent. The residue was washed with 200-300 mesh silica gel, eluent (volume ratio V) Petroleum ether :V Ethyl acetate = 5:1-3:1) column chromatography to obtain the compound I-1The product of the compound is identified by nuclear magnetism (hydrogen spectrum, carbon spectrum) and high-resolution mass spectrum.
N,N-Dimethyl-4-((2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline(43mg,Yield＝66％,R f ＝0.25(PE/EA＝5:1))was isolated as a light brown paste. 1 H NMR(400MHz,CDCl 3 )δ7.84–7.79(m,2H),7.74(dt,J＝6.9,1.2Hz,1H),7.67(dt,J＝9.1,1.1Hz,1H),7.46–7.40(m,2H),7.37–7.32(m,1H),7.16(ddd,J＝9.0,6.7,1.3Hz,1H),7.01(d,J＝8.7Hz,2H),6.72–6.65(m,3H),4.40(s,2H),2.92(s,6H)； 13 CNMR(100MHz,CDCl 3 )δ149.73,144.92,143.94,134.78,128.72,128.50,128.35,127.73,124.30,124.14,123.76,118.62,117.54,113.25,112.16,40.78,29.00；HRMS(ESI)m/z:[M+H] + Calcd for C 22 H 22 N 3 328.1808；Found 328.1808.
Compound I-2
Figure BDA0003799320870000061
N,N,3-Trimethyl-4-((2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline(42mg,Yield＝59％,R f ＝0.25(PE/EA＝5:1))was isolated as a light brown paste. 1 H NMR(400MHz,CDCl 3 )δ7.78–7.74(m,2H),7.70(dt,J＝9.0,1.1Hz,1H),7.66(dt,J＝6.9,1.2Hz,1H),7.44–7.39(m,2H),7.35–7.31(m,1H),7.18(ddd,J＝9.1,6.7,1.3Hz,1H),6.72–6.68(m,2H),6.54(d,J＝8.5Hz,1H),6.41(dd,J＝8.5,2.8Hz,1H),4.28(s,2H),2.91(s,6H),2.41(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ149.73,144.94,144.16,137.03,134.73,128.68,128.24,127.65,127.57,124.08,123.67,122.40,118.30,117.52,115.06,112.17,110.66,40.73,26.83,20.40；HRMS(ESI)m/z:[M+H] + Calcd for C 23 H 24 N 3 342.1965；Found 342.1963.
Compound I-3
Figure BDA0003799320870000062
N-Methyl-N-pentyl-4-((2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline(45mg,Yield＝59％,R f ＝0.25(PE/EA＝5:1))was isolated as a light brown paste. 1 H NMR(400MHz,CDCl 3 )δ7.84–7.80(m,2H),7.76(dt,J＝6.9,1.2Hz,1H),7.68(dt,J＝9.0,1.1Hz,1H),7.46–7.40(m,2H),7.37–7.32(m,1H),7.17(ddd,J＝9.1,6.7,1.2Hz,1H),6.99(d,J＝8.7Hz,2H),6.70(td,J＝6.8,1.2Hz,1H),6.65–6.59(m,2H),4.39(s,2H),3.26(t,J＝7.5Hz,2H),2.89(s,3H),1.61–1.51(m,2H),1.37–1.24(m,4H),0.89(t,J＝7.0Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ148.46,144.86,143.83,134.75,128.71,128.57,128.35,127.72,124.16,123.82,123.36,118.72,117.50,112.62,112.16,52.97,38.41,29.45,28.96,26.47,22.72,14.22；HRMS(ESI)m/z:[M+H] + Calcd for C 26 H 30 N 3 384.2434；Found 384.2437.
Compound I-4
Figure BDA0003799320870000071
4-((2-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(49mg,Yield＝69％,R f ＝0.2(PE/EA＝5:1))was isolated as a light brown paste. 1 H NMR(400MHz,CDCl 3 )δ7.80–7.68(m,3H),7.65(dt,J＝9.1,1.2Hz,1H),7.17–7.09(m,1H),7.03–6.92(m,4H),6.70–6.62(m,3H),4.36(s,2H),3.82(s,3H),2.90(s,6H)； 13 C NMR(100MHz,CDCl 3 )δ159.34,149.66,144.75,143.72,129.45,128.43,127.35,124.35,123.91,123.57,117.87,117.25,114.13,113.20,111.97,55.35,40.72,28.93；HRMS(ESI)m/z:[M+H] + Calcd for C 23 H 24 N 3 O 358.1914；Found 358.1916.
Compound I-5
Figure BDA0003799320870000081
4-((2-(3-Methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(42mg,Yield＝59％,R f ＝0.2(PE/EA＝5:1))was isolated as a light brown paste. 1 H NMR(400MHz,CDCl 3 )δ7.75(dt,J＝6.9,1.2Hz,1H),7.67(dt,J＝9.1,1.2Hz,1H),7.40(dd,J＝2.7,1.5Hz,1H),7.37–7.32(m,2H),7.17(ddd,J＝9.1,6.7,1.3Hz,1H),7.03–6.98(m,2H),6.90(ddd,J＝7.9,2.6,1.4Hz,1H),6.72–6.65(m,3H),4.41(s,2H),3.82(s,3H),2.91(s,6H)； 13 C NMR(100MHz,CDCl 3 )δ159.98,149.74,144.86,143.83,136.19,129.68,128.51,124.36,124.16,123.75,120.73,118.84,117.59,114.16,113.28,112.20,55.44,40.80,29.04(1C is merged with other peaks)；HRMS(ESI)m/z:[M+H] + Calcd for C 23 H 24 N 3 O 358.1914；Found 358.1915.
Compound I-6
Figure BDA0003799320870000082
N,N-Dimethyl-4-((2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)methyl)aniline(42mg,Yield＝61％,R f ＝0.25(PE/EA＝5:1))was isolated as a light brown paste. 1 H NMR(400MHz,CDCl 3 )δ7.75–7.63(m,4H),7.27–7.22(m,2H),7.18–7.11(m,1H),7.01(d,J＝12.2Hz,2H),6.72–6.62(m,3H),4.38(s,2H),2.91(s,6H),2.39(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ149.68,144.81,143.93,137.45,131.85,129.41,128.48,128.18,124.38,123.98,123.65,118.31,117.39,113.21,112.03,40.74,28.99,21.37；HRMS(ESI)m/z:[M+H] + Calcd for C 23 H 24 N 3 342.1965；Found 342.1962.
Compound I-7
Figure BDA0003799320870000091
4-((2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(46mg,Yield＝67％,R f ＝0.3(PE/EA＝2:1))was isolated as a light brown solid；mp94–95℃. 1 H NMR(400MHz,CDCl 3 )δ7.78–7.72(m,3H),7.66(dt,J＝9.1,1.2Hz,1H),7.17(ddd,J＝9.1,6.7,1.3Hz,1H),7.14–7.08(m,2H),7.02–6.96(m,2H),6.73–6.65(m,3H),4.36(s,2H),2.91(s,6H).； 13 C NMR(100MHz,CDCl 3 )δ162.64(d,J＝245.4Hz),149.76,144.87,143.03,130.89(d,J＝3.3Hz),129.97(d,J＝8.1Hz),128.42,124.30,124.04,123.75,118.41,117.47,115.66(d,J＝21.4Hz),113.24,112.27,40.75,28.90； 19 F NMR(376MHz,CDCl 3 )δ–114.50.HRMS(ESI)m/z:[M+H] + Calcd for C 22 H 21 N 3 F 346.1714；Found 346.1712.
Compound I-8
Figure BDA0003799320870000092
4-((2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(37mg,Yield＝51％,R f ＝0.3(PE/EA＝2:1))was isolated as a light brown solid；mp 124–126℃. 1 H NMR(400MHz,CDCl 3 )δ7.76–7.71(m,3H),7.66(dt,J＝9.1,1.1Hz,1H),7.41–7.36(m,2H),7.18(ddd,J＝9.1,6.7,1.3Hz,1H),7.00–6.96(m,2H),6.71(td,J＝6.7,1.1Hz,1H),6.69–6.65(m,2H),4.37(s,2H),2.91(s,6H)； 13 C NMR(100MHz,CDCl 3 )δ149.79,144.97,142.77,133.66,133.33,129.53,128.91,128.43,124.40,123.94,123.76,118.80,117.56,113.26,112.34,40.74,28.94；HRMS(ESI)m/z:[M+H] + Calcd for C 22 H 21 N 3 Cl 362.1419；Found 362.1415.
Compound I-9
Figure BDA0003799320870000101
4-((2-(3-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(37mg,Yield＝51％,R f ＝0.25(PE/EA＝5:1))was isolated as a light brown paste. 1 H NMR(400MHz,CDCl 3 )δ7.89–7.85(m,1H),7.75(dt,J＝6.8,1.2Hz,1H),7.68–7.62(m,2H),7.36–7.29(m,2H),7.18(ddd,J＝9.0,6.7,1.3Hz,1H),7.02–6.96(m,2H),6.75–6.65(m,3H),4.39(s,2H),2.91(s,6H)； 13 C NMR(100MHz,CDCl 3 )δ149.78,144.96,142.49,136.71,134.73,129.91,128.47,128.40,127.76,126.30,124.46,123.93,123.83,119.18,117.66,113.27,112.38,40.75,28.96.；HRMS(ESI)m/z:[M+H] + Calcd for C 22 H 21 N 3 Cl 362.1419；Found 362.1417.
Compound I-10
Figure BDA0003799320870000102
4-((2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(55mg,Yield＝68％,R f ＝0.25(PE/EA＝5:1))was isolated as a light brown solid；mp108–110℃. 1 H NMR(400MHz,CDCl 3 )δ7.73(dt,J＝6.9,1.2Hz,1H),7.70–7.63(m,3H),7.56–7.50(m,2H),7.17(ddd,J＝9.1,6.7,1.3Hz,1H),7.01–6.94(m,2H),6.73–6.62(m,3H),4.35(s,2H),2.91(s,6H)； 13 C NMR(100MHz,CDCl 3 )δ149.74,144.92,142.68,133.73,131.81,129.79,128.38,124.40,123.84,123.71,121.85,118.81,117.51,113.21,112.32,40.69,28.89；HRMS(ESI)m/z:[M+H] + Calcd for C 22 H 21 N 3 Br 406.0913；Found 406.0914.
Compound I-11
Figure BDA0003799320870000111
N,N-Dimethyl-4-((2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)aniline(40mg,Yield＝50％,R f ＝0.25(PE/EA＝5:1))was isolated as a light brown paste. 1 H NMR(400MHz,CDCl 3 )δ7.92(d,J＝7.9Hz,2H),7.78(dt,J＝6.8,1.2Hz,1H),7.71–7.65(m,3H),7.21(ddd,J＝9.1,6.7,1.2Hz,1H),7.03–6.96(m,2H),6.74(td,J＝6.8,1.2Hz,1H),6.70–6.65(m,2H),4.41(s,2H),2.92(s,6H)； 13 C NMR(100MHz,CDCl 3 )δ149.84,145.09,142.37,138.39,129.38(q,J＝21.7Hz),128.42,125.65(q,J＝3.8Hz),124.69,124.45(q,J＝271.0Hz),123.84,123.71,119.57,117.75,115.02,113.28,112.56,40.72,28.95； 19 F NMR(376MHz,CDCl 3 )δ–62.30.HRMS(ESI)m/z:[M+H] + Calcd for C 23 H 21 N 3 F 3 396.1682；Found396.1683.
Compound I-12
Figure BDA0003799320870000112
N,N-Dimethyl-4-((2-(naphthalen-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)aniline(46mg,Yield＝61％,R f ＝0.2(PE/EA＝5:1))was isolated as a light brown paste. 1 H NMR(400MHz,CDCl 3 )δ8.30(s,1H),7.97(dd,J＝8.5,1.8Hz,1H),7.93–7.83(m,3H),7.79(dt,J＝6.9,1.2Hz,1H),7.73(dt,J＝9.0,1.1Hz,1H),7.51–7.45(m,2H),7.20(ddd,J＝9.0,6.7,1.3Hz,1H),7.01(d,J＝8.6Hz,2H),6.76–6.67(m,3H),4.48(s,2H),2.93(s,6H)； 13 C NMR(100MHz,CDCl 3 )δ149.71,144.96,143.70,133.65,132.92,132.20,128.52,128.45,128.29,127.74,127.15,126.41,126.17,126.04,124.27,123.73,119.09,117.48,113.25,112.23,40.73,29.09(1C is merged with other peaks)；HRMS(ESI)m/z:[M+H] + Calcd for C 26 H 24 N 3 378.1965；Found 378.1962.
Compound I-13
Figure BDA0003799320870000121
N,N-Dimethyl-4-((2-(thiophen-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)aniline(47mg,Yield＝70％,R f ＝0.25(PE/EA＝5:1))was isolated as a light brown paste. 1 H NMR(400MHz,CDCl 3 )δ7.75(dt,J＝7.0,1.2Hz,1H),7.63(dt,J＝9.1,1.1Hz,1H),7.42(dd,J＝3.6,1.1Hz,1H),7.34(dd,J＝5.1,1.1Hz,1H),7.14(ddd,J＝9.2,6.7,1.3Hz,1H),7.08(dd,J＝5.1,3.6Hz,1H),7.05–6.99(m,2H),6.70–6.62(m,3H),4.44(s,2H),2.89(s,6H)； 13 C NMR(100MHz,CDCl 3 )δ149.71,144.77,138.31,137.85,128.53,127.79,125.47,124.55,124.37,123.83,123.45,118.32,117.31,113.16,112.29,40.70,28.95；HRMS(ESI)m/z:[M+H] + Calcd for C 20 H 20 N 3 S 334.1372；Found 334.1375.
Compound I-14
Figure BDA0003799320870000122
4-((7-Methoxy-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(57mg,Yield＝80％,R f ＝0.25(PE/EA＝5:1))was isolated as a light brown paste. 1 H NMR(400MHz,CDCl 3 )δ7.81–7.77(m,2H),7.54(dd,J＝7.5,0.7Hz,1H),7.44–7.38(m,2H),7.35–7.29(m,1H),7.04–6.98(m,2H),6.95(d,J＝2.6Hz,1H),6.69–6.63(m,2H),6.40(dd,J＝7.4,2.5Hz,1H),4.34(s,2H),3.85(s,3H),2.91(s,6H)； 13 C NMR(100MHz,CDCl 3 )δ157.73,149.66,146.19,143.10,134.89,128.64,128.45,128.02,127.46,124.55,124.22,117.35,113.20,107.08,94.72,55.54,40.75,28.89；HRMS(ESI)m/z:[M+H] + Calcd for C 23 H 24 N 3 O358.1914; found 358.1912 Compound I-15
Figure BDA0003799320870000131
N,N-Dimethyl-4-((8-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline(40mg,Yield＝59％,R f ＝0.4(PE/EA＝5:1))was isolated as a light brown solid；mp91–92℃. 1 H NMR(400MHz,CDCl 3 )δ7.82–7.78(m,2H),7.62(d,J＝6.9Hz,1H),7.45–7.40(m,2H),7.35–7.31(m,1H),7.03–6.98(m,2H),6.96(d,J＝6.9Hz,1H),6.70–6.65(m,2H),6.62(t,J＝6.8Hz,1H),4.37(s,2H),2.91(s,6H),2.69(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ149.65,145.34,143.54,135.09,128.68,128.53,127.55,127.45,124.66,122.91,121.63,118.94,113.22,112.13,40.79,29.08,17.32(1C is merged with other peaks)；HRMS(ESI)m/z:[M+H] + Calcd for C 23 H 24 N 3 342.1965；Found 342.1966.
Compound I-16
Figure BDA0003799320870000132
N,N-Dimethyl-4-((7-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline(40mg,Yield＝59％,R f ＝0.25(PE/EA＝5:1))was isolated as a light brown paste. 1 H NMR(400MHz,CDCl 3 )δ7.83–7.78(m,2H),7.60(d,J＝7.0Hz,1H),7.44–7.39(m,3H),7.35–7.30(m,1H),7.02–6.98(m,2H),6.69–6.65(m,2H),6.51(dd,J＝6.9,1.7Hz,1H),4.36(s,2H),2.91(s,6H),2.37(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ149.65,145.28,143.44,134.99,134.90,128.62,128.44,128.22,127.52,124.52,122.94,117.94,115.86,114.72,113.19,40.72,28.90,21.38；HRMS(ESI)m/z:[M+H] + Calcd for C 23 H 24 N 3 342.1965；Found 342.1962.
Compound I-17
Figure BDA0003799320870000141
N,N-Dimethyl-4-((6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline(31mg,Yield＝46％,R f ＝0.25(PE/EA＝5:1))was isolated as a light brown solid；mp 148–150℃. 1 H NMR(400MHz,CDCl 3 )δ7.82–7.77(m,2H),7.58(dd,J＝9.2,1.0Hz,1H),7.54–7.51(m,1H),7.44–7.39(m,2H),7.35–7.29(m,1H),7.04–6.99(m,3H),6.72–6.65(m,2H),4.37(s,2H),2.92(s,6H),2.24(d,J＝1.1Hz,3H)； 13 CNMR(100MHz,CDCl 3 )δ149.63,143.96,143.65,134.89,128.65,128.45,128.16,127.53,127.30,124.51,121.72,121.23,118.28,116.84,113.21,40.75,28.90,18.52；HRMS(ESI)m/z:[M+H] + Calcd for C 23 H 24 N 3 342.1965；Found 342.1966.
Compound I-18
Figure BDA0003799320870000142
N,N-Dimethyl-4-((5-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline(23mg,Yield＝34％,R f ＝0.25(PE/EA＝5:1))was isolated as a light brown paste. 1 H NMR(400MHz,CDCl 3 )δ7.70–7.66(m,2H),7.54(dt,J＝8.9,1.0Hz,1H),7.40–7.35(m,2H),7.34–7.30(m,1H),7.03(dd,J＝9.0,6.8Hz,1H),6.91–6.87(m,2H),6.72–6.65(m,2H),6.40(dt,J＝6.8,1.1Hz,1H),4.56(s,2H),2.92(s,6H),2.64(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ149.29,146.86,145.60,136.59,135.04,128.91,128.75,128.50,128.31,127.63,124.45,119.89,115.88,113.50,113.29,40.76,30.76,20.18；HRMS(ESI)m/z:[M+H] + Calcd for C 23 H 24 N 3 342.1965；Found342.1966.
Compound I-19
Figure BDA0003799320870000151
4-((7-Chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(39mg,Yield＝54％,R f ＝0.3(PE/EA＝5:1))was isolated as a light brown paste. 1 H NMR(400MHz,CDCl 3 )δ7.81–7.75(m,2H),7.68–7.61(m,2H),7.46–7.41(m,2H),7.38–7.34(m,1H),7.01–6.96(m,2H),6.71–6.64(m,3H),4.38(s,2H),2.92(s,6H)； 13 C NMR(100MHz,CDCl 3 )δ149.81,144.81,144.61,134.35,130.67,128.79,128.45,128.32,127.99,124.09,123.73,118.97,116.36,113.74,113.26,40.73,28.94；HRMS(ESI)m/z:[M+H] + Calcd for C 22 H 21 N 3 Cl 362.1419；Found 362.1416.
Biological activity assay
The drug Discovery and design module of a life science prediction tool Discovery Studio (DS) is utilized to virtually butt-joint the product with the active site of the target protein containing the single crystal structure of the target protein, and the products I-1, I-2, I-3, I-6, I-9, I-13 and I-17 are screened out by CDOCKER interaction energy sequencing and have potential anti-breast cancer and anti-colorectal cancer activities. Later, cell experiments show that several products have better anticancer activity, and the experimental method is as follows:
inoculating breast cancer and intestinal cancer cell lines into a 96-well plate, removing the culture solution after 24 hours, adding 200 μ L of cell culture solution containing 20 μ M compound (or equivalent solvent, DMSO), removing the drug-containing culture solution after 72 hours of cell culture, adding 10 μ L of CCK-8 reagent and 100 μ L of cell culture solution into each well, measuring the absorbance (OD 450) of the culture solution by using a microplate reader after 1 hour of culture, and determining the cell survival rate% = OD450 Medicine adding device /OD450 Solvent control group ×100％。
The test result is shown in figure 7, and the figure 7 shows that the compounds I-3, I-3 and I-6 have better anti-breast cancer activity, and the compound I-1 can remarkably inhibit the growth of cells of breast cancer and colorectal cancer, so that the C3-arylmethylimidazo [1,2-a ] pyridine derivatives have certain prospects in application of biological activity.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.

Claims (7)

1. A synthetic method of 4 '-alkylaminobenzyl-3-imidazo [1,2-a ] pyridine derivatives, 4' -N-methyl-N-alkyl benzyl-3-imidazo [1,2-a ] pyridine derivatives with structural formula shown as I
Figure FDA0003799320860000011
Wherein: r 1 Or R 2 Is any one of hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 perfluoroalkyl, halogen, C2-C6 alkylcarbonyl, C6-C12 aryl, benzyl, C2-C6 ester group, C2-C8 alkenyl-containing substituent, C2-C8 alkynyl-containing substituent, C2-C10 heterocyclic group, silicon base and amino;
R 3 or R 4 Is any one of C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkylcarbonyl, C6-C12 aryl, benzyl, C2-C8 alkenyl-containing substituent, C2-C8 alkynyl-containing substituent and C2-C10 heterocyclic radical;
the method is characterized in that the synthesis method is shown as the following formula:
Figure FDA0003799320860000012
in the formula, the preparation method of the compound I comprises the following steps:
s1, placing a compound II, a compound III, an electrolyte and an additive in an organic solvent, placing the organic solvent in an anode and a cathode, and introducing constant direct current for reaction;
s2, after the compound II disappears completely, removing the organic solvent from the reaction mixture under the reduced pressure condition;
and S3, carrying out silica gel column chromatography elution to obtain the compound I.
2. The method for synthesizing the 4' -alkylaminobenzyl-3-imidazo [1,2-a ] pyridine derivative according to claim 1, wherein the method comprises the following steps: the molar ratio of the compound II to the compound III is II: III = 1.0.
3. The method for synthesizing the 4' -alkylaminobenzyl-3-imidazo [1,2-a ] pyridine derivative according to claim 1, wherein the method comprises the following steps: the anode is an electrode made of graphite flakes, graphite rods, reticular glassy carbon, foam carbon, platinum sheets or platinum wires.
4. The method for synthesizing the 4' -alkylaminobenzyl-3-imidazo [1,2-a ] pyridine derivative according to claim 1, wherein the method comprises the following steps: the cathode is an electrode made of graphite flakes, graphite rods, various carbon papers, various carbon cloths, reticular glassy carbon, various graphite felts, foamed carbon, platinum sheets, platinum wires, nickel, iron, stainless steel, aluminum, zinc, tin, titanium, lead, molybdenum, niobium or tantalum.
5. The method for synthesizing 4' -alkylaminobenzyl-3-imidazo [1,2-a ] pyridine derivatives according to claim 1, wherein the method comprises the following steps: the electrolyte comprises tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium perchlorate, tetrabutylammonium iodide, tetraethylammonium tetrafluoroborate, tetraethylammonium hexafluorophosphate, tetraethylammonium paratoluenesulfonate, sodium benzoate, lithium perchlorate, lithium bromide, tetraethylammonium chloride, tetrabutylammonium tetrafluoroborate, ammonium hexafluorophosphate, tetramethylammonium acetate, tetrabutylammonium hydrogen sulfate, tetraethylammonium perchlorate, tetrabutylammonium chloride hydrate and the like, and one or more of the tetrabutylammonium hydrogen sulfate, the tetrabutylammonium perchlorate and the tetrabutylammonium chloride hydrate are selected and mixed to be used as the electrolyte.
6. The method for synthesizing 4' -alkylaminobenzyl-3-imidazo [1,2-a ] pyridine derivatives according to claim 1, wherein the method comprises the following steps: the organic solvent comprises any one or more of benzene, xylene, carbon tetrachloride, ethyl acetate, acetonitrile, ethyl chloride, dichloroethane, 1,2-dichloropropane, 1,4-dioxane, dimethylformamide or dimethylacetamide.
7. According to the claimsClaim 1 of a 4' -alkylaminobenzyl-3-imidazo [1,2-a]The synthesis method of the pyridine derivative is characterized by comprising the following steps: the eluent used for column chromatography is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the eluent to the mixed solution is V Petroleum ether :V Ethyl acetate ＝5:1～1:1。
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