A method for preparing an imidazopyridine derivative

Abstract

The present application discloses a method for preparing an imidazopyridine derivative. The target product is obtained by reacting a 2-aminopyridine derivative, a benzyl alcohol derivative, and nitromethane as reactants, 1,4-dioxane as a solvent, copper(I) iodide as a catalyst, and tert-butyl hydroperoxide as an oxidant. The reaction raw materials and solvents involved in the preparation method of the present application are all commercially available products with low prices; the reaction conditions are simple and mild, the yield is good, the atom utilization rate is high, it has the characteristics of green chemistry, and conforms to the concept of sustainable development.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthetic chemistry, and particularly relates to a method for preparing 3-nitroimidazo[1.2-a]pyridine derivatives. Background Art

[0002] 3-Nitroimidazo[1.2-a]pyridine derivatives are a class of compounds with excellent biological activities and have wide applications in the biomedical field. The existing methods for preparing 3-nitroimidazo[1.2-a]pyridine derivatives mainly include the following two categories:

[0003] One, the reaction of 2-aminopyridine and nitrovinyl, and the chemical reaction formula of this method is shown as formula (1).

[0004]

[0005] The disadvantage of this method is that commercially available nitrovinyl compounds are few, and they need to be prepared in advance, and the economic benefits are not high.

[0006] Method two, 2-aminopyridine, aldehyde and nitromethane participate in the reaction under the action of a copper catalyst or an oxidant, and the chemical reaction formula of this method is shown as formula (2).

[0007]

[0008] Although this method does not require pre-functionalization of the reactants, aromatic aldehyde compounds are unstable and easily oxidized. More importantly, they are more expensive than the corresponding alcohol compounds commercially available, and at the same time, the types of aldehyde compounds are fewer than those of the corresponding alcohol compounds, which affects the scope of application of the substrates and generally reduces the synthetic value of the reaction. Summary of the Invention

[0009] Object of the Invention: The object of the present invention is to provide a simple 3-nitroimidazo[1.2-a]pyridine derivative with easily available raw materials and a preparation method thereof. This preparation method can greatly improve the atom economy and step economy of the reaction, is beneficial to studying the pharmacological activities of such compounds, and is beneficial to environmental protection.

[0010] Technical Solution: The present invention provides a method for preparing 3-nitroimidazo[1.2-a]pyridine derivatives, which is characterized in that the preparation method includes the following steps:

[0011]

[0012] Step (1) Add a 2-aminopyridine structure as shown in formula (1), a benzyl alcohol structure as shown in formula (2), nitromethane, cuprous iodide, tert-butyl hydroperoxide and a reaction solvent into a reaction tube;

[0013] Step (2): Add 1,4-dioxane again, seal the tube for reaction, and obtain the product mixture through one-step synthesis;

[0014] Step (3): After the reaction is completed, extract and filter the product mixture obtained in step (2), and concentrate and separate the obtained filtrate to obtain the 3-nitroimidazo[1,2-a]pyridine derivative of structural formula (3);

[0015] Among them, R1 is selected from H, halogen, and C1-C6 alkyl; R2 is selected from C6-C12 substituted or unsubstituted aryl. Description of the Drawings

[0016] Figure 1 It is the 1H NMR characterization result of the compound prepared in Example 1 of this application;

[0017] Figure 2 It is the 13C NMR characterization result of the compound prepared in Example 1 of this application;

[0018] Figure 3 It is the 1H NMR characterization result of the compound prepared in Example 2 of this application;

[0019] Figure 4 It is the 13C NMR characterization result of the compound prepared in Example 2 of this application;

[0020] Figure 5 It is the 1H NMR characterization result of the compound prepared in Example 3 of this application;

[0021] Figure 6 It is the 13C NMR characterization result of the compound prepared in Example 3 of this application;

[0022] Figure 7 It is the 1H NMR characterization result of the compound prepared in Example 4 of this application;

[0023] Figure 8 It is the 13C NMR characterization result of the compound prepared in Example 4 of this application;

[0024] Figure 9 It is the 1H NMR characterization result of the compound prepared in Example 5 of this application;

[0025] Figure 10 It is the 13C NMR characterization result of the compound prepared in Example 5 of this application;

[0026] Figure 11 It is the 1H NMR characterization result of the compound prepared in Example 6 of this application;

[0027] Figure 12 It is the 13C NMR characterization result of the compound prepared in Example 6 of this application;

[0028] Figure 13 It is the 1H NMR characterization result of the compound prepared in Example 7 of this application;

[0029] Figure 14 This is the carbon spectrum characterization result of the compound prepared in Example 7 of this application;

[0030] Figure 15 This is the hydrogen spectrum characterization result of the compound prepared in Example 8 of this application;

[0031] Figure 16 This is the carbon spectrum characterization result of the compound prepared in Example 8 of this application;

[0032] Beneficial effects:

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] 1. One of the reaction raw materials of the present invention is an aromatic alcohol compound. Aromatic alcohol is an upstream product of aromatic aldehyde. Enabling aromatic alcohol to directly participate in the reaction increases the reaction difficulty and makes the reaction more valuable for theoretical research.

[0035] 2. Aromatic alcohol is more stable. Most importantly, it is cheaper than the corresponding aromatic aldehyde and there are also more varieties. In summary, the present invention greatly improves the atomic economy and step economy of the reaction, is beneficial to environmental protection, and conforms to the concepts of green chemistry and "dual carbon".

[0036] 3. The 3-nitroimidazo[1.2-a]pyridine derivative prepared by the present invention has excellent biological activities and can be used for the treatment of insomnia, leprosy, heart failure, etc. Specific embodiments

[0037] The following further clarifies the preparation method of the 3-nitroimidazo[1.2-a]pyridine derivative involved in the present invention through specific examples, but does not limit the content of the present invention.

[0038] One embodiment of this application provides a preparation method of a 3-nitroimidazo[1.2-a]pyridine derivative, characterized in that the preparation method includes the following steps:

[0039]

[0040] Step (1) Add a 2-aminopyridine structure as shown in formula (1) and a benzyl alcohol structure

[0041] as shown in formula (2), nitromethane, copper(I) iodide, tert-butyl hydroperoxide, and a reaction solvent into a reaction tube; Step (2) Then add 1,4-dioxane, seal the tube and react to synthesize a product mixture in one step;

[0042] Step (3) After the reaction is completed, extract and filter the product mixture obtained in step (2), and the obtained filtrate is

[0043] The 3-nitroimidazo[1,2-a]pyridine derivative represented by structural formula (3) is obtained by concentration and separation;

[0044] Among them, R1 is selected from H, halogen, and C1-C6 alkyl; R2 is selected from C6-C12 substituted or unsubstituted aryl.

[0045] In one embodiment, the chemical structure of the 2-aminopyridine is any one of the following structural formulas:

[0046]

[0047] In one embodiment, the chemical structure of the benzyl alcohol is any one of the following structural formulas:

[0048]

[0049] In one embodiment, the structural formula of the 3-nitroimidazo[1,2-a]pyridine derivative is:

[0050]

[0051] In one embodiment, the reaction conditions shown in formula 1 are to react at 80 °C for 6 hours, and the solvent used in the reaction is 1,4-dioxane.

[0052] In one embodiment, the molar ratio of the compound (1), compound (2), and nitromethane added in the reaction shown in formula 1 is 1:1:1.

[0053] In one embodiment, the molar ratio of the compound (1) to cuprous iodide added in the reaction shown in formula 1 is 1:0.1.

[0054] In one embodiment, the molar ratio of the compound (1) to tert-butyl hydroperoxide added in the reaction shown in formula 1 is 1:3.

[0055] In one embodiment, this method further includes the step of separating and purifying the product after the reaction ends.

[0056] In one embodiment, in step (3), the obtained crude product is separated by column chromatography to obtain a 3-nitroimidazo[1,2-a]pyridine derivative in the form of a yellow solid or oil; the yield of the 3-nitroimidazo[1,2-a]pyridine derivative product is 62%-85%.

[0057] Example 1

[0058]

[0059] Synthetic method of 3a: Add 2-aminopyridine (0.4 mmol), benzyl alcohol (0.4 mmol), and nitromethane (0.4 mmol) into a reaction tube, add 2 mL of 1,4-dioxane, and then add 0.04 mmol of copper(I) iodide and 1.2 mmol of tert-butyl hydroperoxide respectively. After thorough mixing, assemble the reaction apparatus and react at 80 °C for 6 h. After the reaction is complete, extract and filter, then concentrate the filtrate by rotary evaporation, and separate by silica gel column chromatography to obtain a yellow solid. Yield: 74.5 mg, yield rate: 78%. Mp: 171 - 173 °C. The characterization results are shown in Figure 1 and Figure 2 。 1 1H NMR (400 MHz, CDCl3) δ: 9.53 (d, J = 7.2 Hz, 1H), 7.93 - 7.87 (m, 3H), 7.68 (t, J = 8.0 Hz, 1H), 7.53 - 7.51 (m, 3H), 7.30 (td, J = 7.2, 0.8 Hz, 1H). 13 13C NMR (100 MHz, CDCl3) δ: 150.3, 145.2, 131.9, 130.9, 130.3, 128.3, 128.2, 118.4, 116.5. HRMS (ESI) m / z calcd for C 13 H 10 N3O2 [M + H] + 240.0773, found 240.0770.

[0060] Example 2

[0061]

[0062] Synthetic method of 3b: Add 2-amino-4-methylpyridine (0.4 mmol), benzyl alcohol (0.4 mmol), and nitromethane (0.4 mmol) into a reaction tube, add 2 mL of 1,4-dioxane, and then add 0.04 mmol of copper(I) iodide and 1.2 mmol of tert-butyl hydroperoxide respectively. After thorough mixing, assemble the reaction apparatus and react at 80 °C for 6 h. After the reaction is complete, extract and filter, then concentrate the filtrate by rotary evaporation, and separate by silica gel column chromatography to obtain a yellow solid. Yield: 75.9 mg, yield rate: 75%. Mp: 168 - 169 °C. The characterization results are shown in Figure 3 and Figure 4 。 11H NMR (400 MHz, CDCl3) δ: 9.38 (d, J = 6.9 Hz, 1H), 7.92 - 7.89 (m, 2H), 7.52 - 7.48 (m, 3H), 7.45 (d, J = 7.1 Hz, 1H), 7.18 (t, J = 7.1 Hz, 1H), 2.73 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 149.8, 145.2, 132.2, 130.1, 130.0, 129.9, 128.6, 128.1, 125.9, 116.5, 16.6. HRMS (ESI) m / z calcd for C 14 H 12 N3O2 [M + H]+ 254.0930, found, 254.0922.

[0063] Example 3

[0064]

[0065] Synthesis method of 3c: Add 2 - aminopyridine - 5 - methyl (0.4 mmol), benzyl alcohol (0.4 mmol), nitromethane (0.4 mmol) into a reaction tube, add 2 mL of 1,4 - dioxane, then add 0.04 mmol of cuprous iodide and 1.2 mmol of tert - butyl hydroperoxide respectively. After mixing well, assemble the reaction apparatus and react at 80 °C for 6 h. After the reaction is complete, extract and filter, then concentrate the filtrate by rotary evaporation, and separate by silica gel column chromatography to obtain a yellow solid. Yield: 68.6 mg, yield: 68%. Mp: 166 - 167 °C. The characterization results are shown in Figure 5 and Figure 6 . 1 1H NMR (400 MHz, CDCl3) δ: 9.32 (s, 1H), 7.90 - 7.87 (m, 2H), 7.73 (d, J = 9.0 Hz, 1H), 7.51 - 7.48 (m, 4H), 2.51 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 150.1, 144.1, 133.7, 132.0, 130.0, 129.9, 128.1, 126.9, 126.1, 117.5, 18.7. HRMS (ESI) m / z calcd for C 14 H 12 N3O2 [M + H] + 254.0930, found, 254.0936.

[0066] Example 4

[0067]

[0068] Synthetic method of 3d: Add 2-amino-5-methylpyridine (0.4 mmol), benzyl alcohol (0.4 mmol), and nitromethane (0.4 mmol) into a reaction tube. Add 2 mL of 1,4-dioxane, and then add 0.04 mmol of copper(I) iodide and 1.2 mmol of tert-butyl hydroperoxide respectively. After thorough mixing, assemble the reaction apparatus and react at 80 °C for 6 h. After the reaction is complete, extract and filter, then concentrate the filtrate by rotary evaporation, and separate it by silica gel column chromatography to obtain a yellow liquid. Yield: 71 mg, yield rate: 70%. The characterization results are shown in Figure 7 and Figure 8 。 1 1H NMR (400 MHz, CDCl3) δ: 8.00 (dd, J = 8.3, 1.2 Hz, 2H), 7.76 (s, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.15 (dd, J = 9.1, 6.9 Hz, 1H), 6.63 (d, J = 6.8 Hz, 1H), 2.62 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 146.2, 145.8, 134.3, 133.9, 128.7, 127.9, 126.1, 124.9, 114.9, 111.6, 105.3, 18.8. HRMS (ESI) m / z calcd for C 14 H 12 N3O2 [M + H] + 254.0930, found, 254.0928.

[0069] Example 5

[0070]

[0071] Synthetic method of 3e: Add 2-aminopyridine (0.4 mmol), 4-chlorobenzyl alcohol (0.4 mmol), and nitromethane (0.4 mmol) into a reaction tube. Add 2 mL of 1,4-dioxane, and then add 0.04 mmol of copper(I) iodide and 1.2 mmol of tert-butyl hydroperoxide respectively. After thorough mixing, assemble the reaction apparatus and react at 80 °C for 6 h. After the reaction is complete, extract and filter, then concentrate the filtrate by rotary evaporation, and separate it by silica gel column chromatography to obtain a yellow solid. Yield: 87.3 mg, yield rate: 80%, Mp: 184 - 185 °C. The characterization results are shown in Figure 9 and Figure 10 。 11H NMR (400 MHz, CDCl3) δ: 9.52 (d, J = 7.0 Hz, 1H), 7.92 - 7.81 (m, 3H), 7.73 - 7.61 (m, 1H), 7.49 (d, J = 8.6 Hz, 2H), 7.30 (td, J = 7.0, 1.2 Hz, 1H). 13 13C NMR (100 MHz, CDCl3) δ 149.0, 145.1, 136.5, 131.5, 131.1, 130.3, 128.5, 128.2, 118.4, 116.7. HRMS (ESI) m / z calcd for C 13 9H9ClN3O2 [M+H] + 274.0383, found, 274.0378.

[0072] Example 6

[0073]

[0074] Synthesis method of 3f: Add 2-aminopyridine (0.4 mmol), 4-nitrobenzyl alcohol (0.4 mmol), and nitromethane (0.4 mmol) into a reaction tube. Add 2 mL of 1,4-dioxane, and then add 0.04 mmol of copper(I) iodide and 1.2 mmol of tert-butyl hydroperoxide respectively. After thorough mixing, assemble the reaction apparatus and react at 80 °C for 6 h. After the reaction is complete, extract and filter, then concentrate the filtrate by rotary evaporation, and separate by silica gel column chromatography to obtain a yellow solid. Yield: 70.5 mg, yield: 62%, Mp: 216 - 218 °C. The characterization results are shown in Figure 11 and Figure 12 . 1 1H NMR (400 MHz, CDCl3) δ: 9.53 (d, J = 7.0 Hz, 1H), 8.36 (d, J = 8.9 Hz, 2H), 8.09 (d, J = 8.9 Hz, 2H), 7.89 (d, J = 8.9 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.36 (td, J = 7.0, 1.1 Hz, 1H). 13 13C NMR (100 MHz, CDCl3) δ 148.7, 147.4, 145.2, 138.2, 131.4, 131.3, 128.1, 123.3, 118.7, 117.2. HRMS (ESI) m / z calcd for C 13 9H9N4O4 [M+H] + 285.0624, found, 285.0621

[0075] Example 7

[0076]

[0077] Synthesis method of 3g: Add 2-aminopyridine (0.4 mmol), 4-methylbenzyl alcohol (0.4 mmol), and nitromethane (0.4 mmol) into a reaction tube. Add 2 mL of 1,4-dioxane, and then add 0.04 mmol of copper(I) iodide and 1.2 mmol of tert-butyl hydroperoxide respectively. After thorough mixing, assemble the reaction apparatus and react at 80 °C for 6 h. After the reaction is complete, extract and filter. Then, concentrate the filtrate by rotary evaporation, and separate it by silica gel column chromatography to obtain a yellow solid. Yield: 78.8 mg, yield rate: 78%, Mp: 203 - 204 °C. The characterization results are shown in Figure 13 and Figure 14 。 1 1H NMR (400 MHz, CDCl3) δ: 9.52 (d, J = 7.0 Hz, 1H), 7.85 - 7.80 (m, 3H), 7.70 - 7.61 (m, 1H), 7.32 (d, J = 7.9 Hz, 2H), 7.28 (dd, J = 7.0, 1.2 Hz, 1H), 2.44 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 150.5, 145.2, 140.6, 130.8, 130.0, 128.9, 128.2, 118.2, 116.3, 21.6. HRMS (ESI) m / z calcd for C 14 H 12 N3O2 [M + H] + 254.0930, found, 254.0925.

[0078] Example 8

[0079]

[0080] Synthesis method of 3h: Add 2-aminopyridine (0.4 mmol), 4-methoxybenzyl alcohol (0.4 mmol), and nitromethane (0.4 mmol) into a reaction tube. Add 2 mL of 1,4-dioxane, and then add 0.04 mmol of copper(I) iodide and 1.2 mmol of tert-butyl hydroperoxide respectively. After thorough mixing, assemble the reaction apparatus and react at 80 °C for 6 h. After the reaction is complete, extract and filter. Then, concentrate the filtrate by rotary evaporation, and separate it by silica gel column chromatography to obtain a yellow solid. Yield: 88.2 mg, yield rate: 82%, Mp: 169 - 170 °C. The characterization results are shown in Figure 15 and Figure 16 。 11H NMR (400 MHz, CDCl3) δ: 9.51 (d, J = 7.0 Hz, 1H), 7.94 (d, J = 8.9 Hz, 2H), 7.81 (d, J = 8.9 Hz, 1H), 7.68 - 7.54 (m, 1H), 7.24 (dd, J = 7.0, 1.2 Hz, 1H), 7.02 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 161.3, 150.3, 145.2, 131.9, 130.9, 128.3, 124.0, 118.1, 116.2, 113.6, 55.4. HRMS (ESI) m / z calcd for C14H12N3O3 [M + H] + 270.0879, found, 270.0876.

[0081] The above are only the preferred embodiments of the present invention, and the protection scope of the present invention is not limited to the above embodiments. All technical solutions falling within the idea of the present invention belong to the protection scope of the present invention. It should be noted that for those of ordinary skill in the art, several improvements and refinements made without departing from the principle of the present invention should be regarded as within the protection scope of the present invention.

Claims

1. A method for preparing a 3-nitroimidazo[1,2-a]pyridine derivative, characterized in that, The preparation method comprises the following steps: Formula 1: Step (1): Add a 2-aminopyridine structure such as compound 1, a benzyl alcohol structure such as compound 2, nitromethane, cuprous iodide, tert-butyl hydroperoxide, and a reaction solvent into a reaction tube, wherein the reaction solvent used in the reaction is 1,4-dioxane; Step (2): Add 1,4-dioxane again, seal the tube for reaction, and obtain a product mixture by one-step synthesis; Step (3): After the reaction is completed, extract and filter the product mixture obtained in step (2), and concentrate and separate the obtained filtrate to obtain a 3-nitroimidazo[1,2-a]pyridine derivative with a structural formula such as compound 3; Among them, R1 is selected from H, halogen, and C1-C6 alkyl; among them, the chemical structure of the benzyl alcohol is any one of the following structural formulas: , , , , .

2. The preparation method of the 3-nitroimidazo[1,2-a]pyridine derivative according to claim 1, characterized in that, The chemical structure of the 2-aminopyridine is any one of the following structural formulas: , , , .

3. The preparation method of the 3-nitroimidazo[1,2-a]pyridine derivative according to claim 1, characterized in that, The structural formula of the 3-nitroimidazo[1,2-a]pyridine derivative is: 。 4. The preparation method of the 3-nitroimidazo[1,2-a]pyridine derivative according to claim 1, characterized in that, In the reaction shown in Formula 1, the molar ratio of compound 1, compound 2, and nitromethane added is 1:1:

1.

5. The method for preparing a 3-nitroimidazo[1,2-a]pyridine derivative according to claim 1 or 3, characterized in that, In the reaction shown in Formula 1, the molar ratio of compound 1 to cuprous iodide added is 1:0.

1.

6. The preparation method of the 3-nitroimidazo[1,2-a]pyridine derivative according to claim 1, characterized in that, In the reaction shown in Formula 1, the molar ratio of compound 1 to tert-butyl hydroperoxide added is 1:

3.

7. The preparation method of the 3-nitroimidazo[1,2-a]pyridine derivative according to claim 1, characterized in that, The method further comprises the step of separating and purifying the product after the reaction is completed.

8. The preparation method of the 3-nitroimidazo[1,2-a]pyridine derivative according to claim 1, characterized in that: In step (3), the obtained crude product is separated by column chromatography to obtain a 3-nitroimidazo[1,2-a]pyridine derivative in the form of a yellow solid or oil; the yield of the 3-nitroimidazo[1,2-a]pyridine derivative product is 62%-85%.

Images