Process for the catalytic synthesis of imidazo[1,2-a]pyridine derivatives using dichlorotitanocene

Abstract

The application discloses a method for synthesizing imidazo[1,2-alpha]pyridine derivatives by using dichlorotitanocene as a Lewis acid catalyst. In the method, 2-amino pyridine compounds, benzaldehyde compounds and ethyl isocyanoacetate are used to react at 40-60 DEG C by using a one-pot method without a solvent. The 2-amino pyridine compounds and the benzaldehyde compounds are used to react to generate an imine intermediate under the catalysis of the dichlorotitanocene. The imine intermediate is used to add with the ethyl isocyanoacetate to generate a subsequent intermediate. The imidazo[1,2-alpha]pyridine derivatives are generated by a [4+1] cycloaddition reaction and a 1,3 proton transfer. The method has the advantages of simple operation, low synthesis cost, mild reaction condition, short reaction time, green and solvent-free catalysis, and the like. After the reaction is completed, the product can be separated only by simple column chromatography.

Description

Technical Field

[0001] This invention belongs to the field of synthetic technology of imidazo[1,2-α]pyridine derivatives, specifically relating to a method for synthesizing imidazo[1,2-α]pyridine derivatives by catalysis of titanium dichlorophenocene catalysis of benzaldehyde compounds, 2-aminopyridine compounds and ethyl isocyanate. Background Technology

[0002] N-heterocyclic compounds are widely found in bioactive natural products, drugs, and functional materials, playing an important role in life sciences and materials science. Among the many nitrogen-fused heterocyclic compounds, imidazo[1,2-α]pyridine derivatives are considered a key structural unit due to their wide applications in optics, materials science, and organometallic materials, and are also considered a "drug-preferred" skeleton due to their extensive use in medicinal chemistry.

[0003] In the past decade or so, many synthetic methods have been developed. For example, Mikhail V. Il'in et al. (Il'in MV, Sysoeva AA, Novikov AS, et al. Diaryliodoniums as hybrid hydrogen-and halogen-bond-donating organocatalysts for the Groebke–Blackburn–Bienayméreaction[J].The Journal of Organic Chemistry,2022,87(7):4569-4579.) discovered in 2022 that dibenzoiodonium and dibenzoiodonium trifluoride have high catalytic activity for multi-component reactions that generate a series of imidazolium pyridines. However, the reaction needs to be carried out in chloroform at 50°C. But chloroform is highly toxic and decomposes in light to produce phosgene and hydrogen chloride. Large doses can be fatal, which does not conform to the theme of green chemistry. In 2022, Meenakshi Budhiraja et al. (Budhiraja M, Ali A, Tyagi V. Construction of a Bifunctional Pd (0)-CALB@SiO2 Hybrid Catalyst for the Synthesis and Arylation of Imidazo[1,2-α]pyridine in One Pot[J]. European Journal of Organic Chemistry, 2023, 26(11):e202201426.) reported an efficient strategy for constructing an enzyme-metal biohybrid catalyst [Pd(0)-CALB@SiO2], which catalyzes a multicomponent reaction and couples it with Suzuki methyl to produce a clinically significant imidazo[1,2-α]pyridine derivative by encapsulating Candida antarctic lipase B and Pd(0) in silica. However, this method requires high-temperature heating and overnight reaction, which is too long. 2022, Nicolas S. Anjos et al (Anjos NS, Chapina AI, Santos AR, et al. Groebke-Blackburn-Bienaymé Multicomponent Reaction Catalysed by Reusable Ionic Liquids[J]. European Journal of Organic Chemistry, 2022, 2022(40):e202200615.) studied The application of acidic ionic liquids (BAILs) as catalysts in the Groebke-Blackburn-Bienaymé multicomponent reaction, by microwave heating at 150°C in a sealed tube for 1–4 hours, yields a series of imidazole-fused heterocyclic compounds with yields of 42–93%. However, the temperature is too high and the time is as long as 24 hours. In 2020, Xi Gaolei et al. (Xi Gaolei, Chen Zhifei, Yang Jinchu et al. Solvent-free synthesis of imidazo[1,2-a]pyridine compounds and their antioxidant properties [J]. Synthetic Chemistry, 2020, 28(03)) used ethanol as solvent and LaCl3 catalyzed the Groebke-Blackburn-Bienaymé three-component reaction (GBB-3CR) between 2-aminopyridine, ferrocene formaldehyde and isocyanates to synthesize five ferrocene-imidazo[1,2-a]pyridine compounds under heating conditions of 80°C. However, the temperature was too high. In 2021, Mosayeb Akbari et al. (Akbari M, Maleki A, Bahadorikhalili S, et al. Efficient synthesis of novel 2-(2-chloroquinolin-3-yl)imidazo[1,2-α]pyridin-3-amine derivatives[J]. Journal of the Chinese Chemical Society, 2021, 68(7): 1328-1333.) used 10 mol% trimethylsilyl chloride as a catalyst in acetonitrile. Acetonitrile is highly polar, the post-processing is relatively complex, and it is harmful to the human body. Summary of the Invention

[0004] The purpose of this invention is to provide a method for the efficient synthesis of imidazo[1,2-α]pyridine derivatives that features mild reaction conditions, simple operation, short reaction time, good substrate applicability.

[0005] To achieve the above objectives, the technical solution adopted in this invention is as follows: benzaldehyde compounds represented by Formula I, 2-aminopyridine compounds represented by Formula II, and ethyl isocyanate of Formula III are added to a reaction flask, and titanium dichlorocerocene is added as a catalyst. The reaction is carried out at 40-60°C. After the reaction is completed, the product is separated and purified to obtain the imidazo[1,2-α]pyridine derivative represented by Formula IV.

[0006]

[0007] In the formula, R1 and R2 each independently represent any one of H, halogen, C1-C4 alkyl, C1-C4 alkoxy, and phenyl.

[0008] In the above synthesis method, the preferred molar ratio of the benzaldehyde compound, the 2-aminopyridine compound, and ethyl isocyanate is 1:1.1-1.3:1.1-1.3.

[0009] In the above synthesis method, the amount of titanium dichlorophenoxyacetate added is preferably 8% to 12% of the molar amount of benzaldehyde compounds.

[0010] In the above synthesis method, it is preferred to react at 50°C for 1.5 to 3.5 hours.

[0011] The beneficial effects of this invention are as follows:

[0012] This invention uses titanium dichloropentane as a Lewis acid catalyst, requiring no gas protection. In the absence of solvents, a one-pot reaction is conducted at 40–60°C using 2-aminopyridine compounds, benzaldehyde compounds, and ethyl isocyanate. The 2-aminopyridine and benzaldehyde compounds react under the catalysis of titanium dichloropentane to generate an imine intermediate. This imine intermediate then undergoes an addition reaction with ethyl isocyanate to generate a subsequent intermediate. The final product, an imidazo[1,2-α]pyridine derivative, is obtained through a [4+1] cycloaddition reaction and 1,3 proton transfer. This invention is low-cost, has mild reaction conditions, is simple to operate, has a short reaction time, and utilizes green, solvent-free catalysis. The product can be separated by simple column chromatography after the reaction. The synthesized imidazo[1,2-α]pyridine derivative skeleton is commonly found in antitumor drug molecules, exhibiting sedative and hypnotic effects, some anti-anxiety and anticonvulsant activities, and can also be used as an antibacterial, antiviral, and anti-stress drug molecule, possessing diverse biological and pharmacological activities and other properties. Detailed Implementation

[0013] The present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited to these embodiments.

[0014] Example 1

[0015] Synthesize the following (2-phenylimidazo[1,2-α]pyridin-3-yl)glycine ethyl ester.

[0016]

[0017] 0.1035 g (1.1 mmol) of 2-aminopyridine, 102 μL (1.0 mmol) of benzaldehyde, 131 μL (1.2 mmol) of ethyl isocyanate, and 0.0249 g (0.10 mmol) of dichlorodicyclopentadiene were added to a 20 mL scintillation flask. The mixture was stirred at 50 °C for 3 hours. After the reaction was stopped, the mixture was separated by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:10) to give ethyl (2-phenylimidazo[1,2-α]pyridin-3-yl)glycine in 92.2% yield.

[0018] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.47(d,J=6.9Hz,1H),8.12(d,J=7.7Hz,2H),7.48–7.40(m,3H),7.29(t,J=7.4Hz,1H),7.17(dd,J=9.0 ,6.6Hz,1H),6.89(t,J=6.7Hz,1H),5.42(t,J=6.2Hz,1H),3.98(q,J=7.1Hz,2H),3.79(d,J=6.1Hz,2H),1.06(t,J=7.1Hz,3H); 13 CNMR(101MHz,DMSO-d6)δ171.73,140.40,134.48,133.15,128.47,126.95,126 .36(d,J=8.1Hz),123.98(d,J=10.8Hz),116.60,111.06,60.36,48.77,13.93.

[0019] Example 2

[0020] Synthesize the following ethyl glycine (2-(3-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0021]

[0022] In this embodiment, equimolar amounts of 3-fluorobenzaldehyde were used to replace the benzaldehyde used in Example 1, shortening the reaction time to 2.5 hours. The other steps were the same as in Example 1, yielding ethyl ester of (2-(3-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with a yield of 84.2%.

[0023] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1H NMR(400MHz, DMSO-d6)δ8.46(dd,J=6.8,1.3Hz,1H),8.01–7.95(m,1H),7.91(ddd,J=11.1,2.7,1.5Hz,1H),7.50–7.43(m,2H),7.23–7.18(m,1H),7 .11(dt,J=8.8,4.3Hz,1H),6.91(td,J=6.7,1.2Hz,1H),5.49(t,J=6.3Hz ,1H),3.99(q,J=7.1Hz,2H),3.81(d,J=6.3Hz,2H),1.07(t,J=7.1Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ171.66,163.75,161.35,140.48,136.98,136.90,131.95 ,126.88,124.17,122.33,116.75,113.48,112.78,111.33,60.41,48.74,13.94.

[0024] Example 3

[0025] Synthesize the following ethyl glycine (2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0026]

[0027] In this embodiment, equimolar amounts of 4-fluorobenzaldehyde were used to replace the benzaldehyde used in Example 1, shortening the reaction time to 1.5 hours. The other steps were the same as in Example 1, yielding ethyl (2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with a yield of 94.8%.

[0028] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.47(dd,J=7.0,1.3Hz,1H),8.21–8.14(m,2H),7.46(d,J=9.0Hz,1H),7.26(t,J=8.9Hz,2H),7.17(ddd,J=9.0, 6.7,1.3Hz,1H),6.89(td,J=6.8,1.2Hz,1H),5.43(t,J=6.2Hz,1H),3.98(q,J=7.1Hz,2H),3.79(d,J=6.2Hz,2H),1.06(t,J=7.1Hz,3H); 13C NMR(101MHz,DMSO-d6)δ171.71,162.56,160.13,140.45,132.61,131.02,128.36(d ,J=7.9Hz),126.02,124.08,116.59,115.39,115.18,111.11,60.37,48.76,13.91.

[0029] Example 4

[0030] Synthesize the following ethyl glycine (2-(4-methoxyphenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0031]

[0032] In this embodiment, equimolar amounts of 4-methoxybenzaldehyde were used to replace the benzaldehyde used in Example 1, and the reaction time was extended to 3.5 hours. The other steps were the same as in Example 1, yielding ethyl (2-(4-methoxyphenyl)imidazo[1,2-α]pyridin-3-yl)glycine with a yield of 88.7%.

[0033] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.46(d,J=6.8Hz,1H),8.08(d,J=8.8Hz,2H),7.44(d,J=9.0Hz,1H),7.17–7.12(m,1H),7.01(d,J=8 .5Hz,2H),6.87(t,J=6.7Hz,1H),5.35(t,J=6.1Hz,1H),3.99(q,J=7.1Hz,2H),3.79(d,J=5.7Hz,5H),1.06(t,J=7.1Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ171.78,158.42,140.34,133.56,127.75,127.03,12 5.24,123.90,123.62,116.36,113.88,110.85,60.34,55.09,48.76,13.92.

[0034] Example 5

[0035] Synthesize the following ethyl glycine (2-(2-bromophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0036]

[0037] In this embodiment, equimolar amounts of 2-bromobenzaldehyde were used to replace the benzaldehyde used in Example 1, and the other steps were the same as in Example 1, to obtain ethyl (2-(2-bromophenyl)imidazo[1,2-α]pyridin-3-yl)glycine, with a yield of 80.7%.

[0038] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.35(d,J=6.9Hz,1H),7.72(d,J=8.0Hz,1H),7.48–7.42(m,3H),7.34(td,J=7.5,2.2Hz,1H),7.15(dd,J= 9.1,6.6Hz,1H),6.91(t,J=6.8Hz,1H),5.40(t,J=6.2Hz,1H),3.88(q,J=7.1Hz,2H),3.60(d,J=6.2Hz,2H),1.01(t,J=7.1Hz,3H); 13 CNMR(101MHz,DMSO-d6)δ171.16,139.22,136.06,132.75,132.44,131.27,12 9.79,127.26,123.93,123.34,122.95,116.85,111.25,60.25,47.87,13.93.

[0039] Example 6

[0040] Synthesize the following ethyl glycine (2-(3-bromophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0041]

[0042] In this embodiment, equimolar amounts of 3-bromobenzaldehyde were used to replace the benzaldehyde used in Example 1, shortening the reaction time to 2 hours. The other steps were the same as in Example 1, yielding ethyl 2-(3-bromophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with a yield of 81.3%.

[0043] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1H NMR (400MHz, DMSO-d6) δ8.47(dt,J=7.0,1.3Hz,1H),8.31(t,J=1.8Hz,1H),8.13(dt,J=7.8,1.4Hz,1H),7.49–7.45(m,2H),7.40(t,J=7.8Hz,1H),7.2 0(ddd,J=9.0,6.6,1.3Hz,1H),6.91(td,J=6.8,1.2Hz,1H),5.51(t,J=6.3H z,1H),3.99(q,J=7.1Hz,2H),3.80(d,J=6.3Hz,2H),1.07(t,J=7.1Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ171.60,140.53,136.86,131.50,130.67,129.53,128.76 ,126.94,125.10,124.46,124.19,122.05,116.74,111.36,60.42,48.70,13.95.

[0044] Example 7

[0045] Synthesize the following ethyl glycine (2-(2-methoxyphenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0046]

[0047] In this embodiment, equimolar amounts of 2-methoxybenzaldehyde were used to replace the benzaldehyde used in Example 1, and the reaction time was extended to 3.5 hours. The other steps were the same as in Example 1, yielding ethyl (2-(2-methoxyphenyl)imidazo[1,2-α]pyridin-3-yl)glycine with a yield of 87.8%.

[0048] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1H NMR (400MHz, DMSO-d6) δ8.29 (dt, J=6.9, 1.2Hz, 1H), 7.64 (dd, J=7.6, 1.8Hz, 1H) ,7.49(dt,J=9.1,1.1Hz,1H),7.36(ddd,J=8.3,7.3,1.8Hz,1H),7.17–7.10(m,2 H),7.05(td,J=7.4,1.1Hz,1H),6.88(td,J=6.8,1.2Hz,1H),4.99(t,J=6.2Hz,1 H),3.91–3.85(m,2H),3.84(s,3H),3.68(d,J=6.2Hz,2H),0.99(t,J=7.1Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ171.20,156.17,140.39,131.38,130.72,129.02,127.36, 123.70, 123.05, 120.59, 116.77, 111.38 (d, J = 2.6Hz), 60.38, 55.60, 48.27, 13.86.

[0049] Example 8

[0050] Synthesize ethyl 2-([1,1'-biphenyl]-4-yl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0051]

[0052] In this embodiment, equimolar amounts of p-phenylbenzaldehyde were used to replace the benzaldehyde used in Example 1, shortening the reaction time to 2 hours. The other steps were the same as in Example 1, yielding 2-([1,1'-biphenyl]-4-yl)imidazo[1,2-α]pyridin-3-yl)glycine ethyl ester with a yield of 93.0%.

[0053] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1H NMR(400MHz,DMSO-d6)δ8.49(dt,J=7.0,1.3Hz,1H),8.26–8.22(m,2H),7.7 8–7.71(m,4H),7.47(dd,J=8.5,7.1Hz,3H),7.36(td,J=7.2,1.3Hz,1H),7. 18(ddd,J=8.9,6.7,1.3Hz,1H),6.90(td,J=6.7,1.2Hz,1H),5.49(t,J=6.3 Hz, 1H), 3.99 (q, J = 7.1Hz, 2H), 3.84 (d, J = 6.2Hz, 2H), 1.06 (t, J = 7.1Hz, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.74,140.50,139.88,138.44,133.65,132.79,129.01,127. 42,126.89,126.69,126.51,124.03(d,J=7.8Hz),116.61,111.07,60.37,48.82,13.93.

[0054] Example 9

[0055] Synthesize the following ethyl glycine (6-chloro-2-phenylimidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0056]

[0057] In this embodiment, equimolar amounts of 2-amino-5-chloropyridine were used to replace the 2-aminopyridine used in Example 1, shortening the reaction time to 2.5 hours. The other steps were the same as in Example 1, yielding ethyl (6-chloro-2-phenylimidazo[1,2-α]pyridin-3-yl)glycine with a yield of 92.9%.

[0058] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.72–8.67(m,1H),8.16–8.10(m,2H),7.51(d,J=9.5Hz,1H),7.44(t,J=7.6Hz,2H),7.32–7.27(m,1 H),7.18(dd,J=9.5,2.1Hz,1H),5.56(t,J=6.3Hz,1H),3.98(q,J=7.1Hz,2H),3.82(d,J=6.3Hz,2H),1.06(t,J=7.1Hz,3H); 13C NMR(101MHz,DMSO-d6)δ171.79,138.67,134.04,133.93,128.51,127.17(d ,J=2.1Hz),126.33,124.42,122.08,118.16,117.47,60.43,48.65,13.86.

[0059] Example 10

[0060] Synthesize the ethyl ester of (5-chloro-2-phenylimidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0061]

[0062] In this embodiment, equimolar amounts of 2-amino-6-chloropyridine were used to replace the 2-aminopyridine used in Example 1, shortening the reaction time to 2.5 hours. The other steps were the same as in Example 1, yielding ethyl 5-chloro-2-phenylimidazo[1,2-α]pyridin-3-yl)glycine with a yield of 94.4%.

[0063] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.26–8.20(m,2H),7.49(dd,J=8.9,1.1Hz,1H),7.42(dd,J=8.4,7.0Hz,2H),7.33–7.28(m,1H),7.15(dd,J=8. 9,7.2Hz,1H),6.94(dd,J=7.2,1.1Hz,1H),4.98(t,J=6.0Hz,1H),4.04(q,J=7.1Hz,2H),3.76(d,J=6.0Hz,2H),1.10(t,J=7.1Hz,3H); 13 C NMR (101MHz, DMSO-d6) δ170.54,143.04,136.78,133.85,128.28,127.42,127.04,126.92,125.33,124.57,116.16,113.83,60.31,51.14,13.88.

[0064] Example 11

[0065] Synthesize the following ethyl glycine (2-(3-chlorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0066]

[0067] In this embodiment, equimolar amounts of 3-chlorobenzaldehyde were used to replace the benzaldehyde used in Example 1, and the reaction time was extended to 3.5 hours. The other steps were the same as in Example 1, yielding ethyl (2-(3-chlorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with a yield of 82.1%.

[0068] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR(400MHz, DMSO-d6)δ8.48(dd,J=6.9,1.1Hz,1H),8.16–8.11(m,2H),7.46(t,J=7.7Hz,2H),7.38–7.30(m,2H), 6.89(t,J=7.0Hz,1H),5.56(t,J=6.2Hz,1H),3.97(q,J=7.1Hz,2H),3.81(d,J=6.2Hz,2H),1.05(t,J=7.1Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ171.63,162.24,148.11,133.42,131.73,130.35,126.95 ,126.65,125.89,124.78,124.41,124.18,116.77,111.34,60.42,48.74,13.92.

[0069] Example 12

[0070] Synthesize the following (8-chloro-2-phenylimidazo[1,2-α]pyridin-3-yl)glycine ethyl ester.

[0071]

[0072] In this embodiment, equimolar amounts of 2-amino-3-chloropyridine were used to replace the 2-aminopyridine used in Example 1, and the other steps were the same as in Example 1, to obtain (8-chloro-2-phenylimidazo[1,2-α]pyridin-3-yl)glycine ethyl ester with a yield of 84.2%.

[0073] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1H NMR(400MHz, DMSO-d6)δ8.48(dd,J=6.9,1.1Hz,1H),8.16–8.11(m,2H),7.46(t,J=7.7Hz,2H),7.38–7.30(m,2H), 6.89(t,J=7.0Hz,1H),5.56(t,J=6.2Hz,1H),3.97(q,J=7.1Hz,2H),3.81(d,J=6.2Hz,2H),1.05(t,J=7.1Hz,3H); 13 C NMR (101MHz, DMSO-d6) δ171.55,137.13,133.91,133.63,128.47,127.91,127.23,126.53,123.32,122.88,121.14,110.76,60.34,48.53,13.87.

[0074] Example 13

[0075] Synthesize the following (8-fluoro-2-phenylimidazo[1,2-α]pyridin-3-yl)glycine ethyl ester.

[0076]

[0077] In this embodiment, equimolar amounts of 2-amino-3-fluoropyridine were used to replace the 2-aminopyridine used in Example 1, and the reaction time was shortened to 2 hours. The other steps were the same as in Example 1, yielding (8-fluoro-2-phenylimidazo[1,2-α]pyridin-3-yl)glycine ethyl ester with a yield of 86.8%.

[0078] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.35(dd,J=6.8,0.9Hz,1H),8.14(dd,J=8.3,1.4Hz,2H),7.45(t,J=7.7Hz,2H),7.34–7.28(m,1H),7.08–7 .02(m,1H),6.85(td,J=7.2,4.6Hz,1H),5.56(t,J=6.2Hz,1H),3.98(q,J=7.1Hz,2H),3.82(d,J=6.2Hz,2H),1.05(t,J=7.1Hz,3H); 13C NMR(101MHz,DMSO-d6)δ171.54,151.72,149.25,133.95,133.41,132.69,132.40,128.46,127.96 ,127.20,126.48,120.76(d,J=4.6Hz),109.98(d,J=6.8Hz),106.48,106.32,60.34,48.55,13.84.

[0079] Example 14

[0080] Synthesize the following (7-methyl-2-phenylimidazo[1,2-α]pyridin-3-yl)glycine ethyl ester.

[0081]

[0082] In this embodiment, 2-aminopyridine used in Example 1 was replaced with an equimolar amount of 2-amino-4-methylpyridine, and the reaction time was extended to 3.5 hours. The other steps were the same as in Example 1, and (7-methyl-2-phenylimidazo[1,2-α]pyridin-3-yl)glycine ethyl ester was obtained with a yield of 80.1%.

[0083] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.36(d,J=7.0Hz,1H),8.14–8.10(m,2H),7.42(t,J=7.6Hz,2H),7.29–7.22(m,2H),6.72(dd,J=7.1 ,1.7Hz,1H),5.36(t,J=6.2Hz,1H),3.98(q,J=7.1Hz,2H),3.78(d,J=6.2Hz,2H),2.35–2.30(m,3H),1.06(t,J=7.1Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ171.77,140.87,134.65,134.35,132.85,128.42,12 6.78,126.32,125.89,123.37,114.83,113.56,60.36,48.89,20.82,13.95.

[0084] Example 15

[0085] Synthesize the following (8-bromo-2-phenylimidazo[1,2-α]pyridin-3-yl)glycine ethyl ester.

[0086]

[0087] In this embodiment, equimolar amounts of 2-amino-3-bromopyridine were used to replace the 2-aminopyridine used in Example 1, and the other steps were the same as in Example 1, to obtain (8-bromo-2-phenylimidazo[1,2-α]pyridin-3-yl)glycine ethyl ester with a yield of 82.6%.

[0088] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.54(dd,J=6.9,1.1Hz,1H),8.18–8.13(m,2H),7.51(dd,J=7.3,1.0Hz,1H),7.46(t,J=7.7Hz,2H),7.34 –7.29(m,1H),6.83(t,J=7.0Hz,1H),5.59(t,J=6.2Hz,1H),3.96(q,J=7.1Hz,2H),3.83(d,J=6.2Hz,2H),1.04(t,J=7.1Hz,3H); 13 C NMR (101MHz, DMSO-d6) δ171.61,137.78,133.96,133.71,128.49,128.02,127.24,126.57,126.21,123.84,111.24,110.23,60.39,48.58,13.88.

[0089] Example 16

[0090] Synthesize the following (7-bromo-2-phenylimidazo[1,2-α]pyridin-3-yl)glycine ethyl ester.

[0091]

[0092] In this embodiment, 2-aminopyridine used in Example 1 was replaced with an equimolar amount of 2-amino-4-bromopyridine, and the other steps were the same as in Example 1, to obtain (7-bromo-2-phenylimidazo[1,2-α]pyridin-3-yl)glycine ethyl ester with a yield of 90.2%.

[0093] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1H NMR (400MHz, DMSO-d6) δ8.47–8.43(m,1H),8.14–8.09(m,2H),7.79–7.74(m,1H),7.43(t,J=7.7Hz,2H),7.32–7.26(m,1H ),7.06(dd,J=7.3,2.0Hz,1H),5.52(t,J=6.2Hz,1H),3.97(q,J=7.1Hz,2H),3.80(d,J=6.2Hz,2H),1.04(t,J=7.1Hz,3H); 13 C NMR (101MHz, DMSO-d6) δ171.72,140.40,134.01,133.59,128.52,127.20,126.89,126.42,125.15,118.43,116.83,114.43,60.41,48.58,13.92.

[0094] Example 17

[0095] Synthesize the following ethyl glycine (7-bromo-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0096]

[0097] In this embodiment, 2-aminopyridine used in Example 1 was replaced with an equimolar amount of 2-amino-4-bromopyridine, and benzaldehyde used in Example 1 was replaced with an equimolar amount of 4-fluorobenzaldehyde. The other steps were the same as in Example 1, and (7-bromo-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine ethyl ester was obtained with a yield of 82.4%.

[0098] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.46–8.41(m,1H),8.17–8.11(m,2H),7.76–7.71(m,1H),7.28–7.22(m,2H),7.05(dd, J=7.3,2.0Hz,1H),5.50(t,J=6.2Hz,1H),3.98(q,J=7.1Hz,2H),3.79(d,J=6.2Hz,2H),1.05(t,J=7.1Hz,3H); 13C NMR(101MHz,DMSO-d6)δ171.71,162.68,160.25,140.43,133.02,130.49(d,J=3.0Hz),128.39 (d,J=7.9Hz),126.57,125.17,118.41,116.96,115.45,115.24,114.48,60.43,48.58,13.91.

[0099] Example 18

[0100] Synthesize the following ethyl glycine (8-bromo-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0101]

[0102] In this embodiment, 2-aminopyridine used in Example 1 was replaced with an equimolar amount of 2-amino-3-bromopyridine, and benzaldehyde used in Example 1 was replaced with an equimolar amount of 4-fluorobenzaldehyde. The reaction time was extended to 3.5 hours. The other steps were the same as in Example 1, yielding ethyl (8-bromo-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with a yield of 80.8%.

[0103] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.51(d,J=6.9Hz,1H),8.17(ddd,J=8.7,5.5,2.5Hz,2H),7.56–7.49(m,1H),7.31–7.24(m,2 H),6.83(t,J=7.0Hz,1H),5.56(t,J=6.2Hz,1H),3.97(q,J=7.1Hz,2H),3.81(d,J=6.1Hz,2H),1.05(t,J=7.1Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ171.61,162.72,160.29,137.80,133.08,130.43(d,J=3.0Hz),128.54 (d,J=8.0Hz),127.72,126.39,123.90,115.47,115.26,111.35,110.18,60.41,48.56,13.91.

[0104] Example 19

[0105] Synthesize the following ethyl glycine (2-(4-fluorophenyl)-7-methylimidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0106]

[0107] In this embodiment, 2-aminopyridine used in Example 1 was replaced with an equimolar amount of 2-amino-4-methylpyridine, and benzaldehyde used in Example 1 was replaced with an equimolar amount of 4-fluorobenzaldehyde. The reaction time was extended to 3.5 hours. Other steps were the same as in Example 1, yielding ethyl (2-(4-fluorophenyl)-7-methylimidazo[1,2-α]pyridin-3-yl)glycine with a yield of 80.1%.

[0108] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.36–8.33(m,1H),8.17–8.13(m,2H),7.27–7.20(m,3H),6.72(dd,J=7.0,1.7Hz,1H),5 .34(t,J=6.2Hz,1H),3.98(q,J=7.1Hz,2H),3.77(d,J=6.1Hz,2H),2.32(d,J=1.1Hz,3H),1.06(t,J=7.1Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ171.78,160.07,147.80,140.95,134.55,132.30,128.27(d,J=7.8 Hz),125.59,123.42,115.35,115.14,114.84,113.66,111.38,60.40,48.89,20.82,13.95.

[0109] Example 20

[0110] Synthesize the following ethyl glycine (8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0111]

[0112] In this embodiment, 2-aminopyridine used in Example 1 was replaced with an equimolar amount of 2-amino-3-chloropyridine, and benzaldehyde used in Example 1 was replaced with an equimolar amount of 4-fluorobenzaldehyde. The other steps were the same as in Example 1, and (8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine ethyl ester was obtained with a yield of 82.7%.

[0113] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1H NMR(400MHz, DMSO-d6)δ8.48(d,J=6.9Hz,1H),8.22–8.13(m,2H),7.35(d,J=7.2Hz,1H),7.27(t,J=8.9Hz,2H),6 .89(t,J=7.1Hz,1H),5.57(t,J=6.2Hz,1H),3.98(q,J=7.1Hz,2H),3.82(d,J=6.2Hz,2H),1.05(t,J=7.1Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ171.61,162.72,160.29,146.36,137.21,133.05,130.41,128.52(d ,J=7.9Hz),127.65,123.38,123.01,121.17,115.43,115.22,110.82,60.39,48.56,13.87.

[0114] Example 21

[0115] Synthesize the following ethyl glycine (2-(4-bromophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0116]

[0117] In this embodiment, equimolar amounts of 4-bromobenzaldehyde were used to replace the benzaldehyde used in Example 1, shortening the reaction time to 2.5 hours. The other steps were the same as in Example 1, yielding ethyl (2-(4-bromophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with a yield of 90.2%.

[0118] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.47(d,J=6.9Hz,1H),8.09(d,J=8.6Hz,2H),7.64–7.58(m,2H),7.46(d,J=9.0Hz,1H),7.18(dd,J=9.0 ,6.7Hz,1H),6.89(t,J=6.8Hz,1H),5.49(t,J=6.3Hz,1H),3.98(q,J=7.2Hz,2H),3.79(d,J=6.2Hz,2H),1.05(t,J=7.1Hz,3H); 13CNMR(101MHz,DMSO-d6)δ171.67,140.49,133.76,132.06,131.37,128.36,126.67,124.20,120.00,116.66,111.19,60.38,48.70,13.92.

[0119] Example 22

[0120] Synthesize the following ethyl glycine (6-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0121]

[0122] In this embodiment, 2-aminopyridine used in Example 1 was replaced with an equimolar amount of 2-amino-5-chloropyridine, and benzaldehyde used in Example 1 was replaced with an equimolar amount of 4-fluorobenzaldehyde. The reaction time was shortened to 2 hours, and the other steps were the same as in Example 1, yielding ethyl (6-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with a yield of 88.2%.

[0123] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR(400MHz, DMSO-d6)δ8.67(dd,J=2.1,0.9Hz,1H),8.17–8.11(m,2H),7.50(dd,J=9.5,0.8Hz,1H),7.30–7.23(m,2H), 7.19(dd,J=9.5,2.1Hz,1H),5.52(t,J=6.3Hz,1H),3.99(q,J=7.1Hz,2H),3.80(d,J=6.3Hz,2H),1.07(t,J=7.1Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ171.79,162.66,160.23,138.69,133.29,130.49,128.31(d,J= 7.9Hz),126.86,124.61,122.14,118.22,117.46,115.49,115.28,60.46,48.64,13.89.

[0124] Example 23

[0125] Synthesize the following ethyl glycine (8-fluoro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0126]

[0127] In this embodiment, 2-aminopyridine used in Example 1 was replaced with an equimolar amount of 2-amino-3-fluoropyridine, and benzaldehyde used in Example 1 was replaced with an equimolar amount of 4-fluorobenzaldehyde. The reaction time was shortened to 2 hours, and the other steps were the same as in Example 1, yielding ethyl (8-fluoro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with a yield of 85.6%.

[0128] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR(400MHz, DMSO-d6)δ8.35(dd,J=6.9,0.9Hz,1H),8.22–8.16(m,2H),7.29–7.23(m,2H),7.04(ddd,J=11.3,7.6,0.9Hz,1 H),6.85(td,J=7.2,4.5Hz,1H),5.57(t,J=6.2Hz,1H),3.98(q,J=7.1Hz,2H),3.82(d,J=6.2Hz,2H),1.05(t,J=7.1Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ171.63,162.76,160.33,151.76,149.29,132.87,132.50 ,130.46,128.53,127.71,120.86,115.42,110.03,106.63,60.41,48.58,13.84.

[0129] Example 24

[0130] Synthesize the following ethyl glycine (5-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0131]

[0132] In this embodiment, 2-aminopyridine used in Example 1 was replaced with an equimolar amount of 2-amino-6-chloropyridine, and benzaldehyde used in Example 1 was replaced with an equimolar amount of 4-fluorobenzaldehyde. The reaction time was shortened to 2.5 hours. The other steps were the same as in Example 1, and (5-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)glycine ethyl ester was obtained with a yield of 95.4%.

[0133] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1H NMR(400MHz, DMSO-d6)δ8.30–8.24(m,2H),7.49(dd,J=8.9,1.1Hz,1H),7.28–7.22(m,2H),7.17(dd,J=8.9,7.2Hz,1H), 6.96(dd,J=7.2,1.1Hz,1H), 4.99(t,J=6.0Hz,1H), 4.04(q,J=7.1Hz,2H), 3.75(d,J=5.9Hz,2H), 1.11(t,J=7.1Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ170.61,162.86,160.43,143.10,136.17,130.33,129.00 ,126.76,125.40,124.85,116.17,115.28,115.07,113.94,60.38,51.26,13.95.

[0134] Example 25

[0135] Synthesize the following ethyl glycine (8-bromo-2-(3-bromophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0136]

[0137] In this embodiment, 2-aminopyridine used in Example 1 was replaced with an equimolar amount of 2-amino-3-bromopyridine, and benzaldehyde used in Example 1 was replaced with an equimolar amount of 3-bromobenzaldehyde. The other steps were the same as in Example 1, yielding (8-bromo-2-(3-bromophenyl)imidazo[1,2-α]pyridin-3-yl)glycine ethyl ester with a yield of 79.5%.

[0138] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.51(dd,J=6.9,1.0Hz,1H),8.29(t,J=1.8Hz,1H),8.13(dt,J=7.8,1.3Hz,1H),7.55(dd,J=7.2,1.0Hz,1H),7.50(ddd,J=8.0,2 .1,1.1Hz,1H),7.42(t,J=7.8Hz,1H),6.86(t,J=7.0Hz,1H),5.64(t,J=6.3 Hz, 1H), 3.99 (q, J = 7.1Hz, 2H), 3.82 (d, J = 6.3Hz, 2H), 1.06 (t, J = 7.1Hz, 3H); 13C NMR(101MHz,DMSO-d6)δ171.50,137.90,136.32,131.99,130.74,129.86,128.82 ,128.61,126.75,125.25,124.01,122.06,111.57,110.30,60.45,48.50,13.93..

[0139] Example 26

[0140] Synthesize the following ethyl glycine (7-bromo-2-(3-bromophenyl)imidazo[1,2-α]pyridin-3-yl)glycine with the following structural formula.

[0141]

[0142] In this embodiment, 2-aminopyridine used in Example 1 was replaced with an equimolar amount of 2-amino-4-bromopyridine, and benzaldehyde used in Example 1 was replaced with an equimolar amount of 3-bromobenzaldehyde. The other steps were the same as in Example 1, and (7-bromo-2-(3-bromophenyl)imidazo[1,2-α]pyridin-3-yl)glycine ethyl ester was obtained with a yield of 80.5%.

[0143] The obtained product was characterized using a 400MHz nuclear magnetic resonance spectrometer. The characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.45–8.41(m,1H),8.27(t,J=1.8 Hz,1H),8.10(dt,J=7.9,1.4 Hz,1H),7.78(d,J=1.8 Hz,1H),7.48(ddd,J=8.0,2.1,1.1 Hz,1H),7.40(t,J=7.9 Hz,1H),7.09(dd,J=7.3,2.0 Hz,1H),5.58(t,J=6.3 Hz,1H),3.99(q,J=7.1 Hz,2H),3.80(d,J=6.3Hz,2H),1.07(t,J=7.1 Hz,3H); 13 C NMR(101 MHz, DMSO-d6)δ171.57,140.47,136.37,131.87,130.71,129.76,128.74,12 7.49,125.27,125.08,122.07,118.56,117.34,114.70,60.44,48.50,13.94.

Claims

1. A method for synthesizing imidazo[1,2-α]pyridine derivatives catalyzed by titanium dichlorophenocene, characterized in that: Under solvent-free conditions, benzaldehyde compounds of Formula I, 2-aminopyridine compounds of Formula II, and ethyl isocyanate of Formula III were added to a reaction flask, and titanium dichlorocerocene was added as a catalyst. The reaction was carried out at 40-60°C. After the reaction was completed, the product was separated and purified to obtain the imidazo[1,2-α]pyridine derivative of Formula IV. I II III IV In the formula, R1 and R2 each independently represent any one of H, halogen, C1-C4 alkyl, C1-C4 alkoxy, and phenyl. The molar ratio of the benzaldehyde compound, the 2-aminopyridine compound, and the ethyl isocyanate is 1:1.1-1.3:1.1-1.3; The amount of titanium dichlorophenocene added is 8% to 12% of the molar amount of benzaldehyde compounds.

2. The method for synthesizing imidazo[1,2-α]pyridine derivatives catalyzed by titanium dichlorophenocene according to claim 1, characterized in that: The reaction is carried out at 50°C for 1.5 to 3.5 hours.

Images