Method for preparing 2-aminopyridine compound based on dearomatization-aromatization strategy

Abstract

The invention discloses a method for preparing a 2-aminopyridine compound based on a dearomatization-aromatization strategy, and belongs to the technical field of organic synthesis. According to the present invention, pyridine is subjected to dearomatization under the mediation of DMAD / isocyanate, and then is subjected to aromatization under the alkali effect so as to highly selectively achieve the direct amination of the ortho-position C-H bond of pyridine, such that the 2-aminopyridine compound is obtained; according to the preparation method, metal catalysis is not needed, pyridine pre-activation is not needed, all used reagents are common reagents, operation is easy, and the yield is high. The obtained product 2-aminopyridine compound has wide application prospects in medicine, agriculture, materials and chemical synthesis.

Description

Technical Field

[0001] This application relates to a method for preparing 2-aminopyridine compounds based on a dearomatization-aromatization strategy, belonging to the field of organic synthesis technology. Background Technology

[0002] Pyridine, as an important class of nitrogen-containing aromatic heterocycles, is widely found in natural products, drug molecules, and functional materials. Selective modification of the CH bond in pyridine can significantly enhance its functional diversity; therefore, the selective functionalization of the CH bond in pyridine has always been a hot research topic in organic synthesis. Among them, 2-aminopyridine is one of the most common pyridine-substituted molecules in small drug molecules and is considered the simplest building block for synthesizing active heterocyclic molecules. Examples include isopropiram for treating neuropathic pain, tenoxicam for relieving non-inflammatory pain, the microtubule polymerization inhibitor ABT-751, and the CFTR protein regulator Lumacaftor. Furthermore, both the pyridine nitrogen atom and the amino group in 2-aminopyridine are nucleophilic and are often used as important reaction precursors in organic synthesis to prepare heterocyclic structures such as pyridine-imidazolium and pyridotriazole, serving as crucial building blocks for constructing complex nitrogen-containing molecules.

[0003] Currently, methods for constructing 2-aminopyridine via the direct amination of the ortho-CH bond of pyridine mainly use pyridine N-oxides or pyridine salts as reactants, and these methods require pre-activation of pyridine. However, methods for synthesizing 2-aminopyridine directly via the ortho-CH bond of pyridine without pre-activation are quite limited. Therefore, exploring a simple and efficient method for the direct amination of unactivated pyridine via the ortho-CH bond is of great significance. Summary of the Invention

[0004] To address the problems of complex and inefficient synthesis processes caused by the need for pre-activation and metal involvement in existing technologies for 2-aminopyridine compounds, this application provides a technical solution for preparing 2-aminopyridine compounds based on a dearomatization-aromatization strategy. Under conditions without metal involvement and without the need for pre-activation, direct amination of the ortho-CH bond of pyridine is achieved through a dearomatization process mediated by dimethyl butynedioate (DMAD) / isocyanate and a base-promoted rearomatization process, thereby efficiently constructing 2-aminopyridine compounds.

[0005] The technical solution adopted in this application is as follows: According to a first aspect of this application, a method for preparing 2-aminopyridine compounds based on a dearomatization-aromatization strategy is provided, comprising: Dimethyl butynedioate was slowly added to a mixture containing a pyridine compound of Formula 1, an isocyanate compound of Formula 2, and a solvent, and reaction I was carried out under stirring to obtain a solution containing the intermediate. A base reagent was added to a solution containing the intermediate, and reaction II was carried out under stirring to obtain the 2-aminopyridine compound having the structure shown in Formula 3; Formula 1, Equation 2, Formula 3; Among them, R 1 Selected from one of hydrogen, halogen, alkyl, cyano, and acetyl groups, R 2 It is an alkyl or aromatic group; The reaction steps and reaction formulas for reactions I and II are shown in Formula 4, where INT is an intermediate. Formula 4.

[0006] Optionally, R 1 When it is hydrogen, the substituent R 2 It is selected from one of 2-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 2-trifluoromethoxyphenyl, 3,5-dimethylphenyl, 3,4-difluorophenyl, allyl, cyclohexyl, cyclopentyl, isopropyl, and n-octyl.

[0007] Optionally, R 2 When R is 2-bromophenyl, 1 It is a halogen, wherein the halogen is selected from one of fluorine, chlorine, bromine, and iodine, and the halogen is substituted at the meta position of pyridine.

[0008] Optionally, R 1 When it is an alkyl group, the alkyl group is ethyl or tert-butyl, wherein the ethyl group is substituted at the meta position of pyridine, and the tert-butyl group is substituted at the para position of pyridine.

[0009] Optionally, R 1 When it is a cyano group, the cyano group is substituted at the para-pyridine position.

[0010] Optionally, R 1 When the acetyl group is used, the acetyl group is substituted at the para-pyridine position.

[0011] Optionally, the 2-aminopyridine compound is selected from compounds with a structure of formula 3a to 3u:

[0012] .

[0013] Optionally, the solvent is selected from toluene, tetrahydrofuran, acetonitrile, etc.N, N - At least one of dimethylformamide and dimethyl sulfoxide.

[0014] Optionally, the alkaline reagent is selected from at least one of triethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, and potassium phosphate.

[0015] Optionally, the molar ratio of the pyridine compound shown in Formula 1 to the isocyanate compound shown in Formula 2 is 1:1 to 1:2.

[0016] Optionally, the ratio of the pyridine compound shown in Formula 1 to the solvent is 1 mmol: 1.5 mL to 1 mmol: 4 mL.

[0017] Optionally, the molar ratio of the pyridine compound shown in Formula 1 to dimethyl butynedioate is 1:1 to 1:2.

[0018] Optionally, the molar ratio of the pyridine compound shown in Formula 1 to the base reagent is 1:1 to 1:2.

[0019] Optionally, the conditions for reaction I include: a reaction time of 2 to 36 hours; Optionally, the conditions for reaction II include a reaction temperature of 30~120°C.

[0020] The beneficial effects of this application include: The 2-aminopyridine compound preparation route developed in this application has significant advantages: it requires no metal involvement and no pre-activation of the starting materials, achieving highly selective direct amination of the ortho-CH bond of pyridine through a multi-step, one-pot method. This method is simple to operate, concise, and yields high results, exhibiting high site selectivity and good functional group tolerance. The obtained 2-aminopyridine compounds are widely found in drug molecules and natural products, and are also important building blocks for the synthesis of complex nitrogen-containing aromatic heterocycles. Therefore, the technical route described in this application will provide important technical support for the development of nitrogen-containing aromatic heterocycle drugs and the total synthesis of natural products. Detailed Implementation

[0021] The present application is described in detail below with reference to the embodiments, but the present application is not limited to these embodiments.

[0022] Unless otherwise specified, all raw materials used in the embodiments of this application were purchased through commercial channels.

[0023] Unless otherwise specified, all test methods are standard and all instrument settings are those recommended by the manufacturer.

[0024] According to one embodiment of this application, a method for preparing 2-aminopyridine compounds based on a dearomatization-aromatization strategy includes: To a mixture containing a pyridine compound of Formula 1, an isocyanate compound of Formula 2, and a solvent, dimethyl butynedioate (DMAD) is slowly added, and reaction I (step I) is carried out under stirring to obtain a solution containing an intermediate (INT). A base reagent was added to a solution containing the intermediate (INT), and reaction II (step II) was carried out under stirring to obtain the 2-aminopyridine compound having the structure shown in Formula 3; Formula 1, Equation 2, Formula 3; Among them, R 1 Selected from one of hydrogen, halogen, alkyl, cyano, and acetyl groups, R 2 It is an alkyl or aromatic group.

[0025] The technical route of this application is shown in Formula 4. Through a dearomatization mediated by dimethyl butyrynyl diacidate (DMAD) / isocyanate and a base-promoted rearomatization process, direct amination of the ortho-CH bond of pyridine is achieved, efficiently constructing 2-aminopyridine. Specifically, compound 1 and compound 2 are first dissolved in a solvent, then DMAD is slowly added dropwise while stirring the reaction to obtain an intermediate (INT). After the reaction is complete, without purification, a base reagent is directly added, and the reaction continues at a certain temperature. After the reaction is complete, compound 3 is obtained through post-processing.

[0026]

[0027] Formula 4.

[0028] In one implementation, R 1 When it is hydrogen, the substituent R 2 It is selected from one of 2-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 2-trifluoromethoxyphenyl, 3,5-dimethylphenyl, 3,4-difluorophenyl, allyl, cyclohexyl, cyclopentyl, isopropyl, and n-octyl.

[0029] In one implementation, R 2 When R is 2-bromophenyl, 1 It is a halogen, wherein the halogen is selected from one of fluorine, chlorine, bromine, and iodine, and the halogen is substituted at the meta position of pyridine.

[0030] In one implementation, R 1 When it is an alkyl group, the alkyl group is ethyl or tert-butyl, wherein the ethyl group is substituted at the meta position of pyridine, and the tert-butyl group is substituted at the para position of pyridine.

[0031] In one implementation, R 1 When it is a cyano group, the cyano group is substituted at the para-pyridine position.

[0032] In one implementation, R 1 When the acetyl group is used, the substitution position of the acetyl group is the meta-pyridine position.

[0033] In one embodiment, the 2-aminopyridine compound is selected from compounds with a structure of formula 3a to 3u:

[0034] .

[0035] In one embodiment, the solvent is selected from toluene, tetrahydrofuran, acetonitrile, etc. N, N - At least one of dimethylformamide and dimethyl sulfoxide. Preferably, toluene and dimethyl sulfoxide.

[0036] In one embodiment, the base reagent is selected from at least one of triethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, and potassium phosphate. Preferably, it is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium carbonate.

[0037] In one embodiment, the slow addition method described in this application is not strictly limited in terms of speed. Those skilled in the art can select and adjust it according to the realization of the reaction process, for example, it can be dropwise addition.

[0038] In one embodiment, the molar ratio of the pyridine compound of Formula 1 to the isocyanate compound of Formula 2 is 1:1 to 1:2.

[0039] In one embodiment, the ratio of the pyridine compound shown in Formula 1 to the solvent is 1 mmol: 1.5 mL to 1 mmol: 4 mL.

[0040] In one embodiment, the molar ratio of the pyridine compound shown in Formula 1 to dimethyl butynedioate (DMAD) is 1:1 to 1:2.

[0041] In one embodiment, the molar ratio of the pyridine compound shown in Formula 1 to the base reagent is 1:1 to 1:2.

[0042] In one embodiment, the conditions for reaction I include a reaction time of 2 to 36 hours.

[0043] In one embodiment, the conditions for reaction II include a reaction temperature of 30-120°C.

[0044] In one embodiment, the reaction temperature in the conditions of reaction II is selected from any value of 30°C, 60°C, 90°C, 120°C, or a range between any two.

[0045] In one embodiment, reaction II is monitored using TLC, and after the reaction is completed, reaction II is quenched, for example, by using a saturated sodium chloride solution.

[0046] In one embodiment, the method further includes: extracting, drying, filtering, and concentrating the product of reaction II, and then purifying the residue by column chromatography to obtain the 2-aminopyridine compound, exemplarily by extraction with ethyl acetate and drying with anhydrous sodium sulfate; subsequently filtering and concentrating under reduced pressure, and purifying the residue by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1).

[0047] Example 1 At room temperature, 1.0 mmol of pyridine and 2.0 mmol of 2-bromoisocyanate were dissolved in dry dimethyl sulfoxide (2 mL), followed by the slow addition of 1.0 mmol of DMAD. After stirring for 2 h, 2.0 mmol of triethylamine was added, and the mixture was heated to 90 °C. The reaction was monitored by TLC. After the reaction was complete, the solution was quenched with saturated sodium chloride solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The mixture was then filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to give a white solid product 3a in 20% yield.

[0048] Example 2 At room temperature, 1.0 mmol of pyridine and 2.0 mmol of 2-bromoisocyanate were dissolved in dry dimethyl sulfoxide (2 mL), followed by the slow addition of 1.0 mmol of DMAD. After stirring for 2 h, 2.0 mmol of DBU was added, and the mixture was heated to 90 °C. The reaction was monitored by TLC. After the reaction was complete, the solution was quenched with saturated sodium chloride solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The mixture was then filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to give a white solid product 3a in 68% yield.

[0049] Example 3 At room temperature, 1.0 mmol of pyridine and 2.0 mmol of 2-bromoisocyanate were dissolved in dry dimethyl sulfoxide (2 mL), followed by the slow addition of 1.0 mmol of DMAD. After stirring for 2 h, 2.0 mmol of DBU was added, and the mixture was heated to 120 °C. The reaction was monitored by TLC. After the reaction was completed, the solution was quenched with saturated sodium chloride solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The mixture was then filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to give a white solid product 3a in 73% yield.

[0050] Example 4-16 The synthesis process was the same as in Example 3, except that 2-bromoisocyanate was replaced with the raw materials in Table 1, resulting in compounds 3b to 3m of the products shown in Table 1.

[0051] Table 1

[0052] Examples 17-24 The synthesis process was the same as in Example 3, except that pyridine was replaced with the raw materials in Table 2, and the product compounds 3n to 3u shown in Table 2 were obtained respectively.

[0053] Table 2

[0054] The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry, and the characterization data are as follows: Compound 3a Yield 73%, 1 H NMR (400 MHz, CDCl3): d 8.21 (d, J = 5.0 Hz, 1H), 7.98 (d, J =8.2 Hz, 1H), 7.55 – 7.45 (m, 2H), 7.23 (d, J = 7.7 Hz, 1H), 6.87 – 6.73 (m, 4H)ppm. HRMS (ESI-TOF) calculated values ​​correspond to C 11 H 10 BrN2[M+H] + : 249.0022, Measured value: 249.0020.

[0055] Compound 3b 60% yield 1 H NMR (400 MHz, CDCl3) d8.20 (dd, J = 5.2, 1.8 Hz, 1H), 7.53(ddd, J = 8.9, 7.3, 1.9 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 2.2 Hz, 1H), 7.26 (s, 1H), 6.84 – 6.75 (m, 2H), 6.72 (s, 1H) ppm. HRMS (ESI-TOF) calculated values ​​correspond to C 11 H 10 BrN2[M+H] + : 249.0022, Measured value: 249.0021.

[0056] Compound 3c Yield 85%, 1 H NMR (400 MHz, CDCl3) d 8.26 (d, J = 5.6 Hz, 1H), 8.08 (dd, J =8.3, 1.6 Hz, 1H), 7.58 – 7.50 (m, 1H), 7.39 (dd, J = 8.0, 1.5 Hz, 1H), 7.29 –7.23 (m, 1H), 6.94 (td, J = 7.7, 1.6 Hz, 1H), 6.86 (d, J = 8.1 Hz, 2H), 6.81 (dd, J = 7.2, 5.1 Hz, 1H) ppm. HRMS (ESI-TOF) calculated value corresponding to C 11 H 10 ClN2[M+H] + : 205.0527, measured value: 205.0524.

[0057] Compound 3d Yield 58%, 1 H NMR (400 MHz, CDCl3) d 8.26 – 8.20 (m, 1H), 7.53 (ddd, J= 8.8, 7.3, 1.9 Hz, 1H), 7.37 – 7.29 (m, 4H), 6.86 – 6.75 (m, 2H), 6.64 (s, 1H) ppm.HRMS (ESI-TOF) calculated values ​​corresponding to C 11 H 10 N₂Cl [M+H] + : 205.0527, Measured value: 205.0527.

[0058] Compound 3e Yield 58%, 1 H NMR (400 MHz, CDCl3) d 8.17 – 8.12 (m, 1H), 7.43 (ddd, J = 8.7, 7.1, 1.9 Hz, 1H), 7.27 – 7.20 (m, 2H), 6.93 – 6.86 (m, 2H), 6.71 – 6.62 (m, 3H), 3.81 (s, 3H) ppm. HRMS (ESI-TOF) calculated values ​​correspond to C 12 H 13 N2O [M+H] + : 201.1022, Measured value: 201.1019.

[0059] Compound 3f Yield 46%, 1 H NMR (400 MHz, CDCl3) d 8.24 (dd, J = 5.1, 1.9 Hz, 1H), 8.10(dd, J = 8.5, 1.6 Hz, 1H), 7.52 (ddd, J = 8.9, 7.3, 1.9 Hz, 1H), 7.26 – 7.21 (m,2H), 6.97 (td, J = 7.8, 1.6 Hz, 1H), 6.86 – 6.75 (m, 2H), 6.66 (s, 1H) ppm. 19 FNMR (565 MHz, CDCl3) d -57.59 ppm. HRMS (ESI-TOF) calculated value corresponding to C 12 H 10 F3N2O [M+H] +:255.0740, Measured value: 255.0739.

[0060] 3g of compound Yield 85%, 1 H NMR (400 MHz, CDCl3) d 8.22 – 8.18 (m, 1H), 7.48 (ddd, J = 8.8,7.1, 1.9 Hz, 1H), 6.95 – 6.90 (m, 3H), 6.71 (ddd, J = 7.1, 4.5, 1.7 Hz, 2H), 6.45 – 6.33 (m, 1H), 2.32 (s, 6H) ppm. HRMS (ESI-TOF) calculated values ​​correspond to C 13 H 15 N2[M+H] + : 199.1230, Measured value: 199.1226.

[0061] Compound 3h Yield 35%, 1 H NMR (400 MHz, CDCl3) d 8.21 (dd, J = 5.0, 1.8 Hz, 1H), 7.52(td, J = 7.8, 7.2, 1.9 Hz, 1H), 7.41 (ddd, J = 12.4, 7.0, 2.7 Hz, 1H), 7.09 (q, J =9.2 Hz, 1H), 7.02 – 6.95 (m, 1H), 6.81 – 6.72 (m, 2H), 6.55 (s, 1H) ppm. 19 FNMR (377 MHz, CDCl3) d -136.04 (ddd, J = 21.5, 12.3, 8.7 Hz), -145.32 (dddd, J =21.5, 10.5, 7.0, 3.8 Hz) ppm. HRMS (ESI-TOF) calculated values ​​correspond to C 11 H9F2N2[M+H] + :207.0729, Measured value: 207.0726.

[0062] Compound 3i 55% yield 1 H NMR (400 MHz, CDCl3) d 8.07 (dd, J = 5.3, 1.8 Hz, 1H), 7.40(ddd, J = 8.8, 7.1, 1.9 Hz, 1H), 6.56 (ddd, J = 7.2, 5.0, 1.0 Hz, 1H), 6.38 (d, J =8.4 Hz, 1H), 5.94 (ddt, J = 17.3, 10.4, 5.2 Hz, 1H), 5.26 (dq, J = 17.2, 1.7 Hz, 1H), 5.14 (dq, J = 10.4, 1.5 Hz, 1H), 4.73 (s, 1H), 3.92 (tt, J = 5.5, 1.7 Hz, 2H) ppm. HRMS (ESI-TOF) calculated value corresponds to C8H. 11 N2[M+H] + : 135.0917, Measured value: 135.0914.

[0063] Compound 3j Yield 73%, 1 H NMR (400 MHz, CDCl3) d 8.10 – 8.00 (m, 1H), 7.43 – 7.35 (m,1H), 6.58 – 6.47 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 4.48 (s, 1H), 3.58 – 3.48 (m, 1H), 2.08 – 2.00 (m, 2H), 1.80 – 1.72 (m, 2H), 1.68 – -1.60 (m, 2H), 1.42– 1.33 (m, 2H), 1.25 – 1.17 (m, 2H) ppm. HRMS (ESI-TOF) calculated values ​​correspond to C 11 H 17 N2[M+H] + : 177.1386, Measured value: 177.1386.

[0064] Compound 3k Yield 35%,1 H NMR (400 MHz, CDCl3), d 8.07 (dd, J = 5.1, 1.9 Hz, 1H), 7.43(ddd, J = 8.8, 7.1, 1.9 Hz, 1H), 6.55 (dd, J = 7.1, 5.1 Hz, 1H), 6.40 (d, J = 8.4Hz, 1H), 4.60 (s, 1H), 2.05 (tq, J = 14.9, 8.0, 6.1 Hz, 3H), 1.76 (qd, J = 7.8, 4.0 Hz, 2H), 1.65 (qd, J = 8.6, 7.1, 4.7 Hz, 2H), 1.54 – 1.45 (m, 2H) ppm. HRMS (ESI-TOF) calculated values ​​correspond to C 10 H 15 N2[M+H] + : 163.1230, Measured value: 163.1227.

[0065] Compound 3l 50% yield 1 H NMR (400 MHz, CDCl3) d 8.10 – 8.04 (m, 1H), 7.43 (ddd, J = 8.7,7.1, 1.8 Hz, 1H), 6.55 (ddd, J = 7.2, 5.1, 1.0 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 4.51 (s, 1H), 3.95 – 3.81 (m, 1H), 1.26 (s, 3H), 1.25 (s, 3H) ppm. HRMS (ESI-TOF) calculated values ​​correspond to C8H. 13 N2[M+H] + : 137.1073, Measured value: 137.1072.

[0066] Compound 3m Yield 45%, 1 H NMR (400 MHz, CDCl3) d8.11 – 8.02 (m, 1H), 7.46 – 7.36 (m,1H), 6.59 – 6.52 (m, 1H), 6.38 (d, J = 8.4 Hz, 1H), 4.61 (s, 1H), 3.28 – 3.21(m, 2H), 1.67 – 1.58 (m, 2H), 1.44 – 1.37 (m, 2H), 1.32 – 1.26 (m, 8H), 0.89(t, J = 6.8 Hz, 3H) ppm. HRMS (ESI-TOF) calculated value corresponds to C 13 H 23 N2[M+H] + : 207.1856, Measured value: 207.1852.

[0067] Compound 3n Yield 19%, 1 H NMR (400 MHz, CDCl3) d 8.53 (d, J = 8.3 Hz, 1H), 8.19 (d, J = 4.8Hz, 1H), 8.01 (dd, J = 7.7, 1.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 7.8Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.56 (dd, J = 7.7, 4.8 Hz, 1H) ppm.HRMS (ESI-TOF) calculated value corresponding to C 11 H9BrIN2[M+H] + 374.8988, Measured value: 374.8988.

[0068] Compound 3o Yield 53%, 1 H NMR (400 MHz, CDCl3) d 8.60 (dd, J = 8.3, 1.7 Hz, 1H), 8.22 –8.16 (m, 1H), 7.79 (dd, J= 7.7, 1.7 Hz, 1H), 7.73 (s, 1H), 7.57 (dd, J = 8.0, 1.7 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 6.94 – 6.85 (m, 1H), 6.70 (dd, J = 7.8, 4.9 Hz, 1H) ppm.HRMS (ESI-TOF) calculated value corresponding to C 11 H9Br2N2[M+H] + : 326.9127, Measured value: 326.9129.

[0069] Compound 3p Yield 48%, 1 H NMR (400 MHz, CDCl3) d 8.63 (dd, J = 8.3, 1.5 Hz, 1H), 8.16(dd, J = 4.8, 1.6 Hz, 1H), 7.71 (s, 1H), 7.60 (ddd, J = 18.1, 7.9, 1.5 Hz, 2H),7.38 – 7.29 (m, 1H), 6.94 – 6.86 (m, 1H), 6.77 (dd, J = 7.8, 4.8 Hz, 1H)ppm.HRMS (ESI-TOF) calculated value corresponding to C 11 H9BrClN2[M+H] + : 282.9632, Measured value: 282.9631.

[0070] Compound 3q Yield 38%, 1 H NMR (400 MHz, CDCl3) d 8.62 (dd, J = 8.3, 1.6 Hz, 1H), 8.04 (d, J = 4.9 Hz, 1H), 7.56 (dd, J = 8.0, 1.5 Hz, 1H), 7.33 (ddd, J = 9.2, 7.4, 1.9 Hz,2H), 7.27 (s, 1H), 6.88 (m, J= 7.7, 1.5 Hz, 1H), 6.79 (ddd, J = 8.2, 4.9, 3.6Hz, 1H) ppm. 19 F NMR (377 MHz, CDCl3) d -138.10 ppm. HRMS (ESI-TOF) calculated value corresponding to C 11 H9BrFN2[M+H] + : 266.9928, Measured value: 266.9927.

[0071] Compound 3r Yield 10%, 1 H NMR (400 MHz, CDCl3) d 8.56 (dd, J = 8.3, 1.7 Hz, 1H), 8.14(dd, J = 4.9, 1.9 Hz, 1H), 7.53 (dd, J = 8.0, 1.6 Hz, 1H), 7.43 (dd, J = 7.3, 1.9Hz, 1H), 7.35 – 7.27 (m, 1H), 6.95 (s, 1H), 6.87 – 6.77 (m, 2H), 2.67 (q, J =7.5 Hz, 2H), 1.36 (td, J = 7.8, 1.7 Hz, 3H) ppm. HRMS (ESI-TOF) calculated value corresponding to C 13 H 14 BrN2[M+H] + : 277.0335, Measured value: 277.0333.

[0072] Compound 3s 50% yield 1 H NMR (400 MHz, CDCl3) d 8.20 – 8.14 (m, 1H), 8.06 (dd, J = 8.3, 1.6 Hz, 1H), 7.56 (dd, J = 8.0, 1.5 Hz, 1H), 7.31 – 7.27 (m, 1H), 6.89 – 6.81 (m, 4H), 1.30 (s, 9H) ppm. HRMS (ESI-TOF) calculated values ​​correspond to C15 H 18 BrN2[M+H] + 305.0648, Measured value: 305.0646.

[0073] Compound 3t Yield 35%, 1 H NMR (400 MHz, CDCl3) d 8.37 (d, J = 5.1 Hz, 1H), 7.90 (dd, J =8.2, 1.5 Hz, 1H), 7.62 (dd, J = 8.0, 1.5 Hz, 1H), 7.39 – 7.29 (m, 1H), 7.05 –6.94 (m, 4H). HRMS (ESI-TOF) calculated values ​​correspond to C 12 H9BrN3[M+H] + : 273.9974, Measured value: 273.9971.

[0074] Compound 3u 40% yield 1 H NMR (400 MHz, CDCl3) d 8.84 (d, J = 2.4 Hz, 1H), 8.10 (dd, J =8.8, 2.4 Hz, 1H), 8.03 (dd, J = 8.2, 1.6 Hz, 1H), 7.61 (dd, J = 8.1, 1.5 Hz, 1H),7.39 – 7.30 (m, 1H), 7.23 (s, 1H), 7.00 (td, J = 7.7, 1.6 Hz, 1H), 6.81 (d, J =8.8 Hz, 1H), 2.55 (s, 3H) ppm. HRMS (ESI-TOF) calculated values ​​correspond to C 13 H 12 BrN2O [M+H] + :291.0128, Measured value: 291.0124.

[0075] The above description is merely a few embodiments of this application and is not intended to limit this application in any way. Although this application discloses preferred embodiments as described above, it is not intended to limit this application. Any changes or modifications made by those skilled in the art without departing from the scope of the technical solution of this application using the disclosed technical content are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A method for preparing 2-aminopyridine compounds based on a dearomatization-aromatization strategy, characterized in that, include: Dimethyl butynedioate was slowly added to a mixture containing a pyridine compound of Formula 1, an isocyanate compound of Formula 2, and a solvent, and reaction I was carried out under stirring to obtain a solution containing the intermediate. A base reagent was added to a solution containing the intermediate, and reaction II was carried out under stirring to obtain the 2-aminopyridine compound having the structure shown in Formula 3; Formula 1, Equation 2, Formula 3; Among them, R 1 Selected from one of hydrogen, halogen, alkyl, cyano, and acetyl groups, R 2 It is an alkyl or aromatic group; The reaction formulas for reactions I and II are shown in Formula 4, where INT is an intermediate; Formula 4.

2. The method according to claim 1, characterized in that, R 1 When it is hydrogen, the substituent R 2 It is selected from one of 2-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 2-trifluoromethoxyphenyl, 3,5-dimethylphenyl, 3,4-difluorophenyl, allyl, cyclohexyl, cyclopentyl, isopropyl, and n-octyl.

3. The method according to claim 1, characterized in that, R 2 When R is 2-bromophenyl, 1 It is a halogen, wherein the halogen is selected from one of fluorine, chlorine, bromine, and iodine, and the halogen is substituted at the meta position of pyridine.

4. The method according to claim 1, characterized in that, R 1 When it is an alkyl group, the alkyl group is ethyl or tert-butyl, wherein the ethyl group is substituted at the meta position of pyridine, and the tert-butyl group is substituted at the para position of pyridine.

5. The method according to claim 1, characterized in that, R 1 When it is a cyano group, the cyano group is substituted at the para-pyridine position.

6. The method according to claim 1, characterized in that, R 1 When the acetyl group is used, the substitution position of the acetyl group is the meta-pyridine position.

7. The method according to claim 1, characterized in that, The 2-aminopyridine compounds are selected from compounds with one structure of formula 3a to 3u: 。 8. The method according to claim 1, characterized in that, The solvent is selected from toluene, tetrahydrofuran, acetonitrile, etc. N, N - At least one of dimethylformamide and dimethyl sulfoxide.

9. The method according to claim 1, characterized in that, The alkaline reagent is selected from at least one of triethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, and potassium phosphate.

10. The method according to claim 1, characterized in that, The molar ratio of the pyridine compound shown in Formula 1 to the isocyanate compound shown in Formula 2 is 1:1 to 1:2; The ratio of the pyridine compound to the solvent shown in Formula 1 is 1 mmol: 1.5 mL to 1 mmol: 4 mL; The molar ratio of the pyridine compound shown in Formula 1 to dimethyl butynedioate is 1:1 to 1:

2. The molar ratio of the pyridine compound shown in Formula 1 to the base reagent is 1:1 to 1:2; The conditions for reaction I include: a reaction time of 2 to 36 hours; The conditions for reaction II include a reaction temperature of 30~120°C.

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