A multifunctionalized pyridine compound, its preparation method and application

Abstract

This invention discloses a multifunctionalized pyridine compound, its preparation method, and its applications, belonging to the fields of pharmaceutical intermediates and organic synthesis. The invention uses α-allyl-p-toluenesulfonylmethylene isonitrile and substance A as raw materials, and a free radical cyclization reaction is carried out under the action of a catalyst to obtain a highly functionalized pyridine compound, as shown in formula (Ⅰ). Substance A is phenylboronic acid, cyclohexylboronic acid, [1,1'-biphenyl]-4-boronic acid, p-methylphenylboronic acid, m-methylphenylboronic acid, o-methylphenylboronic acid, p-cyanophenylboronic acid, thiophene-3-boronic acid, or cyclopropylboronic acid. The method of this invention not only has very broad substrate tolerance, inexpensive and readily available raw materials, and a simple reaction process suitable for large-scale synthesis, but also provides a new method for pharmaceutical chemical synthesis. Furthermore, due to the high functionalization and special structure of the pyridine compound, it exhibits better efficacy in treating chronic stable angina pectoris, central respiratory depression and circulatory failure, and in the treatment of various organoiodinated phosphate poisonings.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediates and organic synthesis, specifically relating to a multifunctionalized pyridine compound, its preparation method, and its application. Background Technology

[0002] Pyridine compounds, as important structural units, play a vital role in natural products, bioactive compounds, agrochemicals, functional materials, coordination chemistry, and small molecule catalysis. Furthermore, introducing various functional groups onto the pyridine skeleton can improve its biological activity and physical properties. Therefore, developing simple and efficient new methods for the synthesis of polysubstituted pyridines is of great significance. In the past few decades, partially polysubstituted pyridines have been synthesized through conventional Hantzsch, Bohlmann-Rahtz, and Chichibabin pyridine syntheses. Besides conventional methods based on aldehyde and amine condensation, transition metal-catalyzed ketoxime derivatives have been actively explored to date. These methods, or their improved procedures, rely on various forms of [3+3]-, [4+2]-, [3+2+1]-, [2+2+2]- cycloadditions and cycloisomerizations. However, methods for constructing pyridine skeletons via radical cyclization reactions are rarely reported. Summary of the Invention

[0003] To address the shortcomings of the prior art, this invention provides a multifunctionalized pyridine compound, its preparation method, and its applications.

[0004] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0005] A method for preparing a multifunctional pyridine compound includes the following steps: α-allyl-p-toluenesulfonylmethyleneisocyanate, phenylboronic acid or cyclohexylboronic acid, catalyst, oxidant and base are added sequentially to a solvent and reacted at 80℃~100℃ for 12~18h. After removing the solvent by vacuum distillation, the multifunctional pyridine compound is obtained by column chromatography.

[0006] The chemical structural formula of the multifunctionalized pyridine compound is shown in formula (Ⅰ).

[0007]

[0008] Where: R 1 -H, -CH3, -C6H5, or -Cl; R 2 -C2H5 or -H; R 3 -CH3, -C7H6I, -C8H6F3, -C7H6F, -C8H9; R 4 -C6H5, -C3H4, -C6H 10 -C7H7, -C4H3S, -C7H4N or -C12 H9;

[0009] Substance A is phenylboronic acid, cyclohexylboronic acid, [1,1'-biphenyl]-4-boronic acid, p-methylphenylboronic acid, m-methylphenylboronic acid, o-methylphenylboronic acid, p-cyanophenylboronic acid, thiophene-3-boronic acid, or cyclopropylboronic acid.

[0010] In a preferred embodiment of the present invention, the catalyst is one of ferric oxide, ferrocene, ferric tetroxide, ferric trifluoromethanesulfonate, anhydrous ferric chloride, ferric triacetylacetone, ferrous oxalate, anhydrous ferric acetate, ferric trifluoromethanesulfonate, ferric acetate hydrate, or ferrous acetylacetone.

[0011] In a preferred embodiment of the present invention, the oxidant is one of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tert-butyl peroxide, tert-butyl hydroperoxide, benzoquinone, di-tert-butyl peroxide, hydrogen peroxide, benzoyl peroxide, iodophenylacetic acid, or oxygen.

[0012] In a preferred embodiment of the present invention, the alkali is one of triethylenediamine, cesium carbonate, sodium hydroxide, potassium tert-butoxide, sodium ethoxide, potassium carbonate, or 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0013] In a preferred embodiment of the present invention, the solvent is one of dichloromethane, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, 1,2-dichloroethane, or 1,4-dioxane.

[0014] In a preferred embodiment of the present invention, the molar ratio of α-allyl-p-toluenesulfonylmethyleneisocyanate, phenylboronic acid, catalyst, oxidant, base and solvent is 1:2:0.1:3:2:2.

[0015] This invention also claims protection for the said multifunctionalized pyridine compound, whose chemical structural formula is as follows:

[0016]

[0017] Where: R 1 -H, -CH3, -C6H5, or -Cl; R 2 -C2H5 or -H; R 3 -CH3, -C7H6I, -C8H6F3, -C7H6F, -C8H9; R 4 -C6H5, -C3H4, -C6H 10 -C7H7, -C4H3S, -C7H4N or -C 12 H9.

[0018] The present invention also claims protection for the use of the polyfunctionalized pyridine compound in the preparation of drugs for treating chronic stable angina, central respiratory depression and circulatory failure or for rescuing various organoiodine phosphate poisonings.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) The present invention provides a method for synthesizing multifunctional pyridines, using α-allyl-p-toluenesulfonylmethyleneisocyanate and phenylboronic acid as raw materials, and undergoing a free radical cyclization reaction under the action of a catalyst to obtain highly functionalized pyridine compounds. The method for synthesizing multifunctional pyridine compounds in the present invention can further enrich the methods for synthesizing pyridine compounds. The reaction method is mild, simple to operate, suitable for large-scale synthesis, and can provide a new method for the modification and synthesis of clinical drug molecules.

[0020] (2) The present invention describes a drug that can be used to treat chronic stable angina, central respiratory depression and circulatory failure and to detoxify various organic iodine phosphate poisoning. Due to the high functionalization of pyridine compounds, their special structure makes them more effective in treating chronic stable angina, central respiratory depression and circulatory failure and detoxifying various organic iodine phosphate poisoning. Detailed Implementation

[0021] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0022] Example 1

[0023] The method for synthesizing multifunctionalized pyridine 3a in this embodiment specifically includes the following steps:

[0024] The molar ratio of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, phenylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane was 1:2:0.1:3:2:2. 0.2 mmol of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, 0.4 mmol of phenylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain the compound polyfunctionalized pyridine 3a, with a yield of 45%.

[0025] The reaction equation is as follows:

[0026]

[0027] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ8.05(d,J=7.2Hz,2H),7.74(s,1H),7.69(d,J=7.3Hz,2H),7.55–7.49(m,4H),7.47–7.42(m,2H),7.33(s,1H),2.71(s,3H). 13 C NMR (151MHz, CDCl3) δ158.91,157.72,149.54,139.92,138.87,129.11,128. 94,128.87,128.80,127.22,127.16,119.89,116.22,24.94.HRMS(ESI):mass found:245.1204,calculated mass for C 18 H 15 NH + [M+H + ]:246.1277.

[0028] Example 2

[0029] The synthesis of 2-methyl-6-phenyl-4-(p-tolyl)pyridine 3b in this embodiment specifically includes the following steps:

[0030] The molar ratio of 1-((2-isocyano-4-(p-tolyl)pent-4-en-2-yl)sulfonyl)-4-methylbenzene, phenylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 1-((2-isocyano-4-(p-tolyl)pent-4-en-2-yl)sulfonyl)-4-methylbenzene, 0.4 mmol of phenylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 2-methyl-6-phenyl-4-(p-tolyl)pyridine 3b, with a yield of 36%.

[0031] The reaction equation is as follows:

[0032]

[0033] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows: 1 H NMR(500MHz, CDCl3)δ8.05–8.03(m,2H),7.72(d,J=1.0Hz,1H),7.60(d,J=8.0Hz,2H), 7.51–7.48(m,2H),7.44–7.41(m,1H),7.31(d,J=8.0Hz,3H),2.70(s,3H),2.43(s,3H). 13 C NMR (126MHz, CDCl3) δ158.88,157.74,149.47,140.11,139.01,136.02,129.86, 128.83,128.79,127.26,127.02,119.65,115.98,24.95,21.32.HRMS(ESI):mass found:259.1361,calculatedmass forC 19 H 17 NH + [M+H + ]:260.1434.

[0034] Example 3

[0035] The synthesis of 2-methyl-6-phenyl-4-o-tolylpyridine 3c in this embodiment specifically includes the following steps:

[0036] The molar ratio of 1-(4-isocyano-4-toluenesulfonyl-1-en-2-yl)-2-methylbenzene, phenylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane was 1:2:0.1:3:2:2. 0.2 mmol of 1-(4-isocyano-4-toluenesulfonyl-1-en-2-yl)-2-methylbenzene, 0.4 mmol of phenylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 2-methyl-6-phenyl-4-o-tolylpyridine 3c, with a yield of 24%.

[0037] The reaction equation is as follows:

[0038]

[0039] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows:1 H NMR (500MHz, CDCl3) δ8.04–8.02(m,2H),7.51–7.47(m,3H),7.42(t,J=7.0Hz,1H),7.35–7.26(m,4H),7.09(s,1H),2.69(s,3H),2.33(s,3H). 13 C NMR (151MHz, CDCl3) δ158.37,157.05,150.87,139.88,139.79,135.21,130.72,129.34, 128.90,128.85,128.34,127.23,126.16,122.33,118.65,24.94,20.50.HRMS(ESI):mass found:259.1361,calculated mass for C 19 H 17 NH + [M+H + ]:260.1434.

[0040] Example 4

[0041] The synthesis of 4-([1,1'-biphenyl]-4-yl)-2-methyl-6-phenylpyridine 3d in this example specifically includes the following steps:

[0042] The molar ratio of 4-(4-isocyano-4-toluenesulfonyl-1-en-2-yl)-1,1'-biphenyl, phenylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 4-(4-isocyano-4-toluenesulfonyl-1-en-2-yl)-1,1'-biphenyl, 0.4 mmol of phenylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 4-([1,1'-biphenyl]-4-yl)-2-methyl-6-phenylpyridine 3d, with a yield of 32%.

[0043] The reaction equation is as follows:

[0044]

[0045] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows: 1H NMR (600MHz, CDCl3) δ8.06(d,J=7.2Hz,2H),7.78(d,J=7.8Hz,3H),7.74(d,J=8.2 Hz,2H),7.67(d,J=7.4Hz,2H),7.53–7.48(m,4H),7.46–7.38(m,3H),2.73(s,3H). 13 CNMR(151MHz, CDCl3)δ159.02,157.85,149.03,141.84,140.40,139.98,137.70,129.02,128. 93,128.86,127.84,127.80,127.60,127.27,127.21,119.73,116.08,25.01.HRMS(ESI):mass found:321.1517,calculated mass for C 24 H 19 NNa + [M+Na + ]:344.1410.

[0046] Example 5

[0047] The synthesis of 4-(4-chlorophenyl)-2-methyl-6-phenylpyridine 3e in this example specifically includes the following steps:

[0048] The molar ratio of 1-chloro-4-(4-isocyano-4-toluenesulfonyl-1-en-2-yl)benzene, phenylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane was 1:2:0.1:3:2:2. 0.2 mmol of 1-chloro-4-(4-isocyano-4-toluenesulfonyl-1-en-2-yl)benzene, 0.4 mmol of phenylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 4-(4-chlorophenyl)-2-methyl-6-phenylpyridine 3e, with a yield of 27%.

[0049] The reaction equation is as follows:

[0050]

[0051] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows: 1H NMR (500MHz, CDCl3) δ8.02(d,J=7.0Hz,2H),7.68(s,1H),7.61(d,J=8.5Hz,2H),7.50–7.46(m,4H),7.42(t,J=7.0Hz,1H),7.28(s,1H),2.69(s,3H). 13 C NMR (126MHz, CDCl3) δ159.20,158.00,148.38,139.84,137.46,135.20,129. 40,129.05,128.89,128.51,127.27,119.67,115.98,24.99.HRMS(ESI):mass found:279.0815,calculatedmass for C 18 H 14 ClNH + [M+H + ]:280.0888.

[0052] Example 6

[0053] The synthesis of 3-ethyl-polyfunctionalized pyridine 3f in this embodiment specifically includes the following steps:

[0054] The molar ratio of 1-((3-ethyl-2-isocyano-4-phenyl-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, phenylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 1-((3-ethyl-2-isocyano-4-phenyl-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, 0.4 mmol of phenylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 3-ethyl-polyfunctionalized pyridine 3f, with a yield of 17%.

[0055] The reaction equation is as follows:

[0056]

[0057] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows: 1H NMR (500MHz, CDCl3) δ7.50–7.48(m,2H),7.46–7.35(m,8H),7.00(s,1H),2.62–2.58(m,5H),0.73(t,J=7.5Hz,3H). 13 C NMR (126MHz, CDCl3) δ159.35,154.62,151.04,141.53,140.28,131.93,129.30,128.86,128.55,12 8.35,128.25,127.69,123.72,24.09,22.07,15.02.HRMS(ESI):massfound:273.1517,calculated mass for C 20 H 19 NNa + [M+Na + ]:296.1410.

[0058] Example 7

[0059] The synthesis of 3g of 2-(4-methylbenzyl)-4,6-diphenylpyridine in this example specifically includes the following steps:

[0060] The molar ratio of 1-((2-isocyano-4-phenyl-1-(p-tolyl)pent-4-en-2-yl)sulfonyl)-4-methylbenzene, phenylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 1-((2-isocyano-4-phenyl-1-(p-tolyl)pent-4-en-2-yl)sulfonyl)-4-methylbenzene, 0.4 mmol of phenylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain 3 g of compound 2-(4-methylbenzyl)-4,6-diphenylpyridine, with a yield of 38%.

[0061] The reaction equation is as follows:

[0062]

[0063] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows: 1H NMR (500MHz, CDCl3) δ8.13–8.11(m,2H),7.78(s,1H),7.64(d,J=7.5Hz,2H),7.54–7.44(m,6H) ,7.32(d,J=7.6Hz,2H),7.27(d,J=8.2Hz,1H),7.17(d,J=7.7Hz,2H),4.30(s,2H),2.36(s,3H). 13 CNMR(126MHz, CDCl3)δ161.82,157.62,149.88,139.92,139.04,136.77,135.95,129.38,129.24, 129.10,128.96,128.93,128.82,127.29,127.25,119.64,116.54,44.72,21.18.HRMS(ESI):mass found:335.1674,calculated mass for C 25 H 21 NH + [M+H + ]:336.1747.

[0064] Example 8

[0065] The synthesis of 2-(3-methylbenzyl)-4,6-diphenylpyridine 3h in this example specifically includes the following steps:

[0066] The molar ratio of 1-(2-isocyano-4-phenyl-2-p-toluenesulfonyl-4-en-1-yl)-3-methylbenzene, phenylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 1-(2-isocyano-4-phenyl-2-p-toluenesulfonyl-4-en-1-yl)-3-methylbenzene, 0.4 mmol of phenylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 2-(3-methylbenzyl)-4,6-diphenylpyridine, with a yield of 41%.

[0067] The reaction equation is as follows:

[0068]

[0069] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows: 1 H NMR(500MHz, CDCl3)δ8.11(d,J=7.5Hz,2H),7.78(d,J=1.5Hz,1H),7.65–7.63(m,2H),7.53–7.4 1(m,6H),7.27(d,J=1.0Hz,1H),7.24–7.21(m,3H),7.08–7.06(m,1H),4.29(s,2H),2.36(s,3H). 13 C NMR (126MHz, CDCl3) δ161.67,157.62,149.88,139.92,139.74,139.05,138.23,130.17,129.10,128.97, 128.93,128.82,128.56,127.29,127.25,126.41,123.64,119.71,116.55,45.09,21.55.HRMS(ESI):mass found:335.1674,calculated mass for C 25 H 21 NH + [M+H + ]:336.1747.

[0070] Example 9

[0071] The synthesis of 2,4-diphenyl-6-(4-(trifluoromethyl)benzyl)pyridine 3i in this example specifically includes the following steps:

[0072] The molar ratio of 1-((2-isocyano-4-phenyl-1-(4-(trifluoromethyl)phenyl)pent-4-en-2-yl)sulfonyl)-4-methylbenzene, phenylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 1-((2-isocyano-4-phenyl-1-(4-(trifluoromethyl)phenyl)pent-4-en-2-yl)sulfonyl)-4-methylbenzene, 0.4 mmol of phenylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 2,4-diphenyl-6-(4-(trifluoromethyl)benzyl)pyridine 3i, with a yield of 40%.

[0073] The reaction equation is as follows:

[0074]

[0075] The product's 1H NMR, 1C NMR, fluorine NMR, and high-resolution mass spectrometry characterization data are as follows: 1 HNMR (500MHz, CDCl3) δ8.09–8.07(m,2H),7.80(s,1H),7.65–7.63(m,2H),7.59(d,J=8.0Hz,2H),7.53–7.43(m,8H),7.27(s,1H),4.35(s,2H). 13 C NMR (126MHz, CDCl3) δ160.33,157.91,150.22,143.96,143.95,139.65,138.80,129.64,129.20,129.17,129.1 4,128.89,128.84(q,J=28.9Hz),127.24,125.58(q,J=3.8Hz),124.48(q,J=212.0Hz),119.74,116.85,44.83. 19 FNMR(471MHz, CDCl3)δ-62.34(s,3F).HRMS(ESI):mass found:389.1391,calculated massfor C 25 H 18 F3NNa + [M+Na + ]:412.1284.

[0076] Example 10

[0077] The synthesis of 2-(4-fluorobenzyl)-4,6-diphenylpyridine 3j in this example specifically includes the following steps:

[0078] The molar ratio of 1-fluoro-4-(2-isocyano-4-phenyl-2-toluenesulfonyl-4-en-1-yl)benzene, phenylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 1-fluoro-4-(2-isocyano-4-phenyl-2-toluenesulfonyl-4-en-1-yl)benzene, 0.4 mmol of phenylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 2-(4-fluorobenzyl)-4,6-diphenylpyridine 3j, with a yield of 30%.

[0079] The reaction equation is as follows:

[0080]

[0081] The product's 1H NMR, 1C NMR, fluorine NMR, and high-resolution mass spectrometry characterization data are as follows: 1 HNMR(500MHz, CDCl3)δ8.10(d,J=7.5Hz,2H),7.80(s,1H),7.66–7.64(m,2H),7.54– 7.45(m,6H),7.40–7.36(m,2H),7.30–7.28(m,1H),7.07–7.03(m,2H),4.30(s,2H). 13 C NMR (126MHz, CDCl3) δ 161.78 (d, J = 244.6Hz), 161.30, 157.77, 150.05, 139.79, 138.93, 135.53 (d, J = 3.2Hz), 130. 78(d,J=7.8Hz),129.17,129.08,129.06,128.87,127.27,127.24,118.14(d,J=369.7Hz),115.53,115.36,44.23. 19 F NMR(471MHz,CDCl3)δ-116.98(s,1F).HRMS(ESI):mass found:339.1423,calculated mass for C 24 H 18 FNH + [M+H + ]:340.1496.

[0082] Example 11

[0083] The synthesis of 2-(4-iodobenzyl)-4,6-diphenylpyridine 3k in this example specifically includes the following steps:

[0084] The molar ratio of 1-iodo-4-(2-isocyano-4-phenyl-2-p-toluenesulfon-4-en-1-yl)benzene, phenylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 1-iodo-4-(2-isocyano-4-phenyl-2-p-toluenesulfon-4-en-1-yl)benzene, 0.4 mmol of phenylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 2-(4-iodobenzyl)-4,6-diphenylpyridine 3k, with a yield of 42%.

[0085] The reaction equation is as follows:

[0086]

[0087] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows: 1 H NMR(500MHz, CDCl3)δ8.09–8.07(m,2H),7.79(d,J=5.0Hz,1H),7.67–7.62( m,4H),7.51–7.44(m,6H),7.24(s,1H),7.16(d,J=8.3Hz,2H),4.24(s,2H). 13 C NMR (126MHz, CDCl3) δ160.76,157.80,150.11,139.72,139.54,138.87,137.89,137.72,131. 43,129.17,129.10,129.07,128.86,127.25,119.63,116.73,91.81,44.55.HRMS(ESI):mass found:447.0484,calculatedmass forC 24 H 18 INH+[M+H + ]:448.0557.

[0088] Example 12

[0089] The synthesis of 2-([1,1'-biphenyl]-4-yl)-6-methyl-4-phenylpyridine 3l in this embodiment specifically includes the following steps:

[0090] The molar ratio of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, [1,1'-biphenyl]-4-boronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, 0.4 mmol of [1,1'-biphenyl]-4-boric acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 2-([1,1'-biphenyl]-4-yl)-6-methyl-4-phenylpyridine 3l, with a yield of 44%.

[0091] The reaction equation is as follows:

[0092]

[0093] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ8.16 (d, J = 8.4Hz, 2H), 7.80 (s, 1H), 7.76 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H),7.72–7.69(m,3H),7.54–7.47(m,5H),7.40(t,J=7.2Hz,1H),7.35(s,1H),2.74(s,3H). 13 C NMR (151MHz, CDCl3) δ159.02,157.30,149.61,141.62,140.78,138.94,138.85,129.17,1 29.00,128.93,127.63,127.58,127.55,127.23,119.98,116.13,25.00.HRMS(ESI):mass found:321.1517,calculated mass for C 24 H 19 NNa + [M+Na + ]:344.1410.

[0094] Example 13

[0095] The synthesis of 2-methyl-4-phenyl-6-p-tolylpyridine 3m in this embodiment specifically includes the following steps:

[0096] The molar ratio of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, p-methylphenylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, 0.4 mmol of p-methylphenylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 2-methyl-4-phenyl-6-p-tolylpyridine 3m, with a yield of 50%.

[0097] The reaction equation is as follows:

[0098]

[0099] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization are as follows: 1 H NMR (600MHz, CDCl3) δ7.95–7.94(m,2H),7.71–7.68(m,3H),7.51–7.49(m,2H),7.46–7.45(m,1H),7.30(s,3H),2.69(s,3H),2.42(s,3H). 13 C NMR (151MHz, CDCl3) δ158.83,157.74,149.52,139.02,138.86,137.12,129.55, 129.12,128.92,127.21,127.10,119.67,115.95,24.97,21.42.HRMS(ESI):mass found:259.1361,calculated mass for C 19 H 17 NH + [M+H + ]:260.1437.

[0100] Example 14

[0101] The synthesis of 2-methyl-4-phenyl-6-m-toluidine 3n in this embodiment specifically includes the following steps:

[0102] The molar ratio of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, m-methylphenylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, 0.4 mmol of m-methylphenylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 2-methyl-4-phenyl-6-m-toluidine 3n, with a yield of 52%.

[0103] The reaction equation is as follows:

[0104]

[0105] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.87(s,1H),7.80(d,J=7.8Hz,1H),7.72(s,1H),7.71–7.68(m,2H),7.51(t,J=7.2Hz,2H ),7.45(t,J=7.2Hz,1H),7.38(t,J=7.2Hz,1H),7.32(s,1H),7.24(d,J=7.8Hz,1H),2.71(s,3H),2.46(s,3H). 13 C NMR (151MHz, CDCl3) δ158.90,158.00,149.55,139.96,138.99,138.49,129.70,129.16, 128.97,128.75,127.98,127.23,124.37,119.88,116.38,25.01,21.72.HRMS(ESI):mass found:259.1361,calculated mass for C 19 H 17 NH + [M+H + ]:260.1437.

[0106] Example 15

[0107] The synthesis of 2-methyl-4-phenyl-6-o-toluidine 3o in this embodiment specifically includes the following steps:

[0108] The molar ratio of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, o-methylphenylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, 0.4 mmol of o-methylphenylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 2-methyl-4-phenyl-6-o-tolylpyridine 3o, with a yield of 41%.

[0109] The reaction equation is as follows:

[0110]

[0111] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.67(d,J=7.2Hz,2H),7.49(t,J=7.2Hz,2H),7.45–7.43(m,3H),7.35(s,1H),7.31–7.28(m,3H),2.69(s,3H),2.41(s,3H). 13 C NMR (151MHz, CDCl3) δ160.11,158.46,148.96,140.85,138.71,135.90,130.83,129.68, 129.17,129.01,128.31,127.20,126.01,119.41,119.36,24.89,20.48.HRMS(ESI):mass found:259.1361,calculated mass for C 19 H 17 NH + [M+H + ]:260.1437.

[0112] Example 16

[0113] The synthesis of 4-(6-methyl-4-phenylpyridin-2-yl)benzonitrile 3p in this example specifically includes the following steps:

[0114] The molar ratio of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, p-cyanoboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, 0.4 mmol of p-cyanobenonic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 4-(6-methyl-4-phenylpyridin-2-yl)benzonitrile 3p, with a yield of 41%.

[0115] The reaction equation is as follows:

[0116]

[0117] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ8.16(d,J=8.4Hz,2H),7.80(s,1H),7.78–7.75(m,3H),7.68–7.67(m,2H),7.51–7.47(m,2H),7.40(s,1H),2.70(s,3H). 13 C NMR (151MHz, CDCl3) δ159.52,155.43,150.04,144.06,138.43,132.92,132.67,1 29.28,127.78,127.21,121.17,119.10,116.68,112.32,24.93.HRMS(ESI):mass found:270.1157,calculatedmass for C 19 H 14 N2Na + [M+Na + ]:293.1049.

[0118] Example 17

[0119] The synthesis of 2-methyl-4-phenyl-6-(thiophen-3-yl)pyridine 3q in this embodiment specifically includes the following steps:

[0120] The molar ratio of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, thiophene-3-boronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, 0.4 mmol of thiophene-3-boric acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 2-methyl-4-phenyl-6-(thiophene-3-yl)pyridine 3q, with a yield of 37%.

[0121] The reaction equation is as follows:

[0122]

[0123] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.94(d,J=1.2Hz,1H),7.69(d,J=4.8Hz,1H),7.66(d,J=7.2Hz,2H),7.61(s,1H) ,7.49(t,J=7.4Hz,2H),7.44(t,J=7.3Hz,1H),7.40–7.39(m,1H),7.25(d,J=2.5Hz,1H),2.66(s,3H). 13 C NMR (151MHz, CDCl3) δ158.98,153.66,149.61,142.61,138.88,129.16,129. 00,127.19,126.53,126.35,123.70,119.74,115.92,24.92.HRMS(ESI):mass found:251.0769,calculated mass for C 16 H 13 NSH + [M+H + ]:252.0841.

[0124] Example 18

[0125] The synthesis of 2-cyclopropyl-6-methyl-4-phenylpyridine 3r in this embodiment specifically includes the following steps:

[0126] The molar ratio of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, cyclopropylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, 0.4 mmol of cyclopropylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 2-cyclopropyl-6-methyl-4-phenylpyridine 3r, with a yield of 25%.

[0127] The reaction equation is as follows:

[0128]

[0129] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.60(d,J=7.2Hz,2H),7.46(t,J=7.4Hz,2H),7.41(t,J=7.3Hz ,1H),7.12(s,1H),7.06(s,1H),2.55(s,3H),2.12–2.08(m,1H),1.01–0.99(m,4H). 13 CNMR(151MHz, CDCl3)δ162.90,158.28,148.86,139.10,129.05,128.78,127.17,118.40,115.60,24.78,17.54,9.72.HRMS(ESI):mass found:209.1204,calculated mass for C 15 H 15 NH + [M+H + ]:210.1277.

[0130] Example 19

[0131] The synthesis method of 2-cyclohexyl-6-methyl-4-phenylpyridine 3S in this embodiment specifically includes the following steps:

[0132] The molar ratio of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, cyclohexylboronic acid, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and 1,2-dichloroethane is 1:2:0.1:3:2:2. 0.2 mmol of 1-((2-isocyano-4-phenyl-4-penten-2-yl)sulfonyl)-4-methylbenzene, 0.4 mmol of cyclohexylboronic acid, 0.02 mmol of iron triacetylacetone, 0.6 mmol of di-tert-butyl peroxide, 0.4 mmol of sodium hydroxide, and 0.4 mmol of 1,2-dichloroethane were added sequentially to a reactor, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 1:20) to obtain compound 2-cyclohexyl-6-methyl-4-phenylpyridine 3s, with a yield of 15%.

[0133] The reaction equation is as follows:

[0134]

[0135] The product's proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrometry characterization data are as follows: 1 H NMR (500MHz, CDCl3) δ7.62–7.60(m,2H),7.47–7.44(m,2H),7.42–7.38(m,1H),7.17(d,J=1.6Hz,2H),2.78–2.71(m ,1H),2.59(s,3H),2.03–2.00(m,2H),1.88–1.84(m,2H),1.78–1.74(m,1H),1.58–1.40(m,4H),1.34–1.26(m,1H). 13 C NMR (126MHz, CDCl3) δ166.79,158.04,149.22,139.32,129.03,128.73,127.20,118.90,115.81,46.98,33.34,26.79,26.28,24.79.HRMS(ESI):mass found:251.1674,calculatedmass for C 18 H 21 NH + [M+H + ]:252.1747.

[0136] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A method for preparing a multifunctionalized pyridine compound, characterized in that, The process includes the following steps: α-allyl-p-toluenesulfonylmethyleneisocyanate, substance A, iron triacetylacetone, di-tert-butyl peroxide, and sodium hydroxide are added sequentially to a solvent and reacted at 80℃~100℃ for 12~18h. After removing the solvent by vacuum distillation, the product is subjected to column chromatography to obtain the polyfunctionalized pyridine compound.

2. The method for preparing the multifunctionalized pyridine compound as described in claim 1, characterized in that, The solvent is one of dichloromethane, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, 1,2-dichloroethane, or 1,4-dioxane.

3. The method for preparing the multifunctionalized pyridine compound as described in claim 1, characterized in that, The molar ratio of α-allyl-p-toluenesulfonylmethyleneisocyanate, substance A, iron triacetylacetone, di-tert-butyl peroxide, sodium hydroxide, and solvent is 1:2:0.1:3:2:2.

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