A method for synthesizing 3-acylimidazo[1,5-a]pyridine compounds

Abstract

The application discloses a new method for synthesizing 3-acyl imidazo[1,5-a]pyridine compounds. The method comprises the following steps: adding 2-pyridyl-p-methanequinone (2-Py-p-QMs), terminal alkyne and p-toluenesulfonyl azide (TsN3), catalyst CuI, organic solvent and alkali into a reaction container under the condition of RT and O2 atmosphere, stirring the reaction for 4 hours, and then separating and purifying 3-acyl imidazo[1,5-a]pyridine compounds after the reaction is completed. The method expands the structure range of 3-acyl imidazo[1,5-a]pyridine products, and more compounds with rich structures can be obtained. Compared with the previous method for synthesizing the target product, the method is efficient, the reaction reagent is non-corrosive, the method design is novel, the raw material is cheap, the operation method is simple, and the product can be directly obtained under mild conditions.

Description

Technical Field

[0001] This invention relates to a novel method for synthesizing 3-acylimidazo[1,5-a]pyridine compounds, specifically a novel method for preparing 3-acylimidazo[1,5-a]pyridine compounds using 2-pyridyl-p-methylenebenzoquinone (2-Py-p-QMs), terminal alkynes, and p-toluenesulfonyl azide (TsN3) as substrates, belonging to the field of organic synthesis technology. Background Technology

[0002] Compounds containing the imidazo[1,5-a]pyridine skeleton are considered highly valuable organic frameworks due to their wide applications in pharmaceutical and materials science. In recent years, various methods have been used to develop and design novel organic molecules containing the imidazo[1,5-a]pyridine skeleton to achieve desired application properties. For example, using structure-activity relationships (SARs), medicinal chemists have also discovered many valuable new drugs containing the imidazo[1,5-a]pyridine skeleton in drug discovery. Due to its unique structure containing a 3-acyl group, the 3-acylimidazo[1,5-a]pyridine skeleton has also been widely found in bioactive compounds and exhibits unique physiological activities. For example, such as... Figure 1As shown, compound A is commonly used as a CB2 agonist to treat inflammatory pain and osteoarthritis pain caused by iodoacetic acid monosodium phosphate. Compound B is a fibroblast growth factor receptor antagonist used to treat bladder cancer, and compound C exhibits therapeutic activity as a retinoid receptor-associated orphan receptor γ-C agonist for autoimmune diseases. Furthermore, compounds with the 3-acylimidazo[1,5-a]pyridine skeleton show advantages over other substituted imidazo[1,5-a]pyridines in their application in the field of aggregation-induced emission (AIE) properties. Over the past few decades, the potential properties and applications of these molecules have inspired organic chemists to design attractive synthetic routes to synthesize these high-value N-heterocyclic skeletons. However, careful literature review reveals that most conventional methods for obtaining imidazo[1,5-a]pyridines have significant limitations in the synthesis of 3-acylimidazo[1,5-a]pyridines. Traditionally, the synthetic routes for 3-acylimidazo[1,5-a]pyridine include two methods, both of which use 2-pyridinemethylamine as a substrate and proceed through multiple steps to obtain the desired product under suitable conditions (J.Med.Chem. 2013, 56, 8224–8256; Eur.J.Med.Chem. 2015, 97, 719–731). However, these methods suffer from numerous drawbacks, such as the use of highly corrosive reagents, severe environmental pollution, cumbersome experimental procedures, and low efficiency, which have hindered their widespread application in production and daily life. Therefore, it is necessary to design more novel synthetic strategies to circumvent the shortcomings of the above methods and efficiently generate 3-acylimidazo[1,5-a]pyridine. Recently, with the combined effect of oxygen and elemental iodine, Li's research group used phenylacetylene or styrene as substrates to first achieve Csp-H or Csp... 2 After activation with -H, it reacts directly with 2-pyridinemethylamine to synthesize 3-acylimidazo[1,5-a]pyridine. (Chin.Chem.Lett.2021, 32, 3083–3086) Subsequently, Wang's group successfully obtained the desired product in one step via an electrochemical tandem process using acetophenone and 2-pyridinemethylamine as substrates. (ACS Omega 2022, 7, 4305–4310) In 2023, Wang's group also reported a new method for synthesizing 3-acylimidazo[1,5-a]pyridine via a [4+1] cyclization reaction using 2-pyridinemethylamine and 1,3-dicarbonyl compounds as substrates, regulated by elemental iodine. (J.Org.Chem.2023, 88, 10.1021 / acs.joc.3c01425). Therefore, the methods for synthesizing 3-acylimidazo[1,5-a]pyridine reported above all use 2-pyridinemethylamine as a substrate, which limits the synthesis method to a single raw material. Summary of the Invention

[0003] The technical problem to be solved by the present invention is that the existing methods for preparing 3-acylimidazo[1,5-a]pyridine compounds have disadvantages such as the use of highly corrosive reaction reagents, serious environmental pollution, cumbersome experimental operations, the use of expensive raw material 2-pyridinemethylamine, and low efficiency.

[0004] To address the aforementioned technical problems, this invention provides a novel method for synthesizing 3-acylimidazo[1,5-a]pyridine compounds, comprising the following steps:

[0005] Step 1): Add the following raw materials to the reaction vessel: 2-pyridyl-p-methylenebenzoquinone compound 2-Py-p-QMs, terminal alkyne, azide compound TsN3, catalyst cuprous iodide, organic solvent A and base, and stir the reaction at room temperature and under O2 atmosphere;

[0006] Step 2): After the reaction is complete, add saturated sodium chloride solution to dilute the reaction mixture, then add organic solvent B for extraction and separation, dry the organic phase, concentrate, and perform column chromatography to separate and purify to obtain the target product 3-acylimidazo[1,5-a]pyridine compound.

[0007] The reaction equation is shown in Equation I:

[0008]

[0009] In the above formula I, R 1 H or methyl; R 2 It is tert-butyl or isopropyl; R 3 The substance is cyclopropyl, phenyl, or substituted phenyl, wherein the substituted phenyl is a phenyl with a substituent at the ortho or para position (ortho or para refers to the substitution position relative to the terminal alkyne), and the substituent is an electron-donating group such as methyl, methoxy, tert-butyl, ethyl, or an electron-withdrawing group such as nitro, fluorine, chlorine, bromine, -CF3, -OCF3, COOMe, etc.

[0010] Preferably, the preparation method of the raw material compound 2-Py-p-QMs in step 1) includes: mixing 2,6-disubstituted phenol, 2-pyridinecarboxaldehyde with different substituents, toluene, piperidine, and acetic anhydride, and reacting them under reflux conditions to prepare 2-Py-p-QMs; wherein the 2,6-disubstituted phenol is 2,6-di-tert-butylphenol or 2,6-diisopropylphenol; and the chemical structural formula of the 2-pyridinecarboxaldehyde with different substituents is shown in Formula II.

[0011]

[0012] In Equation II above, R 1 It is H or methyl;

[0013] Preferably, the organic solvent A in step 1) is at least one of tetrahydrofuran (THF), chloroform (CHCl3), acetonitrile, dichloromethane, and 1,4-dioxane;

[0014] Preferably, the base in step 1) is at least one of potassium carbonate, triethylamine, cesium carbonate, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicycloundec-7-ene (DBU), and pyridine.

[0015] Preferably, the molar ratio of 2-Py-p-QMs, terminal alkyne, TsN3, cuprous iodide and base in step 1) is 0.6:1:1:0.1:2.

[0016] Preferably, the organic solvent B in step 1) is a chloroalkane solvent.

[0017] Preferably, the chlorinated organic solvent is at least one selected from dichloromethane, chloroform, and 2,6-dichloroethane.

[0018] Preferably, the eluent used in the column chromatography separation in step 2) is a mixture of petroleum ether and ethyl acetate.

[0019] Preferably, the volume ratio of petroleum ether to ethyl acetate in the mixture is 20 to 40:1.

[0020] Compared with the prior art, the present invention has the following advantages:

[0021] (1) The method of preparing 3-acylimidazo[1,5-a]pyridine compounds using 2-pyridyl-p-methylenebenzoquinone (2-Py-p-QMs), terminal alkynes and p-toluenesulfonyl azide (TsN3) as substrates has wide applicability. Compared with previous methods, the present invention adopts a route with efficient and non-corrosive reaction reagents, and the synthetic route design is novel. The operation method is simple, and the product can be directly obtained under mild reaction conditions.

[0022] (2) This invention extends the synthetic route of 3-acylimidazo[1,5-a]pyridine, yielding more structurally rich compounds, and is of great significance to the synthetic route of 3-acylimidazo[1,5-a]pyridine. Attached Figure Description

[0023] Figure 1 The chemical structural formula of compound AC mentioned in the background section is shown below.

[0024] Figure 2 The single crystal spectrum of the product (1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl)(phenyl) methyl ketone) from Example 1 is shown.

[0025] Figure 3 The 1H NMR spectrum of the product (1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl)(phenyl)methyl ketone) from Example 1;

[0026] Figure 4 The carbon NMR spectrum of the product (1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl)(phenyl)methyl ketone) from Example 1. Detailed Implementation

[0027] To make the present invention more apparent and understandable, preferred embodiments are described in detail below with reference to the accompanying drawings.

[0028] In the following examples, 2-Py-p-QMs were prepared by reacting a mixture of 2,6-disubstituted phenol (2,6-di-tert-butylphenol or 2,6-diisopropylphenol), 2-pyridinecarboxaldehyde with different substituents, toluene, piperidine, and acetic anhydride under reflux conditions; wherein, the chemical structural formulas of 2-pyridinecarboxaldehyde with different substituents are shown below:

[0029]

[0030] The following is a method for synthesizing 3-acylimidazo[1,5-a]pyridine from 2-Py-p-QMs, terminal alkynes, and TsN3:

[0031]

[0032] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers and then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding 3-acylimidazo[1,5-a]pyridine.

[0033] Example 1

[0034]

[0035] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl)(phenyl)methyl ketone (4a) in 87% yield.

[0036] 1 H NMR (501MHz, CDCl3): δ9.81 (d, J=7.3Hz, 1H), 8.44 (d, J=7.6Hz, 2H), 7.85 (d, J=8.8Hz, 1H), 7.62 (s, 2H), 7.47–7.33 (m, 3H), 7.15–7.08 (m, 1H), 6.92 (t, J=6.8Hz, 1H), 5.22 (s, 1H), 1.40 (s, 18H); 13 C NMR (100MHz, CDCl3): δ181.92, 153.94, 138.47, 136.51, 136.27, 133.90, 131.99, 131.15, 130. 97, 127.96, 127.38, 124.69, 124.52, 118.66, 116.44, 34.57, 30.38; HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 28 H 30 N2O2Na 449.2199, Found 449.2200; mp (melting point): 189.7-251.2℃.

[0037] Example 2

[0038]

[0039] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl)(4-fluorophenyl) methyl ketone (4b) in 82% yield.

[0040] 1 H NMR (400MHz, CDCl3): δ9.96 (d, J=7.1Hz, 1H), 8.74–8.67 (m, 2H), 8.03 (d, J=9.0Hz, 1H), 7.83–7.75 ( m, 2H), 7.26 (dt, J=28.2, 7.2Hz, 3H), 7.09 (t, J=6.9Hz, 1H), 5.42–5.37 (m, 1H), 1.62–1.52 (m, 18H); 13 C NMR (100MHz, CDCl3): δ166.56, 164.05, 154.00, 136.57, 136.33, 134.67, 133.74, 133.66, 131 .01, 129.41, 127.38, 125.21, 124.80, 124.48, 118.69, 116.54, 115.09, 114.88, 34.57, 30.37; 19 F NMR (376MHz, CDCl3): δ-107.35; HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 28 H 29 N2O2FNa 467.2105, Found 467.2101; mp: 215.0-218.6℃.

[0041] Example 3

[0042]

[0043] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl)(3-fluorophenyl) methyl ketone (4c) in 81% yield.

[0044] 1 H NMR (400MHz, CDCl3): δ9.98 (dd, J=7.2, 3.0Hz, 1H), 8.50–8.38 (m, 2H), 8.09–8.03 (m, 1H), 7.82 (d, J=3.1Hz, 2H), 7.53 ( dt, J=10.9, 6.6Hz, 1H), 7.33 (dd, J=11.3, 4.8Hz, 2H), 7.15–7.10 (m, 1H), 5.42 (d, J=3.0Hz, 1H), 1.59 (d, J=3.1Hz, 18H); 13 C NMR (100MHz, CDCl3): δ179.93, 163.63, 161.20, 154.07, 140.35, 136.57, 133.62, 131.24, 130. 26, 129.43, 127.44, 126.68, 125.14, 124.50, 118.99, 118.77, 118.32, 118.09, 116.79, 34.58. 19 F NMR (376MHz, CDCl3) δ-113.27; HRMS (ESI-FT) m / z: [M+Na] + Calcd forC 28 H 29 N2O2FNa 467.2105, Found 467.2101; mp: 178.6-185.3℃.

[0045] Example 4

[0046]

[0047] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. The mixture was diluted with saturated sodium chloride solution (5 ml), stirred, and separated into two layers. The layers were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (4-chlorophenyl)(1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl) methyl ketone (4d) in 78% yield.

[0048] 1 H NMR (400MHz, CDCl3): δ9.97 (d, J=7.1Hz, 1H), 8.62 (d, J=8.2Hz, 2H), 8.04 (d, J=9.0Hz, 1H), 7.79 (s , 2H), 7.52 (d, J=8.2Hz, 2H), 7.35–7.30 (m, 1H), 7.11 (t, J=6.9Hz, 1H), 5.40 (s, 1H), 1.57 (s, 18H); 13 C NMR (100MHz, CDCl3): δ154.04, 138.38, 136.77, 136.58, 132.58, 131.15, 128.23, 127 .42, 125.15, 124.96, 124.49, 118.72, 116.66, 34.57, 30.37; HRMS (ESI-FT) m / z: [M+H] + Calcd for C 28 H 29 N2O2ClH 461.1990, Found 461.1984; mp: 214.0-214.9°C.

[0049] Example 5

[0050]

[0051] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (3-chlorophenyl)(1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl) methyl ketone (4e) in 77% yield.

[0052] 1 H NMR (400MHz, CDCl3): δ9.97 (d, J=7.2Hz, 1H), 8.80 (s, 1H), 8.44 (d, J=7.8Hz, 1H), 8.06 (d, J=9.0Hz, 1H), 7.84 (s, 2H) , 7.57 (d, J=8.8Hz, 1H), 7.48 (t, J=7.9Hz, 1H), 7.38–7.27 (m, 1H), 7.12 (t, J=6.9Hz, 1H), 5.40 (s, 1H), 1.58 (s, 18H); 13 C NMR (100MHz, CDCl3): δ179.79, 154.05, 139.95, 136.57, 133.99, 133.55, 131.82, 131.64, 131.18, 129 .26, 128.90, 127.44, 125.15, 125.09, 124.41, 118.78, 116.77, 34.58, 30.37; HRMS (ESI-FT) m / z: [M+H] + Calcd for C 28 H 29 N2O2ClH 461.1990, Found 461.1984; mp: 185.6-190.1℃.

[0053] Example 6

[0054]

[0055] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (4-bromophenyl)(1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl) methyl ketone (4f) in 76% yield.

[0056] 1 H NMR (400MHz, CDCl3): δ9.97 (d, J=7.1Hz, 1H), 8.58–8.51 (m, 2H), 8.04 (d, J=9.0Hz, 1H), 7.79 (s, 2 H), 7.72–7.66 (m, 2H), 7.35–7.28 (m, 1H), 7.11 (td, J=7.0, 1.2Hz, 1H), 5.41 (s, 1H), 1.58 (s, 18H); 13 C NMR (100MHz, CDCl3): δ154.05, 137.21, 136.57, 136.53, 133.67, 132.73, 131.20, 127. 42, 127.13, 125.13, 125.01, 124.50, 118.72, 116.70, 30.38; HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 28 H 29 N2O2BrNa 527.1304, Found 527.1306; mp: 216.0-216.2℃.

[0057] Example 7

[0058]

[0059] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (3-bromophenyl)(1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl) methyl ketone (4 g), with a yield of 74%.

[0060] 1 H NMR (400MHz, CDCl3): δ9.97 (d, J=7.1Hz, 1H), 8.98 (s, 1H), 8.48 (d, J=7.8Hz, 1H), 8.07 (d, J=9.0Hz, 1H), 7.85 (s, 2H), 7 .73 (dd, J=7.9, 2.1Hz, 1H), 7.43 (t, J=7.9Hz, 1H), 7.35-7.28 (m, 1H), 7.12 (t, J=6.9Hz, 1H), 5.41 (s, 1H), 1.59 (s, 18H); 13 C NMR (100MHz, CDCl3): δ179.64, 154.06, 140.19, 136.59, 134.71, 134.60, 133.54, 131.17, 129.56, 129. 30, 127.45, 125.17, 125.09, 124.40, 122.05, 118.79, 116.78, 34.60, 30.40; HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 28 H 29 N2O2BrNa 527.1304, Found 527.1306; mp: 174.4-213.6℃.

[0061] Example 8

[0062]

[0063] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl)(4-nitrophenyl) methyl ketone (4 h), with a yield of 85%.

[0064] 1 H NMR (400MHz, CDCl3): δ10.00 (d, J=7.1Hz, 1H), 8.79–8.72 (m, 2H), 8.42–8.35 (m, 2H), 8.08 (d, J=8 .9Hz, 1H), 7.77 (s, 2H), 7.40 (t, J=7.7Hz, 1H), 7.19 (t, J=6.9Hz, 1H), 5.44 (s, 1H), 1.57 (s, 18H); 13 C NMR (100MHz, CDCl3) δ179.02, 154.29, 149.51, 143.79, 137.49, 136.67, 133.57, 131.98, 131.82, 1 27.55, 125.89, 124.75, 124.54, 123.04, 118.90, 117.35, 34.58, 30.35; HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 28 H 29 N3O4Na 494.2050, Found494.2053; mp: 255.7-262.9℃.

[0065] Example 9

[0066]

[0067] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl)(4-(trifluoromethyl)phenyl) ketone (4i), with a yield of 84%.

[0068] 1 H NMR (400MHz, CDCl3): δ10.00 (dd, J=7.3, 2.2Hz, 1H), 8.74–8.68 (m, 2H), 8.09–8.03 (m, 1H), 7.84– 7.76 (m, 4H), 7.37–7.29 (m, 1H), 7.15 (t, J=6.9Hz, 1H), 5.42 (d, J=2.2Hz, 1H), 1.60–1.55 (m, 18H); 13 C NMR (100MHz, CDCl3): δ180.21, 154.15, 141.50, 137.04, 136.59, 133.63, 131.51, 131 .34, 127.47, 125.41, 124.95, 124.91, 124.87, 124.55, 118.80, 117.01, 34.57, 30.35; 19 F NMR (376MHz, CDCl3): δ-62.83; HRMS (ESI-FT) m / z: [M+Na] + Calcdfor C 29 H 29 N2O2F3Na 517.2073, Found 517.2077; mp: 194.1-199.5℃.

[0069] Example 10

[0070]

[0071] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl)(4-(trifluoromethoxy)phenyl) ketone (4j), with a yield of 79%.

[0072] 1 H NMR (400MHz, CDCl3): δ9.98 (d, J=7.1Hz, 1H), 8.71 (d, J=8.8Hz, 2H), 8.05 (d, J=9.0Hz, 1H), 7.79 (s, 2H), 7.39 (d, J=8.4Hz, 2H), 7.32 (t, J=8.1Hz, 1H), 7.12 (t, J=6.9Hz, 1H), 5.43 (s, 1H), 1.58 (s, 18H); 13 C NMR (100MHz, CDCl3): δ179.94, 154.10, 151.90, 136.77, 136.68, 136.58, 133.62, 133 .04, 131.25, 127.42, 125.11, 125.07, 124.54, 119.89, 118.74, 116.79, 34.58, 30.36. 19 F NMR (376MHz, CDCl3): δ-57.43; HRMS: calcd.forC 26 H 30 FNO3[M+Na] + 446.2101, found 446.2100; mp: 159.2-204.6℃.

[0073] Example 11

[0074]

[0075] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding methyl 4-(1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridine-3-carbonyl)benzoate (4k), with a yield of 76%.

[0076] 1 H NMR (400MHz, CDCl3): δ9.99 (d, J=7.3Hz, 1H), 8.69–8.63 (m, 2H), 8.21 (dd, J=8.4, 2.3Hz, 2H), 8.05 (d, J=9.3Hz, 1H), 7.79 (d, J=2 .4Hz, 2H), 7.37–7.29 (m, 1H), 7.14 (dt, J=9.0, 4.5Hz, 1H), 5.42 (d, J=2.3Hz, 1H), 4.01 (d, J=2.3Hz, 3H), 1.57 (d, J=2.4Hz, 18H); 13 C NMR (100MHz, CDCl3): δ180.72, 166.85, 154.11, 142.25, 136.87, 136.58, 133.78, 132.61, 131.38, 130.99, 129.14, 127.47, 125.30, 125.04, 124.53, 118.77, 116.90, 52.41, 34.58, 30.37; HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 30 H 33 N2O4Na 507.2254, Found507.2255; mp: 208.2-262.6℃

[0077] Example 12

[0078]

[0079] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl)(4-methoxyphenyl) methyl ketone (4 l), with a yield of 75%.

[0080] 1 H NMR (400MHz, CDCl3): δ9.95 (d, J=7.2Hz, 1H), 8.72 (d, J=8.8Hz, 2H), 8.01 (d, J=9.0Hz, 1H), 7. 81(s, 2H), 7.28–7.20(m, 1H), 7.05(d, J=8.4Hz, 3H), 5.38(s, 1H), 3.95(s, 3H), 1.58(s, 18H); 13 C NMR: (100MHz, CDCl3) δ180.60, 162.94, 153.85, 136.49, 135.78, 134.01, 133.43, 131.20, 130.62, 127 .35, 125.47, 124.48, 124.27, 118.59, 116.12, 113.31, 55.49, 34.57, 30.39; HRMS (ESI-FT) m / z: [M+H] + Calcd for C 29 H 32 N2O3H 457.2485, Found457.2482; mp: 173.7-189.3℃.

[0081] Example 13

[0082]

[0083] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 x 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl)(3-methoxyphenyl) methyl ketone (4 m) in 79% yield.

[0084] 1 H NMR (400MHz, CDCl3): δ9.98 (d, J=7.1Hz, 1H), 8.24 (d, J=5.4Hz, 2H), 8.04 (d, J=9.0Hz, 1H), 7.80 (s, 2H), 7.46 (t, J=7 .8Hz, 1H), 7.30 (s, 1H), 7.17 (d, J=8.2Hz, 1H), 7.10 (d, J=7.1Hz, 1H), 5.39 (s, 1H), 4.02–3.90 (m, 3H), 1.57 (s, 18H); 13 C NMR (100MHz, CDCl3): δ181.45, 159.28, 153.93, 139.63, 136.51, 136.29, 133.91, 131.01, 128.97, 127.41, 125 .33, 124.76, 124.46, 123.85, 119.04, 118.69, 116.50, 115.26, 55.47, 34.56, 30.38; HRMS (ESI-FT) m / z: [M+H] + Calcd for C 29 H 32 N2O3H 457.2485, Found 457.2482; mp: 156.3-159.0℃.

[0085] Example 14

[0086]

[0087] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (4-(tert-butyl)phenyl)(1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl)methyl ketone (4n) in 68% yield.

[0088] 1 H NMR (400MHz, CDCl3): δ9.99 (d, J=7.1Hz, 1H), 8.59 (dt, J=8.6, 2.0Hz, 2H), 8.02 (d, J=8.9Hz, 1H), 7.80 (d, J=2.4Hz, 2H), 7.59 (dd, J=8.4, 2.0Hz, 2H), 7.32–7.22 (m, 1H), 7.07 (t, J=6.9Hz, 1H), 5.39 (d, J=2.8Hz, 1H), 1.59 (d, J=1.9Hz, 18H), 1.44 (d, J=1.7Hz, 9H); 13 C NMR (100MHz, CDCl3) δ181.71, 155.55, 153.90, 136.49, 136.16, 135.76, 134.03, 131.05, 130.85, 127.37 , 125.43, 125.01, 124.59, 124.47, 118.61, 116.29, 35.10, 34.58, 31.27, 30.41; HRMS (ESI-FT) m / z: [M+H] + Calcd for C 32 H 38 N2O2H 483.3006, Found483.3008; mp: 235.6-237.3℃.

[0089] Example 15

[0090]

[0091] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 x 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl)(p-tolyl) methyl ketone (4o) in 65% yield.

[0092] 1 H NMR (400MHz, CDCl3): δ9.97 (d, J=7.3Hz, 1H), 8.56 (d, J=8.3Hz, 2H), 8.02 (d, J=9.0Hz, 1H), 7.80 (s, 2H), 7.36 (d, J=8.2Hz, 2H), 7.29–7.24 (m, 1H), 7.07 (t, J=6.9Hz, 1H), 5.38 (s, 1H), 2.49 (s, 3H), 1.57 (s, 18H); 13 C NMR (100MHz, CDCl3): δ181.65, 153.87, 142.65, 136.48, 136.00, 135.78, 133.98, 131.28, 130.79, 128 .72, 127.36, 125.42, 124.50, 124.45, 118.61, 116.25, 34.56, 30.39, 21.71; HRMS (ESI-FT) m / z: [M+H] + Calcd forC 29 H 32 N2O2H441.2536, Found 441.2537; mp: 172.9-189.4℃.

[0093] Example 16

[0094]

[0095] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl)(m-tolyl) methyl ketone (4p), with a yield of 48%.

[0096] 1 H NMR (400MHz, CDCl3): δ9.98 (d, J=7.2Hz, 1H), 8.51 (s, 1H), 8.39 (d, J=6.7Hz, 1H), 8.05 (d, J=9.0Hz, 1H), 7.85 (s, 2 H), 7.45 (d, J=7.1Hz, 2H), 7.29 (dd, J=9.1, 6.5Hz, 1H), 7.11–7.06 (m, 1H), 5.40 (s, 1H), 2.53 (s, 3H), 1.59 (s, 18H); 13 C NMR (100MHz, CDCl3) δ182.10, 153.90, 138.43, 137.48, 136.47, 136.06, 133.91, 132.80, 131.90, 130.84, 128 .26, 127.93, 127.38, 125.38, 124.69, 124.42, 118.65, 116.42, 34.59, 30.39, 21.61; HRMS (ESI-FT) m / z: [M+H] + Calcd for C 29 H 32 N2O3H 441.2536, Found 441.2537; mp: 172.9-198.9℃.

[0097] Example 17

[0098]

[0099] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl)(4-ethylphenyl) methyl ketone (4q) in 53% yield.

[0100] 1 H NMR (400MHz, CDCl3): δ9.97 (dt, J=7.2, 1.1Hz, 1H), 8.59–8.55 (m, 2H), 8.01 (dt, J=9.0, 1.3Hz, 1H), 7.79 (s, 2H), 7.38 (d, J=8.3H z, 2H), 7.18–7.16 (m, 1H), 7.07 (td, J=6.9, 1.3Hz, 1H), 5.38 (s, 1H), 2.79 (q, J=7.6Hz, 2H), 1.57 (s, 18H), 1.34 (t, J=7.6Hz, 3H); 13 C NMR (100MHz, CDCl3) δ181.72, 153.88, 148.88, 144.64, 142.10, 136.56, 131.36, 130.26, 129.42, 127.66, 127.57, 127.36, 125.38, 124.53, 118.62, 116.31, 34.56, 30.38, 21.55, 15.41; HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 30 H 34 N2O3Na 477.2512, Found477.2514; mp: 152.8-167.5℃.

[0101] Example 18

[0102]

[0103] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridin-3-yl)(phenyl) methyl ketone (4r) in 84% yield.

[0104] 1 H NMR (400MHz, CDCl3): δ9.84 (s, 1H), 8.64–8.58 (m, 2H), 7.94 (d, J=9.1Hz, 1H), 7.80 (s, 2H), 7 .57(dt, J=14.7, 7.1Hz, 3H), 7.17(d, J=9.1Hz, 1H), 5.37(s, 1H), 2.48(s, 3H), 1.57(s, 18H); 13 C NMR (100MHz, CDCl3): δ181.72, 153.87, 138.63, 136.47, 136.18, 131.85, 131.12, 130.18, 128.00 , 127.92, 126.68, 125.45, 125.15, 124.41, 117.88, 34.56, 30.37, 18.71; HRMS (ESI-FT) m / z: [M+H] + Calcd for C 29 H 32 N2O2H 441.2536, Found441.2537; mp: 182.1-186.3℃.

[0105] Example 19

[0106]

[0107] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridin-3-yl)(4-fluorophenyl) methyl ketone (4s) in 79% yield.

[0108] 1 H NMR (400MHz, CDCl3): δ9.82 (s, 1H), 8.70 (td, J=5.9, 2.8Hz, 2H), 7.94 (dd, J=9.1, 2.4Hz, 1H), 7.79 (d, J=2.5Hz, 2H), 7.25–7.14 (m, 3H), 5.39 (d, J=2.2Hz, 1H), 2.48 (d, J=2.6Hz, 3H), 1.58 (d, J=2.6Hz, 18H); 13 C NMR (100MHz, CDCl3): δ179.94, 166.48, 163.97, 153.94, 136.53, 136.24, 134.83, 133.70, 133.61, 133 .38, 130.23, 128.11, 126.81, 125.33, 125.15, 124.38, 117.90, 115.03, 114.82, 34.56, 30.36, 18.69; 19 F NMR (376MHz, CDCl3) δ-107.62 (t, J=7.7Hz); HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 29 H 31 N2O2FNa 481.2261, Found 481.2268; mp: 153.4-251.3℃.

[0109] Example 20

[0110]

[0111] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 x 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridin-3-yl)(3-fluorophenyl) methyl ketone (4 t) in 78% yield.

[0112] 1 H NMR (400MHz, CDCl3): δ9.83 (s, 1H), 8.47–8.37 (m, 2H), 7.96 (dd, J=9.0, 2.3Hz, 1H), 7.81 (d, J=2.2Hz, 2H), 7.51 (td, J=5.9, 3 .1Hz, 1H), 7.32–7.26 (m, 1H), 7.20 (dd, J=9.1, 1.8Hz, 1H), 5.40 (d, J=2.2Hz, 1H), 2.50–2.48 (m, 3H), 1.57 (d, J=2.1Hz, 18H); 13 C NMR (100MHz, CDCl3): δ179.70, 163.61, 161.18, 154.01, 140.59, 136.52, 133.30, 130.43, 129.45, 129 .37, 128.42, 127.10, 126.66, 125.24, 124.39, 118.83, 118.62, 118.29, 117.98, 34.57, 30.35, 18.73; 19 F NMR (376MHz, CDCl3) δ-113.39; HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 29 H 31 N2O2FNa 481.2261, Found 481.2268; mp: 172.2-256.1℃.

[0113] Example 21

[0114]

[0115] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (4-chlorophenyl)(1-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridin-3-yl) methyl ketone (4 u) in 75% yield.

[0116] 1 H NMR (400MHz, CDCl3): δ9.82 (s, 1H), 8.61 (dd, J=8.7, 2.5Hz, 2H), 7.94 (d, J=9.1Hz, 1H), 7.79 (d, J=2.0Hz, 2H), 7.55–7.49 (m, 2H), 7.18 (d, J=9.0Hz, 1H), 5.40 (d, J=1.8Hz, 1H), 2.48 (s, 3H), 1.58 (d, J=2.2Hz, 18H); 13 C NMR (100MHz, CDCl3): δ179.98, 153.98, 138.22, 136.96, 136.55, 136.42, 133.38, 132.56, 130.36, 128 .28, 128.18, 126.96, 125.28, 125.21, 124.40, 117.94, 34.57, 30.38, 18.71; HRMS (ESI-FT) m / z: [M+H] + Calcd forC 29 H 31 N2O2ClH475.2146, Found 475.2146; mp: 245.4-250.2℃.

[0117] Example 22

[0118]

[0119] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (3-chlorophenyl)(1-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridin-3-yl) methyl ketone (4 v), with a yield of 73%.

[0120] 1 H NMR (400MHz, CDCl3): δ9.82 (s, 1H), 8.80 (s, 1H), 8.43 (d, J = 7.7Hz, 1H), 7.96 (d, J = 9.0Hz, 1H), 7.83(s, 2H), 7.60–7.43(m, 2H), 7.20(d, J=9.3Hz, 1H), 5.39(s, 1H), 2.49(s, 3H), 1.57(s, 18H); 13 C NMR (100MHz, CDCl3): δ179.55, 154.00, 140.14, 136.54, 133.94, 133.24, 131.64, 130.38, 130.24, 129.41, 129 .22, 128.85, 128.45, 127.66, 127.09, 125.26, 124.31, 118.00, 34.58, 30.36, 18.71; HRMS (ESI-FT) m / z: [M+H] + Calcd forC 29 H 31 N2O2ClH475.2146, Found 475.2146; mp: 216.0-210.6℃.

[0121] Example 23

[0122]

[0123] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (4-bromophenyl)(1-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridin-3-yl) methyl ketone (4 w), with a yield of 74%.

[0124] 1 H NMR (400MHz, CDCl3): δ9.82 (s, 1H), 8.58–8.50 (m, 2H), 7.94 (d, J=9.1Hz, 1H), 7. 80–7.64(m, 4H), 7.18(d, J=9.0Hz, 1H), 5.39(s, 1H), 2.48(s, 3H), 1.57(s, 18H); 13 C NMR (100MHz, CDCl3): δ180.08, 153.98, 137.39, 136.54, 136.45, 133.36, 132.71, 131.15, 130 .38, 128.30, 126.98, 125.21, 124.39, 117.94, 34.56, 30.37, 18.71; HRMS (ESI-FT) m / z: [M+H] + Calcd for C 29 H 31 N2O2BrH 519.1641, Found 519.1647; mp: 247.0-248.9℃.

[0125]

[0126] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (3-bromophenyl)(1-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridin-3-yl) methyl ketone (4x) in 73% yield.

[0127] 1 H NMR (400MHz, CDCl3): δ9.82 (s, 1H), 9.00–8.95 (m, 1H), 8.45 (dd, J=7.9, 2.0Hz, 1H), 7.97 (dd, J=9.0, 2.1Hz, 1H), 7.84 (d, J=2.0Hz, 2H), 7.75 –7.68 (m, 1H), 7.42 (td, J=7.9, 2.1Hz, 1H), 7.20 (dt, J=9.2, 1.7Hz, 1H), 5.39 (d, J=2.1Hz, 1H), 2.49 (d, J=2.1Hz, 3H), 1.58 (d, J=2.1Hz, 18H); 13 C NMR (100MHz, CDCl3): δ179.41, 153.99, 140.37, 136.54, 136.47, 134.60, 134.57, 130.37, 129.53, 129.23 , 128.46, 127.10, 125.26, 125.20, 124.29, 122.00, 118.00, 34.58, 30.38, 18.71; HRMS (ESI-FT) m / z: [M+H] + Calcd for C 29 H 31 N2O2BrH519.1641, Found 519.1647; mp: 205.1-209.0℃.

[0128] Example 25

[0129]

[0130] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridin-3-yl)(4-nitrophenyl) methyl ketone (4y) in 79% yield.

[0131] 1H NMR (400MHz, CDCl3): δ9.86–9.84 (m, 1H), 8.74 (d, J=8.9Hz, 2H), 8.39–8.35 (m, 2H), 7.98 ( d, J=9.1Hz, 1H), 7.76 (s, 2H), 7.30–7.25 (m, 1H), 5.43 (s, 1H), 2.52 (s, 3H), 1.56 (s, 18H); 13 C NMR (100MHz, CDCl3) δ178.72, 154.23, 149.41, 144.01, 137.41, 136.63, 133.27, 131.94, 130.99, 129. 14, 127.78, 125.41, 124.87, 124.43, 122.99, 118.10, 34.57, 30.34, 18.76; HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 29 H 31 N3O4Na 508.2207, Found508.2215; mp: 262.0-263.4℃.

[0132] Example 26

[0133]

[0134] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridin-3-yl)(4-(trifluoromethyl)phenyl) ketone (4z) in 82% yield.

[0135] 1 H NMR (400MHz, CDCl3): δ9.86–9.84 (m, 1H), 8.69 (d, J = 8.1Hz, 2H), 7.96 (d, J = 9.1Hz, 1H), 7.79 (d , J=16.7Hz, 4H), 7.23 (dd, J=9.1, 1.5Hz, 1H), 5.41 (s, 1H), 2.50 (d, J=1.2Hz, 3H), 1.57 (s, 18H); 13C NMR (100MHz, CDCl3): δ179.96, 154.09, 141.69, 136.96, 136.56, 133.32, 131.30, 130.69 , 128.68, 127.36, 125.29, 125.08, 124.86, 124.82, 124.44, 118.01, 34.56, 30.34, 18.74; 19 F NMR (376MHz, CDCl3): δ-62.83; HRMS (ESI-FT) m / z: [M+H] + Calcd for C 30 H 31 N2O2F3H 509.2410, Found 509.2409; mp: 192.3-195.7℃.

[0136] Example 27

[0137]

[0138] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridin-3-yl)(4-(trifluoromethoxy)phenyl) ketone (4aa) in 77% yield.

[0139] 1 H NMR (400MHz, CDCl3): δ9.83 (d, J=1.8Hz, 1H), 8.70-8.67 (m, 2H), 7.94 (d, J=9.1Hz, 1H), 7.77 (s , 2H), 7.39–7.35 (m, 2H), 7.20 (dd, J=9.2, 1.5Hz, 1H), 5.40 (s, 1H), 2.49 (s, 3H), 1.56 (s, 18H); 13C NMR (100MHz, CDCl3): δ179.75, 154.02, 151.81, 136.96, 136.54, 133.31, 132.98, 130 .45, 128.39, 127.10, 125.22, 125.18, 124.42, 119.86, 117.96, 34.56, 30.34, 18.73; 19 F NMR (376MHz, CDCl3): δ-57.46; HRMS (ESI-FT) m / z: [M+H] + Calcd forC 30 H 31 N2O3F3H 525.2360, Found 525.2361; mp: 194.4-202.0℃.

[0140] Example 28

[0141]

[0142] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding methyl 4-(1-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridine-3-carbonyl)benzoate (4ab) in 72% yield.

[0143] 1 H NMR (400MHz, CDCl3): δ9.84 (d, J=1.9Hz, 1H), 8.64 (d, J=8.1Hz, 2H), 8.20 (d, J=8.3Hz, 2H), 7.95 (d, J=9. 1Hz, 1H), 7.78 (s, 2H), 7.21 (dd, J=9.1, 1.5Hz, 1H), 5.40 (s, 1H), 4.00 (s, 3H), 2.49 (s, 3H), 1.56 (s, 18H); 13C NMR (100MHz, CDCl3): δ180.47, 166.87, 154.04, 142.44, 136.78, 136.53, 133.46, 132.48, 130.95, 130.57 , 129.10, 128.57, 127.22, 125.28, 124.42, 117.98, 52.39, 34.56, 30.36, 18.74; HRMS (ESI-FT) m / z: [M+Na] + Calcd forC 31 H 34 N2O4Na521.2411, Found 521.2409; mp: 246.5-246.8℃.

[0144] Example 29

[0145]

[0146] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. The mixture was diluted with saturated sodium chloride solution (5 ml), stirred, and separated into two layers. The layers were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridin-3-yl)(4-methoxyphenyl) ketone (4ac) in 73% yield.

[0147] 1 H NMR (400MHz, CDCl3): δ9.81 (s, 1H), 8.72 (s, 2H), 7.47 (dd, J=311.0, 38.1Hz, 6H), 5.37 (s, 1H), 3.95 (s, 3H), 2.46 (s, 3H), 1.57 (s, 18H); 13 C NMR (100MHz, CDCl3): δ136.50, 133.43, 129.88, 127.65, 126.33, 125.64, 125.12 , 124.42, 117.86, 113.32, 55.52, 34.60, 30.43, 18.74; HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 30 H 34N2O4Na 493.2461, Found493.2467; mp: 195.3-216.6℃.

[0148] Example 30

[0149]

[0150] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridin-3-yl)(3-methoxyphenyl) ketone (4ad) in 70% yield.

[0151] 1 H NMR (400MHz, CDCl3): δ9.84 (s, 1H), 8.23 ​​(dt, J=4.7, 2.2Hz, 2H), 7.94 (d, J=9.1Hz, 1H), 7.79 (d, J=1.9Hz, 2H), 7.45 (td, J=8. 2, 1.9Hz, 1H), 7.16 (dd, J=8.1, 3.0Hz, 2H), 5.37 (d, J=1.8Hz, 1H), 3.96 (d, J=1.9Hz, 3H), 2.48 (s, 3H), 1.56 (d, J=2.0Hz, 18H); 13 C NMR (100MHz, CDCl3): δ181.22, 159.25, 153.87, 139.80, 136.47, 136.21, 133.59, 130.22, 128.93, 128.06, 126.75 , 125.45, 125.20, 124.36, 123.81, 118.91, 117.91, 115.25, 55.46, 34.55, 30.37, 18.71; HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 30 H 34 N2O4Na493.2461, Found 493.2467; mp: 202.3-207.7℃.

[0152] Example 31

[0153]

[0154] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (4-(tert-butyl)phenyl)(1-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridin-3-yl) ketone (4ae) in 66% yield.

[0155] 1 H NMR (400MHz, CDCl3): δ9.84 (s, 1H), 8.57 (d, J=8.1Hz, 2H), 7.91 (d, J=9.1Hz, 1H), 7.78 (d, J=2.3Hz, 2H), 7. 57 (d, J=8.2Hz, 2H), 7.14 (d, J=9.1Hz, 1H), 5.36 (s, 1H), 2.47 (s, 3H), 1.57 (s, 18H), 1.42 (d, J=2.4Hz, 9H). 13 C NMR (100MHz, CDCl3): δ181.53, 155.38, 153.83, 136.44, 133.70, 131.00, 130.24, 130.06, 129.41, 127.79, 12 6.50, 125.53, 125.12, 124.96, 124.47, 117.84, 35.07, 34.55, 31.26, 30.39, 18.69; HRMS (ESI-FT) m / z: [M+H] + Calcd for C 30 H 31 N2O2F3H 509.2410, Found 509.2409; mp: 150.1-196.3℃.

[0156] Example 32

[0157]

[0158] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methylimidazo[1,5-a]pyridin-3-yl)(p-tolyl) methyl ketone (4af), with a yield of 64%.

[0159] 1 H NMR (400MHz, CDCl3): δ9.83 (s, 1H), 8.56 (d, J=8.2Hz, 2H), 7.93 (d, J=9.0Hz, 1H), 7.80 (s, 2H), 7.36 (d, J=8.3Hz, 2H), 7.14 (d, J=9.2Hz, 1H), 5.37 (s, 1H), 2.48 (d, J=8.8Hz, 6H), 1.58 (s, 18H); 13 C NMR (100MHz, CDCl3): δ181.45, 153.81, 142.49, 136.45, 135.95, 135.91, 133.67, 131.27, 130.01, 128.68, 1 27.78, 126.46, 125.55, 125.11, 124.40, 117.84, 34.56, 30.39, 21.71, 18.70, 1.09; HRMS (ESI-FT) m / z: [M+H] + Calcd for C 30 H 34 N2O2H455.2693, Found 455.2693; mp: 211.9-219.4℃.

[0160] Example 33

[0161]

[0162] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding cyclopropyl (1-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[1,5-a]pyridin-3-yl) methyl ketone (4 ag), with a yield of 61%.

[0163] 1 H NMR (400MHz, CDCl3): δ9.72 (dt, J=7.2, 1.2Hz, 1H), 7.95 (dt, J=9.1, 1.3Hz, 1H), 7.75 (s, 2H), 7.19 (ddd, J=9.0, 6.6, 1.1Hz, 1H), 6 .99 (td, J=6.9, 1.2Hz, 1H), 5.37 (s, 1H), 3.58 (tt, J=7.9, 4.7Hz, 1H), 1.56 (s, 18H), 1.32–1.28 (m, 2H), 1.13 (dt, J=8.1, 3.4Hz, 2H; 13 C NMR (100MHz, CDCl3): δ190.75, 153.89, 136.49, 135.96, 134.27, 130.79, 126.66, 125.27 , 124.52, 123.86, 118.55, 116.14, 34.58, 30.40, 17.78, 11.49; HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 25 H 30 N2O2Na 413.2199, Found 413.2205; mp: 192.1-210.0℃.

[0164] Example 34

[0165]

[0166] In a dry 10 ml flask, 2-Py-p-QMs (0.3 mmol), terminal alkyne (0.5 mmol), TsN3 (0.5 mmol), triethylamine (1 mmol), CuI (0.05 mmol), and acetonitrile (3 ml) were added sequentially. The mixture was stirred at RT until the reaction was complete. Saturated sodium chloride solution (5 ml) was added for dilution, and the mixture was stirred. The mixture separated into two layers, which were then extracted with CH2Cl2 (3 × 15 ml). The crude product was separated by column chromatography to obtain the corresponding (1-(4-hydroxy-3,5-diisopropylphenyl)imidazo[1,5-a]pyridin-3-yl)(phenyl)methyl ketone (4ah) in 85% yield.

[0167] 1 H NMR (400MHz, CDCl3): δ9.98 (d, J=7.1Hz, 1H), 8.65–8.56 (m, 2H), 8.02 (d, J=9.0Hz, 1H), 7.68–7.53 (m, 4H), 7. 34–7.26 (m, 2H), 7.14–7.05 (m, 1H), 5.02 (d, J=4.3Hz, 1H), 3.29 (hept, J=6.9Hz, 2H), 1.40 (d, J=6.8Hz, 12H); 13 C NMR (100MHz, CDCl3): δ138.44, 136.04, 134.27, 133.90, 132.02, 131.14, 128.00, 127 .36, 126.46, 124.73, 123.11, 118.67, 116.46, 27.49, 22.84; HRMS (ESI-FT) m / z: [M+H] + Calcd for C 26 H 26 N2O2H 399.2067, Found399.2064; mp: 152.5-158.4℃.

Claims

1. A method for synthesizing 3-acylimidazo[1,5-a]pyridine compounds, characterized in that, Includes the following steps: Step 1): Add the starting material 2-pyridyl-p-methylenebenzoquinone compound 2-Py- p -QMs, terminal alkynes, azide compound TsN3, catalyst cuprous iodide, organic solvent A and base, reacted under stirring at room temperature and O2 atmosphere; Step 2): After the reaction is complete, add saturated sodium chloride solution to dilute the reaction mixture, then add organic solvent B for extraction and separation, dry the organic phase, concentrate, and perform column chromatography to separate and purify to obtain the target product 3-acylimidazo[1,5-a]pyridine compound; The reaction equation is shown in Equation I: In the above formula I, R 1 H or methyl; R 2 It is tert-butyl or isopropyl; R 3 It is cyclopropyl, phenyl, or substituted phenyl, wherein the substituted phenyl is a phenyl with a substituent at the ortho or para position, and the substituent is methyl, methoxy, tert-butyl, ethyl, nitro, fluorine, chlorine, bromine, -CF3, -OCF3, or COOMe.

2. The method for synthesizing 3-acylimidazo[1,5-a]pyridine compounds as described in claim 1, characterized in that, The raw material compound 2-Py- in step 1) p The preparation method of -QMs includes: mixing 2,6-disubstituted phenol, 2-pyridinecarboxaldehyde with different substituents, toluene, piperidine, and acetic anhydride, and reacting them under reflux conditions to prepare 2-Py- p -QMs; the 2,6-disubstituted phenol is 2,6-di-tert-butylphenol or 2,6-diisopropylphenol; the chemical structural formulas of the 2-pyridinecarboxaldehyde with different substituents are shown in Formula II: ； In Equation II above, R 1 It is H or methyl.

3. The method for synthesizing 3-acylimidazo[1,5-a]pyridine compounds as described in claim 1, characterized in that, The organic solvent A in step 1) is at least one of tetrahydrofuran, chloroform, acetonitrile, dichloromethane, and 1,4-dioxane.

4. The method for synthesizing 3-acylimidazo[1,5-a]pyridine compounds as described in claim 1, characterized in that, The base in step 1) is at least one of potassium carbonate, triethylamine, cesium carbonate, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicycloundec-7-ene, and pyridine.

5. The method for synthesizing 3-acylimidazo[1,5-a]pyridine compounds as described in claim 1, characterized in that, The 2-Py- in step 1) p The molar ratio of -QMs, terminal alkynes, TsN3, cuprous iodide, and base is 0.6:1:1:0.1:

2.

6. The method for synthesizing 3-acylimidazo[1,5-a]pyridine compounds as described in claim 1, characterized in that, The organic solvent B in step 1) is a chlorinated alkane solvent.

7. The method for synthesizing 3-acylimidazo[1,5-a]pyridine compounds as described in claim 6, characterized in that, The chloroalkane solvent is at least one of dichloromethane, chloroform, and 2,6-dichloroethane.

8. The method for synthesizing 3-acylimidazo[1,5-a]pyridine compounds as described in claim 1, characterized in that, The eluent used in the column chromatography separation in step 2) is a mixture of petroleum ether and ethyl acetate.

9. The method for synthesizing 3-acylimidazo[1,5-a]pyridine compounds as described in claim 8, characterized in that, The volume ratio of petroleum ether to ethyl acetate in the mixture is 20-40:1.

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