Aminomethylation reaction method based on pyrazolo [1, 5-a] pyrimidine nitrogen-containing fused heterocycle substrate, product and application

Abstract

The invention provides an aminomethylation reaction method based on a pyrazolo [1, 5-a] pyrimidine nitrogen-containing fused heterocycle substrate, a product and application, and belongs to the technical field of chemistry. Pyrazolo [1, 5-a] pyrimidine nitrogen-containing fused heterocycle, secondary amine and glyoxylic acid are used as raw materials, an aminomethylation reaction is achieved at the C3 site of pyrazolo [1, 5-a] pyrimidine through heating for the first time, a transition metal catalyst or a chemical oxidizing agent is not needed, the drug purification problem caused by metal residues and oxidation byproduct pollution are avoided, and the purity of the product is improved. The method is a novel efficient, simple, convenient and environment-friendly nitrogen-containing fused heterocyclic aromatic hydrocarbon functionalization strategy, the reaction can be directly carried out at the temperature of 100-120 DEG C, shielding gas does not need to be filled, and compared with some reactions needing high-temperature or high-pressure conditions, the mild reaction conditions are easier to control, side reactions are reduced, and the yield of the target product is increased. Meanwhile, the reaction conditions are also beneficial to reducing energy consumption, and conform to the concept of green chemistry.

Description

Technical Field

[0001] This invention relates to the field of chemical technology, and more particularly to pyrazolo[1,5- a Methods, products, and applications of aminomethylation of pyrimidine nitrogen-containing fused heterocyclic substrates. Background Technology

[0002] Pyrazolo[1,5- a Pyrimidines are a class of nitrogen-containing fused heterocyclic compounds with broad biological activities and application potential. Their structures combine the characteristics of both pyrazolium and pyrimidine dual active units, making them widely used in biological and pharmaceutical fields. Pyrazolo[1,5- a Pyrimidine C-3 aminomethyl derivatives possess biological activities such as antitumor, antibacterial, and treatment of hyperuricemia and gout. Furthermore, they have been developed as kinase inhibitors, hepatitis C virus inhibitors, positron emission tomography (PET) tumor imaging agents, and angiotensin II receptor antagonists, forming the basis for new drug development.

[0003] Aminomethylated structural units are of paramount importance in drug development and materials science. In drug development, these units can enhance the interactions between drug molecules and biological targets (such as enzymes and receptors) (e.g., hydrogen bonds and ionic bonds), thereby improving drug efficacy, metabolic stability, and tissue selectivity. Furthermore, their structural diversity provides a wealth of options for drug discovery. For example, the amino unit in 4-amino-1-methylpiperidine exhibits strong nucleophilicity and can be used to prepare piperidine protein kinase inhibitors. In materials science, aminomethyl structural units can be used to synthesize optoelectronic materials. For instance, 2-amino-6-methylheptane can be used to synthesize the N-type photoconductor N,N′-bis(1,5-dimethylhexyl)-3,4:9,10-dinaphthalene-embedding bis(dicarboximide) (PDHEP), a material with significant applications in optoelectronics.

[0004] Glyoxylic acid, as an important organic synthesis intermediate for industrial-scale production, has wide applications in pharmaceuticals, fragrances, pesticides, food additives, cosmetics, daily chemicals, dyes, and plastics. While glyoxylic acid can serve as a potential "methylene source" precursor in traditional aminomethylation reactions, existing methods typically rely on transition metal catalysts or chemical oxidants to achieve its conversion. These methods suffer from drawbacks such as high toxicity, limited ligand selection, harsh reaction conditions (e.g., strong acidity, high temperature), and poor environmental compatibility, hindering large-scale applications and the development of green chemistry. Therefore, the exploration of catalyst-free, additive-free aminomethylation reactions with environmentally friendly and mild reaction conditions has attracted increasing attention.

[0005] Currently, for pyrazolo[1,5- aFunctionalization studies of pyrimidine compounds have largely focused on reactions such as thiocyanation, halogenation, or nitration at the C3 position, while research on their C3 aminomethylation reactions remains limited. Therefore, developing novel direct aminomethylation strategies that require no external catalysts or additives, operate under mild conditions, and are environmentally friendly is of great significance. Summary of the Invention

[0006] The purpose of this invention is to provide a pyrazolo[1,5-] a The aminomethylation reaction method, products and applications of pyrimidine nitrogen-containing fused heterocyclic substrates can be achieved by heating, without the need for transition metal catalysts or chemical oxidants, thus avoiding drug purification problems and oxidation byproduct contamination caused by metal residues.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a pyrazolo[1,5-] a A method for the aminomethylation of pyrimidine nitrogen-containing fused heterocyclic substrates, wherein the aminomethylation reaction is induced under heating conditions by pyrazolo[1,5-] pyrazolo[I] . a The nitrogen-containing fused heterocyclic pyrimidine substrates undergo aminomethylation with the secondary amine compound shown in formula (II), and the chemical reaction formula is shown below: Formula (I) Formula (II) Formula (III).

[0008] Preferably, R1 includes one of H and Ph; The R2 includes 4-Clphenyl, 4-Brphenyl, 3-Clphenyl, 4-OMephenyl, 3-OMephenyl, heterocyclic aromatic hydrocarbons, t -One of the Bu types.

[0009] Preferably, the molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1:1.5.

[0010] Preferably, the heating temperature is 100~120 ℃ and the heating time is 12~20 h.

[0011] Preferably, the heating temperature is 110 °C.

[0012] The present invention also provides a pyrazolo[1,5-]-based […]. a Products prepared by aminomethylation of pyrimidine nitrogen-containing fused heterocyclic substrates.

[0013] The present invention also provides the above-mentioned pyrazolo[1,5- aApplication of products prepared by aminomethylation of pyrimidine nitrogen-containing fused heterocyclic substrates in drug development.

[0014] The beneficial effects of this invention compared to the prior art are as follows: (1) The present invention uses pyrazolo[1,5- a Using pyrimidine nitrogen-containing fused heterocycles, secondary amines, and glyoxylic acid as raw materials, this is the first time that pyrazolo[1,5-] has been successfully synthesized. a The aminomethylation reaction at the C3 position of pyrimidine is achieved by heating, which does not require transition metal catalysts or chemical oxidants. This avoids the drug purification problems caused by metal residues and the pollution of oxidation byproducts. It is a new strategy for the functionalization of nitrogen-containing fused heterocyclic aromatic hydrocarbons.

[0015] (2) The present invention can be carried out directly at 100~120 °C without the need for a protective gas. Compared with some reactions that require high temperature or high pressure, this mild reaction condition is easier to control, reduces the occurrence of side reactions, and improves the yield of the target product. At the same time, this reaction condition also helps to reduce energy consumption, which is in line with the concept of green chemistry. Attached Figure Description

[0016] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0017] Figure 1 The 3-(morpholinomethyl)-5-phenylpyrazolo[1,5-] in Example 1 of this invention a Synthetic methods of pyrimidine-7-amine; Figure 2 The 5-(4-chlorophenyl)-3-(morpholinomethyl)pyrazolo[1,5-] in Example 2 of this invention a Synthetic methods of pyrimidine-7-amine; Figure 3 The 5-(4-bromophenyl)-3-(morpholinomethyl)pyrazolo[1,5-] in Example 3 of this invention a Synthetic methods of pyrimidine-7-amine; Figure 4 The 5-(3-chlorophenyl)-3-(morpholinomethyl)pyrazolo[1,5- a Synthetic methods of pyrimidine-7-amine; Figure 5 The 5-(4-methoxyphenyl)-3-(morpholinomethyl)pyrazolo[1,5-] in Example 5 of this invention aSynthetic methods of pyrimidine-7-amine; Figure 6 The 3-(morpholinomethyl)-2,5-diphenylpyrazolo[1,5-] in Example 6 of this invention a Synthetic methods of pyrimidine-7-amine; Figure 7 The 5-(3-methoxyphenyl)-3-(morpholinomethyl)-2-phenylpyrazolo[1,5-] in Example 7 of this invention a Synthetic methods of pyrimidine-7-amine; Figure 8 The 5-(tert-butyl)-3-(morpholinomethyl)-2-phenylpyrazolo[1,5-] in Example 8 of this invention a Synthetic methods of pyrimidine-7-amine; Figure 9 The 3-(morpholinomethyl)-5-(thiophen-2-yl)pyrazolo[1,5-] in Example 9 of this invention a Synthetic methods of pyrimidine-7-amine; Figure 10 The 3-((benzyl(methyl)amino)methyl)-5-phenylpyrazolo[1,5-] in Example 10 of this invention a Synthetic methods of pyrimidine-7-amine; Figure 11 The 5-phenyl-3-(thiomorpholinocarboxyloyl)pyrazolo[1,5-] in Example 11 of this invention a Synthetic methods of pyrimidine-7-amine; Figure 12 The 3-((4-(2-piperidinylethyl)pyridin-1-yl)methyl)-5-phenylpyrazolo[1,5-] in Example 12 of this invention a Synthetic methods for pyrimidine-7-amine. Detailed Implementation

[0018] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0019] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0020] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0021] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0022] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0023] This invention provides a pyrazolo[1,5-] a The method for aminomethylation of pyrimidine nitrogen-containing fused heterocyclic substrates includes the following steps: Pyrazolo[1,5- a A mixture of pyrimidine nitrogen-containing fused heterocyclic substrates, amine derivatives, and glyoxylic acid monohydrate was heated and stirred. After the reaction was complete, ethyl acetate was added to dilute the mixture, and the crude product was transferred. The solvent was removed by extraction with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Finally, the crude product was purified by silica gel rapid chromatography (dichloromethane / anhydrous ethanol = 20:1) to obtain the final product.

[0024] The structure of the glyoxylic acid monohydrate is as follows: R3 and R4 are secondary amines with different substituents; The pyrazolo[1,5- a The molar ratio of pyrimidine nitrogen-containing fused heterocyclic substrates, amine derivatives, and glyoxylic acid monohydrate is 1:1.2:1.5.

[0025] The heating temperature is 100~120 ℃, and the heating time is 12~20 h, more preferably 110 ℃ for 12 h.

[0026] Example 1 Example 1 of this invention provides a 3-(morpholinomethyl)-5-phenylpyrazolo[1,5- a The synthesis method of pyrimidine-7-amine, the reaction formula is as follows: Figure 1As shown, the specific steps are as follows: 5-Phenylopyrazole[1,5-] was added to a 10 mL pressure-resistant tube. a Pyrimidine-7-amine (0.1 mmol, 0.0210 g), glyoxylic acid monohydrate (0.12 mmol, 0.0110 g), morpholine (0.15 mmol, 0.0130 g), and dimethyl sulfoxide (2 mL) were mixed at 110 °C. o Heating and stirring at C for 12 hours, after which ethyl acetate was added to dilute and the crude product was transferred. The solvent was removed by extraction with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Finally, the crude product was purified by silica gel chromatography (dichloromethane / anhydrous ethanol = 20:1) to obtain the final product 3-(morpholinomethyl)-5-phenylpyrazolo[1,5- a Pyrimidine-7-amine (29.8 mg), yield 96%.

[0027] 3-(morpholinomethyl)-5-phenylpyrazolo[1,5- a Pyrimidine-7-amine: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.07 – 8.03 (m, 3H), 7.74 (s, 2H), 7.54 – 7.46 (m, 3H), 6.57 (s, 1H), 3.70 (s, 2H), 3.56 (t, J = 4.4 Hz, 4H), 2.45 (s, 4H). 13 C NMR (101 MHz, DMSO) δ 155.11, 148.22, 147.64, 144.80, 138.29, 129.51, 128.68, 126.70, 103.46, 83.75, 66.20, 52.82, 50.60. Example 2 Example 2 of the invention provides a 5-(4-chlorophenyl)-3-(morpholinomethyl)pyrazolo[1,5- a The synthesis method of pyrimidine-7-amine, the reaction formula is as follows: Figure 2 As shown, the specific steps are as follows: 5-(4-chlorophenyl)pyrazolo[1,5-] was added to a 10 mL pressure-resistant tube. aPyrimidine-7-amine (0.1 mmol, 0.0244 g), glyoxylic acid monohydrate (0.12 mmol, 0.0110 g), morpholine (0.15 mmol, 0.0130 g), and dimethyl sulfoxide (2 mL) were mixed and heated and stirred at 110 °C for 12 hours. After the reaction was complete, ethyl acetate was added to dilute the crude product, which was then extracted with saturated brine to remove the solvent. The product was dried over anhydrous sodium sulfate and the solvent was removed by vacuum distillation. Finally, the crude product was purified by silica gel chromatography (dichloromethane / anhydrous ethanol = 20:1) to obtain the final product 5-(4-chlorophenyl)-3-(morpholinemethyl)pyrazolo[1,5- a Pyrimidine-7-amine (23.7 mg), yield 69%.

[0028] 5-(4-chlorophenyl)-3-(morpholinomethyl)pyrazolo[1,5- a Pyrimidine-7-amine: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.06 (s, 1H), 8.02 – 7.97 (m, 2H), 7.81 (s, 2H), 7.74 – 7.67 (m,2H), 6.57 (s, 1H), 3.73 (s, 2H), 3.57 (t, J = 4.4 Hz, 4H), 2.50 (s, 4H). 13 C NMR (101 MHz, DMSO) δ 153.95, 148.36, 147.66, 145.06, 137.04, 134.36, 128.74, 128.50, 83.76, 65.96, 52.61, 50.45, 40.43. Example 3 Example 3 of the invention provides a 5-(4-bromophenyl)-3-(morpholinomethyl)pyrazolo[1,5- a The synthesis method of pyrimidine-7-amine, the reaction formula is as follows: Figure 3 As shown, the specific steps are as follows: 5-(4-bromophenyl)pyrazolo[1,5-] was added to a 10 mL pressure-resistant tube. aPyrimidine-7-amine (0.1 mmol, 0.0288 g), glyoxylic acid monohydrate (0.12 mmol, 0.0110 g), morpholine (0.15 mmol, 0.0130 g), and dimethyl sulfoxide (2 mL) were mixed and heated and stirred at 110 °C for 12 hours. After the reaction was complete, ethyl acetate was added to dilute the crude product, which was then extracted with saturated brine to remove the solvent. The product was dried over anhydrous sodium sulfate and the solvent was removed by vacuum distillation. Finally, the crude product was purified by silica gel rapid chromatography (dichloromethane / anhydrous ethanol = 15:1) to obtain the final product 5-(4-bromophenyl)-3-(morpholinemethyl)pyrazolo[1,5- a Pyrimidine-7-amine (22.4 mg), yield 58%.

[0029] 5-(4-bromophenyl)-3-(morpholinomethyl)pyrazolo[1,5- a Pyrimidine-7-amine: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.05 (s, 1H), 8.03 – 7.96 (m, 2H), 7.80 (s, 2H), 7.74 – 7.67 (m,2H), 6.56 (s, 1H), 3.70 (s, 2H), 3.56 (t, J = 4.4 Hz, 4H), 2.46 (s, 4H). 13 C NMR (101 MHz, DMSO) δ 153.92, 148.32, 147.57, 144.96, 137.42, 131.65, 128.73, 123.10, 83.61, 66.10, 52.73, 50.53, 40.43. Example 4 Example 4 of the invention provides a 5-(3-chlorophenyl)-3-(morpholinomethyl)pyrazolo[1,5- a The synthesis method of pyrimidine-7-amine, the reaction formula is as follows: Figure 4 As shown, the specific steps are as follows: 5-(3-chlorophenyl)pyrazole[1,5-] was added to a 10 mL pressure-resistant tube. aPyrimidine-7-amine (0.1 mmol, 0.0244 g), glyoxylic acid monohydrate (0.12 mmol, 0.0110 g), morpholine (0.15 mmol, 0.0130 g), and dimethyl sulfoxide (2 mL) were mixed and heated and stirred at 110 °C for 12 hours. After the reaction was complete, ethyl acetate was added to dilute the crude product, which was then transferred to a container. The solvent was removed by extraction with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Finally, the crude product was purified by silica gel chromatography (dichloromethane / anhydrous ethanol = 15:1) to obtain the final product 5-(3-chlorophenyl)-3-(morpholinemethyl)pyrazolo[1,5- a Pyrimidine-7-amine (30.7 mg), yield 89%.

[0030] 5-(3-Chlorophenyl)-3-(morpholinomethyl)pyrazolo[1,5- a Pyrimidine-7-amine: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.07 (m, 2H), 8.00 – 7.95 (m, 1H), 7.81 (s, 2H), 7.53 (m, 2H), 6.59(s, 1H), 3.71 (s, 2H), 3.56 (t, J = 4.4 Hz, 4H), 2.46 (s, 4H). 13 C NMR (101 MHz, DMSO) δ 153.48, 148.36, 147.51, 145.01, 140.42, 133.53, 130.64, 129.28, 126.37, 125.32, 83.92, 66.11, 52.74, 50.52, 40.43. Example 5 Example 5 of the invention provides a 5-(4-methoxyphenyl)-3-(morpholinomethyl)pyrazolo[1,5- a The synthesis method of pyrimidine-7-amine, the reaction formula is as follows: Figure 5 As shown, the specific steps are as follows: 5-(4-methoxyphenyl)pyrazolo[1,5-] was added to a 10 mL pressure-resistant tube. aPyrimidine-7-amine (0.1 mmol, 0.0339 g), glyoxylic acid monohydrate (0.12 mmol, 0.0110 g), morpholine (0.15 mmol, 0.0130 g), and dimethyl sulfoxide (2 mL) were mixed and heated and stirred at 110 °C for 12 hours. After the reaction was complete, ethyl acetate was added to dilute the crude product, which was then transferred to a container. The solvent was removed by extraction with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Finally, the crude product was purified by silica gel chromatography (dichloromethane / anhydrous ethanol = 15:1) to give the final product 5-(4-methoxyphenyl)-3-(morpholinemethyl)pyrazolo[1,5- a Pyrimidine-7-amine (31.3 mg), yield 92%.

[0031] 5-(4-methoxyphenyl)pyrazolo[1,5- a Pyrimidine-7-amine: 1 H NMR (400 MHz, CDCl3) δ 8.02(s, 1H), 7.99 – 7.95 (m, 2H), 6.99 – 6.95 (m, 2H), 6.39 (s, 1H), 5.87 (s,2H), 3.86 (s, 2H), 3.85 (s, 3H), 3.75 (t, J = 4.4 Hz, 4H), 2.63 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 160.52, 154.92, 148.11, 147.72, 144.75, 130.60, 128.13, 114.02, 83.18, 66.06, 55.26, 52.69, 50.55, 40.43. Example 6 Example 6 of the invention provides a 3-(morpholinomethyl)-2,5-diphenylpyrazolo[1,5- a The synthesis method of pyrimidine-7-amine, the reaction formula is as follows: Figure 6 As shown, the specific steps are as follows: 2,5-Diphenylpyrazol[1,5-] was added to a 10 mL pressure-resistant tube. aPyrimidine-7-amine (0.1 mmol, 0.0286 g), glyoxylic acid monohydrate (0.12 mmol, 0.0110 g), morpholine (0.15 mmol, 0.0130 g), and dimethyl sulfoxide (2 mL) were mixed and heated and stirred at 110 °C for 12 hours. After the reaction was complete, ethyl acetate was added to dilute the crude product, which was then transferred to a container. The solvent was removed by extraction with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Finally, the crude product was purified by silica gel chromatography (dichloromethane / anhydrous ethanol = 15:1) to obtain the final product 3-(morpholinomethyl)-2,5-diphenylpyrazolo[1,5- a Pyrimidine-7-amine (26.9 mg), yield 70%.

[0032] 3-(morpholinomethyl)-2,5-diphenylpyrazolo[1,5- a Pyrimidine-7-amine: 1 H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.6 Hz, 2H), 8.10 – 8.05 (m, 2H), 7.51 – 7.42 (m, 6H), 6.52 (s,1H), 5.84 (s, 2H), 3.87 (s, 2H), 3.74 (t, J = 4.4 Hz, 4H), 2.66 (t, J = 4.4Hz, 4H). 13 C NMR (101 MHz, CDCl3) δ 156.90, 156.28, 149.69, 146.63, 138.52, 133.81, 129.93, 129.12, 128.82, 128.70, 128.66, 127.26, 85.47, 77.48, 77.16, 76.84, 67.18, 53.08, 50.70, 29.45, 27.35. Example 7 Example 7 of the invention provides a 5-(3-methoxyphenyl)-3-(morpholinomethyl)-2-phenylpyrazolo[1,5- a The synthesis method of pyrimidine-7-amine, the reaction formula is as follows: Figure 7 As shown, the specific steps are as follows: 5-(3-methoxyphenyl)-2-phenylpyrazolo[1,5-] was added to a 10 mL pressure-resistant tube. aPyrimidine-7-amine (0.1 mmol, 0.0300 g), glyoxylic acid monohydrate (0.12 mmol, 0.0110 g), morpholine (0.15 mmol, 0.0130 g), and dimethyl sulfoxide (2 mL) were mixed and heated and stirred at 110 °C for 12 hours. After the reaction was complete, ethyl acetate was added to dilute the crude product, which was then transferred to a container. The solvent was removed by extraction with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Finally, the crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2:1) to give the final product 5-(3-methoxyphenyl)-3-(morpholinomethyl)-2-phenylpyrazolo[1,5- a Pyrimidine-7-amine (35.7 mg), yield 86%.

[0033] 5-(3-methoxyphenyl)-3-(morpholinomethyl)-2-phenylpyrazolo[1,5- a Pyrimidine-7-amine: 1 H NMR (400 MHz, CDCl3) δ 8.24 – 8.13 (m, 2H), 7.96 (dd, J = 7.6, 1.6 Hz, 1H), 7.49 (m,2H), 7.46 – 7.35 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.72 (dd, J = 3.6, 2.0 Hz, 1H), 5.79 – 5.71 (m, 2H), 3.87 (d, J = 2.0 Hz, 3H),3.83 (s, 2H), 3.73 (t, J = 4.4 Hz, 4H), 2.64 (t, J = 4.4 Hz, 4H). 13 C NMR (101 MHz, CDCl3) δ 157.45, 156.04, 155.80, 149.56, 145.64, 134.02, 131.40, 130.76, 129.15, 128.58, 128.53, 128.49, 121.30, 111.76, 90.20, 67.36, 55.85, 53.14, 50.69. Example 8 Example 8 of the invention provides a 5-(tert-butyl)-3-(morpholinomethyl)-2-phenylpyrazolo[1,5- a The synthesis method of pyrimidine-7-amine, the reaction formula is as follows: Figure 8 As shown, the specific steps are as follows: 5-(tert-butyl)-2-phenylpyrazole[1,5-] was loaded into a 10 mL pressure-resistant tube. a Pyrimidine-7-amine (0.1 mmol, 0.0266 g), glyoxylic acid monohydrate (0.12 mmol, 0.0110 g), morpholine (0.15 mmol, 0.0130 g), and dimethyl sulfoxide (2 mL) were mixed and heated and stirred at 110 °C for 12 hours. After the reaction was complete, ethyl acetate was added to dilute the crude product, which was then transferred to a container. The solvent was removed by extraction with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Finally, the crude product was purified by silica gel chromatography (dichloromethane / anhydrous ethanol = 30:1) to obtain the final product 5-(tert-butyl)-3-(morpholinomethyl)-2-phenylpyrazolo[1,5- a Pyrimidine-7-amine (22.2 mg), yield 61%.

[0034] 5-(tert-butyl)-3-(morpholinomethyl)-2-phenylpyrazolo[1,5- a Pyrimidine-7-amine: 1 H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.6 Hz, 2H), 7.50 – 7.40 (m, 3H), 6.14 (s, 1H), 5.58 (s, 2H), 3.79 (s, 2H), 3.71 (t, J = 4.8 Hz, 4H), 2.60 (m, 4H), 1.36 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 155.83, 149.21, 146.06, 134.09, 129.10, 128.71, 128.61, 128.49, 85.11, 67.27, 53.05, 50.67, 38.11, 30.05, 29.95, 25.18. Example 9 Example 9 of the invention provides a 3-(morpholinomethyl)-5-(thiophen-2-yl)pyrazolo[1,5- a The synthesis method of pyrimidine-7-amine, the reaction formula is as follows: Figure 9 As shown, the specific steps are as follows: Add 5-(thiophene-2-yl)pyrazolo[1,5-] to a 10 mL pressure-resistant tube a Pyrimidine-7-amine (0.1 mmol, 0.0216 g), glyoxylic acid monohydrate (0.12 mmol, 0.0110 g), morpholine (0.15 mmol, 0.0130 g), and dimethyl sulfoxide (2 mL) were mixed and heated and stirred at 110 °C for 12 hours. After the reaction was complete, ethyl acetate was added to dilute the crude product, which was then transferred to a container. The solvent was removed by extraction with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Finally, the crude product was purified by silica gel chromatography (dichloromethane / anhydrous ethanol = 20:1) to obtain the final product 3-(morpholinomethyl)-5-(thiophene-2-yl)pyrazolo[1,5- a Pyrimidine-7-amine (16.4 mg), yield 76%.

[0035] 3-(morpholinomethyl)-5-(thiophen-2-yl)pyrazolo[1,5- a Pyrimidine-7-amine: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.00 (s, 1H), 7.73 (s, 2H), 7.69 – 7.64 (m, 2H), 7.16 (dd, J = 5.2,3.6 Hz, 1H), 6.49 (s, 1H), 3.63 (s, 2H), 3.55 (t, J = 4.8Hz, 4H), 2.42 (t, J =4.4Hz, 4H). 13 C NMR (101 MHz, DMSO) δ 150.64, 148.02, 147.22, 144.75, 144.15, 129.02, 128.26, 125.98, 103.07, 82.48, 66.16, 52.77, 50.53. Example 10 Example 10 of the invention provides a 3-((benzyl(methyl)amino)methyl)-5-phenylpyrazolo[1,5- a The synthesis method of pyrimidine-7-amine, the reaction formula is as follows: Figure 10 As shown, the specific steps are as follows: 5-Phenylopyrazole[1,5-] was added to a 10 mL pressure-resistant tube. aPyrimidine-7-amine (0.1 mmol, 0.0210 g), glyoxylic acid monohydrate (0.12 mmol, 0.0110 g), N-methyl-1-phenylmethylamine (0.15 mmol, 0.0181 g), and dimethyl sulfoxide (2 mL) were mixed and heated and stirred at 110 °C for 20 hours. After the reaction was complete, ethyl acetate was added to dilute the crude product, which was then transferred to a container. The solvent was removed by extraction with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Finally, the crude product was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 2:1) to obtain the final product 3-((benzyl(methyl)amino)methyl)-5-phenylpyrazolo[1,5- a Pyrimidine-7-amine (29.4 mg), yield 86%.

[0036] 3-((benzyl(methyl)amino)methyl)-5-phenylpyrazolo[1,5- a Pyrimidine-7-amine: 1 H NMR (400MHz, CDCl3) δ 7.99 (s, 1H), 7.93 (dt, J = 8.0, 2.0 Hz, 2H), 7.39 – 7.32 (m, 5H), 7.28 – 7.22 (m, 2H), 7.20 – 7.14 (m, 1H), 6.37 – 6.34 (m, 1H), 5.80 (d, J =16.4 Hz, 2H), 3.84 (s, 2H), 3.56 (s, 2H), 2.24 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 156.89, 147.97, 146.95, 145.52, 139.01, 138.58, 129.79, 129.38, 128.71, 128.37, 127.32, 127.11, 105.47, 85.27, 61.33, 49.82, 42.07. Example 11 Example 11 of the invention provides a 5-phenyl-3-(thiomorpholinocarboxyl)pyrazolo[1,5- a The synthesis method of pyrimidine-7-amine, the reaction formula is as follows: Figure 11 As shown, the specific steps are as follows: 5-Phenylopyrazole[1,5-] was added to a 10 mL pressure-resistant tube. aPyrimidine-7-amine (0.1 mmol, 0.0210 g), glyoxylic acid monohydrate (0.12 mmol, 0.0110 g), thiomorpholine (0.15 mmol, 0.0154 g), and dimethyl sulfoxide (2 mL) were mixed and heated and stirred at 110 °C for 12 hours. After the reaction was complete, ethyl acetate was added to dilute the crude product, which was then transferred to a container. The solvent was removed by extraction with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Finally, the crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the final product 5-phenyl-3-(thiomorpholine carboxyl)pyrazolo[1,5- a Pyrimidine-7-amine (27.9 mg), yield 86%.

[0037] 5-Phenyl-3-(thiomorpholinoyl)pyrazolo[1,5- a Pyrimidine-7-amine: 1 H NMR (400 MHz, CDCl3) δ 8.06 – 7.99 (m, 3H), 7.50 – 7.42 (m, 3H), 6.50 (s, 1H), 5.78 (s, 2H), 3.92 (s, 2H), 2.89 (dd, J = 6.8, 3.6 Hz, 4H), 2.76 – 2.69 (m, 4H). 13 C NMR (101MHz, CDCl3) δ 157.09, 148.15, 146.87, 145.58, 138.51, 129.95, 128.83, 127.31, 104.11, 85.37, 54.35, 51.67, 27.91. Example 12 Example 12 of the invention provides a 3-((4-(2-piperidinylethyl)pyridin-1-yl)methyl)-5-phenylpyrazolo[1,5- a The synthesis method of pyrimidine-7-amine, the reaction formula is as follows: Figure 12 As shown, the specific steps are as follows: 5-Phenylopyrazole[1,5-] was added to a 10 mL pressure-resistant tube. aPyrimidine-7-amine (0.1 mmol, 0.0210 g), glyoxylic acid monohydrate (0.12 mmol, 0.0110 g), 4-morpholinyl-2-ethylpiperazine (0.15 mmol, 0.0298 g), and dimethyl sulfoxide (2 mL) were mixed and heated and stirred at 110 °C for 12 hours. After the reaction was complete, ethyl acetate was added to dilute the crude product, which was then extracted with saturated brine to remove the solvent. The product was dried over anhydrous sodium sulfate and the solvent was removed by vacuum distillation. Finally, the crude product was purified by silica gel rapid chromatography (dichloromethane / methanol = 3:1) to obtain the final product 3-((4-(2-piperidinylethyl)pyridin-1-yl)methyl)-5-phenylpyrazolo[1,5- a Pyrimidine-7-amine (22.1 mg), yield 52%.

[0038] 3-((4-(2-piperidinylethyl)pyridin-1-yl)methyl)-5-phenylpyrazolo[1,5- a Pyrimidine-7-amine: 1 HNMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 8.04 – 8.00 (m, 2H), 7.47 – 7.42 (m, 3H), 6.50 (s, 1H), 5.89 (s, 2H), 3.95 (s, 2H), 3.70 – 3.66 (t, J = 4.4Hz, 4H), 2.73(s, 4H), 2.61 (s, 3H), 2.54 – 2.47 (m, 5H), 2.46 – 2.43 (m, 4H). 13 C NMR (101MHz, CDCl3) δ 157.08, 148.23, 146.94, 145.74, 138.48, 129.93, 128.80, 127.30, 85.34, 67.04, 56.48, 55.48, 54.22, 53.26, 52.22, 50.53, 41.14. The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A pyrazolo[1,5-] a A method for aminomethylation of pyrimidine-based nitrogen-containing fused heterocyclic substrates, characterized in that, The aminomethylation reaction method induces the pyrazolo[1,5-] genotype (I) under heating conditions. a The nitrogen-containing fused heterocyclic pyrimidine substrates undergo aminomethylation with the secondary amine compound shown in formula (II), and the chemical reaction formula is shown below: Formula (I) Formula (II) Formula (III).

2. The pyrazolo[1,5-]based [method / method / etc.] according to claim 1 a A method for aminomethylation of pyrimidine-based nitrogen-containing fused heterocyclic substrates, characterized in that, R1 includes one of H and Ph; The R2 includes 4-Clphenyl, 4-Brphenyl, 3-Clphenyl, 4-OMephenyl, 3-OMephenyl, heterocyclic aromatic hydrocarbons, t -One of the Bu types.

3. The pyrazolo[1,5-]based [method / method / etc.] according to claim 1 a A method for aminomethylation of pyrimidine-based nitrogen-containing fused heterocyclic substrates, characterized in that, The molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1:1.

5.

4. The pyrazolo[1,5-]based [method / ...] according to claim 1 a A method for aminomethylation of pyrimidine-based nitrogen-containing fused heterocyclic substrates, characterized in that, The heating temperature is 100~120 ℃, and the heating time is 12~20 h.

5. The pyrazolo[1,5-]-based [method / method / method] according to claim 4 a A method for aminomethylation of pyrimidine-based nitrogen-containing fused heterocyclic substrates, characterized in that, The heating temperature is 110 ℃.

6. A method based on pyrazolo[1,5-] as described in any one of claims 1 to 5 a Products prepared by aminomethylation of pyrimidine nitrogen-containing fused heterocyclic substrates.

7. A pyrazolo[1,5-]-based [method / method / method] according to claim 6 a Application of products prepared by aminomethylation reaction of pyrimidine nitrogen-containing fused heterocyclic substrates in drug development.

Images