Nitrification method of 5-phenylpyrazolo [1, 5-a] pyrimidine-7-amine

Abstract

The invention belongs to the technical field of organic chemistry, and particularly relates to a nitration method of 5-phenylpyrazolo [1, 5-a] pyrimidine-7-amine, which comprises the following steps: adding 5-phenylpyrazolo [1, 5-a] pyrimidine-7-amine and Fe (NO3) 3.9 H2O into a reaction tube, adding a solvent, and after the reaction is completed, separating and purifying the reaction liquid to obtain the final product 3-nitro-5-phenylpyrazolo [1, 5-a] pyrimidine-7-amine. The invention relates to a pyrimidine-7-amine compound. The efficient selective C3 nitration method of 5-phenylpyrazolo [1, 5-a] pyrimidine-7-amine and iron nitrate nonahydrate is realized at room temperature under the action of a solvent by taking non-toxic, cheap and easily available Fe (NO3) 3.9 H2O as a nitro source without additionally adding a metal catalyst, an organic ligand and alkali, a corresponding nitration product is obtained, and the highest yield can reach 94%.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemistry, and particularly relates to a nitration method of 5-phenylpyrazolo[1,5-a]pyrimidin-7-amine. Background Art

[0002] Pyrazolo[1,5-a]pyrimidine, as an important nitrogen-containing heterocycle, is widely used in medicinal chemistry, materials science and the dye industry. Due to its specific biological activity, it widely exists in important drug molecular skeletons, such as approved drugs like the sleeping pill Indiplon, the anti-anxiety drug Ocinaplon and the sedative Zaloplan, as well as the fungicide Pyrazophos. Therefore, the synthesis and modification of pyrazolo[1,5-a]pyrimidine have attracted much attention in the fields of synthetic chemistry and medicinal chemistry.

[0003] Nitroarenes, as an important source of nitrogen-containing arenes, have great economic benefits in the fields of medicine, dyes, pesticides, functional materials, chemical fertilizers, explosives, etc. Thus, the introduction of nitro groups into aromatic or heteroaromatic compounds has become a research focus. However, the well-known polluting nitration industry, which suffers from excessive emissions of flue gas and waste acid, poor functional group tolerance and great purification difficulties, makes mild, efficient and environmentally friendly nitration reactions a daunting challenge.

[0004] Traditional methods for producing nitroarenes mainly rely on aromatic electrophilic substitution reactions of nitronium ions [NO2 + , usually achieved by the "mixed acid" method of concentrated sulfuric acid and nitric acid. This method has harsh reaction conditions, resulting in poor selectivity, over-nitration or the formation of isomer mixtures. In addition, the limitations of nitration reaction conditions (such as high temperature and strong acid), the use of noble metal catalysts (such as Pd, Rh and Ru) and their non-recyclability, as well as the limited reaction scope, all make the development of mild, efficient and environmentally friendly nitration schemes an urgent need to meet the requirements of green and circular economy. To overcome these obstacles, various new nitration reagents have been designed in the past few decades to promote the nitration of aromatic compounds. Among them, Fe(NO3)3·9H2O, as a non-toxic, inexpensive and easily available nitration reagent, has attracted much attention in organic synthesis due to its higher functional group tolerance.

[0005] In 2024, Cheng et al. reported that pyrazolo[1,5-a]pyrimidine compounds with nitro substitution could improve the energy density, thermal stability and detonation performance of energetic materials, while reducing their sensitivity, making them potential new high-performance and low-sensitivity energetic materials. However, for the nitration reaction of pyrazolo[1,5-a]pyrimidine compounds, the reported methods usually employ harsh reaction conditions such as "mixed acid" of concentrated sulfuric acid and nitric acid, microwave or high temperature. Therefore, it is urgent to overcome the problems existing in the prior art and provide a new nitration method for pyrazolo[1,5-a]pyrimidine. Summary of the Invention

[0006] The object of the present invention is to provide a nitration method for 5-phenylpyrazolo[1,5-a]pyrimidin-7-amine. This method uses Fe(NO3)3·9H2O as a non-toxic, inexpensive and easily available nitrating reagent, avoiding the traditional "mixed acid" method of concentrated sulfuric acid and nitric acid, and realizing an efficient and selective C3 nitration method of 5-phenylpyrazolo[1,5-a]pyrimidin-7-amine with ferric nitrate nonahydrate. This method has good efficiency and regioselectivity, a wide range of substrate applicability, high yield in gram-scale reactions, and extensive applications in late-stage functionalization.

[0007] The object of the present invention is achieved by the following technical solutions:

[0008] The present invention provides a nitration method for 5-phenylpyrazolo[1,5-a]pyrimidin-7-amine, and the method comprises the following steps:

[0009] Add 5-phenylpyrazolo[1,5-a]pyrimidin-7-amine and Fe(NO3)3·9H2O into a reaction tube, add a solvent, and after the reaction is completed, separate and purify the reaction solution to obtain the final product 3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine compound.

[0010] Further, the reaction general formula of the method is:

[0011]

[0012] Wherein, R 1 is t-Bu or a substituent at the 3-position of the benzene ring;

[0013] R 2 is a thiophene group or a substituent on the benzene ring.

[0014] Further, when R 1 is a substituent at the 3-position of the benzene ring, it is selected from H, Cl; when R 2 is a substituent on the benzene ring, it is selected from 4-H, 4-F, 4-Cl, 4-Br, 4-Me or 3-CF3.

[0015] Furthermore, the molar ratio of the 5-phenylpyrazolo[1,5-a]pyrimidin-7-amine to Fe(NO3)3·9H2O is 2:1.

[0016] Furthermore, the solvent is trifluoroacetic acid.

[0017] Furthermore, the reaction time is 50 min - 60 min, and the reaction temperature is room temperature.

[0018] Furthermore, the specific steps of separation are to quench the reaction solution with saturated sodium bicarbonate solution, extract 3 times with ethyl acetate, dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure. The specific steps of purification are to purify the crude product by silica gel flash chromatography.

[0019] Furthermore, the ratio of petroleum ether / ethyl acetate in the silica gel flash chromatography is 1:1.

[0020] The present invention also provides 3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine and its derivatives prepared by the method described above.

[0021] The present invention also provides the application of the 3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine and its derivatives in the fields of synthetic chemistry and medicinal chemistry.

[0022] The beneficial effects of the present invention are as follows:

[0023] 1. The present invention uses non-toxic, inexpensive, and readily available Fe(NO3)3·9H2O as the nitro source, without the need to additionally add metal catalysts, organic ligands, and bases. At room temperature, under the action of a solvent, an efficient and selective C3 nitration method of 5-phenylpyrazolo[1,5-a]pyrimidin-7-amine with ferric nitrate nonahydrate is achieved, obtaining the corresponding nitration product, and the highest yield can reach 94%.

[0024] 2. The nitro source Fe(NO3)3·9H2O used in the present invention has high nitration efficiency. Compared with the same type of reactions reported in the literature, the reaction time is short, the reaction conditions are mild, the products are simple and easy to separate, effectively improving the sustainability and environmental friendliness of the reaction, more conforming to the requirements of the development of green chemistry, and having broad application prospects in the preparation of natural products, drugs, and pesticides. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for use in the embodiments. Obviously, the following described drawings are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0026] Figure 1 1H NMR spectrum of 3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine prepared according to the present invention. Detailed implementation manners

[0027] The embodiments of the present invention are described in detail below. The embodiments are intended to explain the present invention and should not be construed as limiting the present invention. For those specific technologies or conditions not specified in the embodiments, they shall be carried out according to the technologies or conditions described in the literature in this field or according to the product specifications. For the reagents or instruments whose manufacturers are not specified, they are all conventional products that can be obtained through commercial purchase.

[0028] The present invention uses 5-phenylpyrazolo[1,5-a]pyrimidin-7-amine and Fe(NO3)3·9H2O as reactants to prepare 3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine and its derivatives. The main steps are as follows: Add 5-phenylpyrazolo[1,5-a]pyrimidin-7-amine and Fe(NO3)3·9H2O into a reaction tube, add a solvent, and after the reaction is completed, separate and purify the reaction solution to obtain the final product, the 3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine compound.

[0029] The structure of the said Fe(NO3)3·9H2O is as follows:

[0030]

[0031] The said solvent is trifluoroacetic acid;

[0032] Furthermore, the general formula of the nitration reaction is as follows:

[0033]

[0034] In the formula, R 1 is H, t-Bu, or a substituent at the 3-position of the benzene ring, selected from the following groups (one of them): H, Cl;

[0035] R 2 is a thiophenyl group, or a substituent on the benzene ring, selected from the following groups (one of them): 4-H, 4-F, 4-Cl, 4-Br, 4-Me, 3-CF3;

[0036] Furthermore, the molar ratio of the said 5-phenylpyrazolo[1,5-a]pyrimidin-7-amine to Fe(NO3)3·9H2O is 2:1;

[0037] Furthermore, the said reaction temperature is room temperature and the time is 50 min - 60 min.

[0038] To have a clearer understanding of the technical features, objectives, and effects of the present invention, the specific embodiments of the present invention will now be described.

[0039] Example 1 3-Nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine

[0040] The preparation steps of 3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine in this example are as follows: Charge 5-phenylpyrazolo[1,5-a]pyrimidin-7-amine (0.2 mmol, 0.0421 g), iron(III) nitrate nonahydrate (0.1 mmol, 0.0404 g), and trifluoroacetic acid (1 mL) into a 10 mL thick-walled pressure-resistant tube, and stir the mixture at room temperature for 1 hour. After the reaction is completed, quench the reaction solution with saturated sodium bicarbonate solution (10 mL), and extract the organic phase with ethyl acetate (15 mL × 3). Then dry the organic layer with anhydrous Na2SO4 and remove the solvent under reduced pressure. Finally, purify the crude product by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 1:1) to obtain 47.98 mg of the final product 3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine, with a yield of 94%. The reaction formula is as follows:

[0041]

[0042] The NMR spectrum of the prepared 3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine is as Figure 1 shown: 1 1H NMR (400 MHz, DMSO-d6) δ: 8.91 (s, 1H), 8.53 (s, 2H), 8.16 - 8.11 (m, 2H), 7.60 - 7.53 (m, 3H), 6.94 (s, 1H); 13 13C NMR (101 MHz, DMSO) δ: 159.78, 149.29, 143.68, 142.63, 136.70, 130.76, 128.91, 127.18, 121.21, 89.55.

[0043] Example 2 5-(4-Fluorophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine

[0044] The preparation steps of 5-(4-fluorophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine in this example are as follows: Charge 5-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.2 mmol, 0.0456 g), iron(III) nitrate nonahydrate (0.1 mmol, 0.0404 g) and trifluoroacetic acid (1 mL) into a 10 mL thick-walled pressure-resistant tube, and stir the mixture at room temperature for 1 hour. After the reaction is completed, quench the reaction solution with saturated sodium bicarbonate solution (10 mL), and extract the organic phase with ethyl acetate (15 mL × 3). Then dry the organic layer with anhydrous Na2SO4 and remove the solvent under reduced pressure. Finally, purify the crude product by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 1:1) to obtain 42.08 mg of the final product 5-(4-fluorophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine, with a yield of 77%. The reaction formula is as follows:

[0045]

[0046] 5-(4-fluorophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine: 1 HNMR(400MHz,DMSO-d6)δ8.90(s,1H),8.55(s,2H),8.22-8.16(m,2H),7.43-7.37(m,2H),6.91(s,1H); 13 CNMR(101MHz,DMSO-d6)δ164.23(d,J=248.5Hz),159.12,149.76,144.09,143.10,133.65(d,J=2.9Hz),130.07(d,J=8.8Hz),121.68,116.36(d,J=21.8Hz),89.81; 19 FNMR(376MHz,DMSO)δ-110.40.

[0047] Example 3 5-(4-bromophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine

[0048] In this example, the preparation steps of 5-(4-bromophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine are as follows: Charge 5-(4-bromophenyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.2 mmol, 0.0578 g), iron(III) nitrate nonahydrate (0.1 mmol, 0.0404 g) and trifluoroacetic acid (1 mL) into a 10 mL thick-walled pressure-resistant tube, and stir the mixture at room temperature for 1 hour. After the reaction is completed, quench the reaction solution with saturated sodium bicarbonate solution (10 mL), and extract the organic phase with ethyl acetate (15 mL × 3). Then dry the organic layer over anhydrous Na2SO4 and remove the solvent under reduced pressure. Finally, purify the crude product by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 1:1) to obtain 46.78 mg of the final product 5-(4-bromophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine, with a yield of 70%.

[0049] The reaction formula is as follows:

[0050]

[0051] 5-(4-bromophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine: 1 HNMR(400MHz,DMSO-d6)δ8.92(s,1H),8.70-8.41(m,2H),8.10-8.04(m,2H),7.80-7.75(m,2H),6.93(s,1H); 13 CNMR(101MHz,DMSO)δ158.47,149.32,143.60,142.66,135.83,131.90,129.14,124.50,121.26,89.47.

[0052] Example 4 5-(4-chlorophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine

[0053] In this example, the preparation steps of 5-(4-bromophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine are as follows: Charge 5-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.2 mmol, 0.0489 g), iron(III) nitrate nonahydrate (0.1 mmol, 0.0404 g) and trifluoroacetic acid (1 mL) into a 10 mL thick-walled pressure-resistant tube, and stir the mixture at room temperature for 1 hour. After the reaction is completed, quench the reaction solution with saturated sodium bicarbonate solution (10 mL), and extract the organic phase with ethyl acetate (15 mL × 3). Then dry the organic layer with anhydrous Na2SO4 and remove the solvent under reduced pressure. Finally, purify the crude product by flash silica gel chromatography (petroleum ether / ethyl acetate = 1:1) to obtain 47.51 mg of the final product 5-(4-chlorophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine, with a yield of 82%.

[0054] The reaction formula is as follows:

[0055]

[0056] 5-(4-chlorophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine: 1 HNMR(400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.71 - 8.47 (m, 2H), 8.18 - 8.12 (m, 2H), 7.66 - 7.61 (m, 2H), 6.93 (s, 1H); 13 CNMR(101 MHz, DMSO) δ 158.38, 149.32, 143.60, 142.66, 135.59, 135.48, 128.97, 128.92, 121.26, 89.51.

[0057] Example 5 3-Nitro-5-(p-tolyl)pyrazolo[1,5-a]pyrimidin-7-amine

[0058] The preparation steps of 5-(4-bromophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine in this example are as follows: Charge 5-(p-tolyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.2 mmol, 0.0449 g), iron(III) nitrate nonahydrate (0.1 mmol, 0.0404 g) and trifluoroacetic acid (1 mL) into a 10 mL thick-walled pressure-resistant tube, and stir the mixture at room temperature for 50 min. After the reaction is completed, quench the reaction solution with saturated sodium bicarbonate solution (10 mL), and extract the organic phase with ethyl acetate (15 mL×3). Then dry the organic layer with anhydrous Na2SO4 and remove the solvent under reduced pressure. Finally, purify the crude product by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 1:1) to obtain the final product 3-nitro-5-(p-tolyl)pyrazolo[1,5-a]pyrimidin-7-amine 37.16 mg, with a yield of 69%.

[0059] The reaction formula is as follows:

[0060]

[0061] 3-nitro-5-(p-tolyl)pyrazolo[1,5-a]pyrimidin-7-amine: 1 HNMR(400MHz,DMSO-d6)δ8.89(s,1H),8.48(s,2H),8.07-7.98(m,2H),7.43-7.33(m,2H),6.91(s,1H),2.39(s,3H); 13 CNMR(101MHz,DMSO)δ160.19,149.69,144.14,143.04,141.20,134.34,129.98,127.58,121.59,89.56,21.44.

[0062] Example 6 3-nitro-5-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-amine

[0063] In this example, the preparation steps of 5-(4-bromophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine are as follows: Charge 5-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.2 mmol, 0.0556 g), iron(III) nitrate nonahydrate (0.1 mmol, 0.0404 g) and trifluoroacetic acid (1 mL) into a 10 mL thick-walled pressure-resistant tube, and stir the mixture at room temperature for 1 hour. After the reaction is completed, quench the reaction solution with saturated sodium bicarbonate solution (10 mL), and extract the organic phase with ethyl acetate (15 mL × 3). Then dry the organic layer over anhydrous Na2SO4 and remove the solvent under reduced pressure. Finally, purify the crude product by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 1:1) to obtain the final product 3-nitro-5-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-amine, 45.25 mg, with a yield of 70%. The reaction formula is as follows:

[0064]

[0065] 3-nitro-5-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-amine: 1 HNMR(400MHz,DMSO-d6)δ8.93(s,1H),8.61(s,2H),8.44-8.36(m,2H),7.91(ddt,J=7.8,1.8,0.9Hz,1H),7.81(t,J=7.8Hz,1H),7.02(s,1H); 13 CN MR(101MHz,DMSO-d6)δ158.31,149.90,144.08,143.22,138.19,131.53,130.68, 130.11(d,J=31.9Hz),127.61(d,J=4.0Hz),123.98(d,J=4.0Hz),121.83,90.52.

[0066] Example 7 3-nitro-2,5-diphenylpyrazolo[1,5-a]pyrimidin-7-amine

[0067] In this example, the preparation steps of 5-(4-bromophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine are as follows: Charge 2,5-diphenylpyrazolo[1,5-a]pyrimidin-7-amine (0.2 mmol, 0.0573 g), iron(III) nitrate nonahydrate (0.1 mmol, 0.0404 g) and trifluoroacetic acid (1 mL) into a 10 mL thick-walled pressure tube, and stir the mixture at room temperature for 1 hour. After the reaction is completed, quench the reaction solution with saturated sodium bicarbonate solution (10 mL), and extract the organic phase with ethyl acetate (15 mL×3). Then dry the organic layer over anhydrous Na2SO4 and remove the solvent under reduced pressure. Finally, purify the crude product by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 1:1) to obtain the final product 3-nitro-2,5-diphenylpyrazolo[1,5-a]pyrimidin-7-amine, 59.64 mg, with a yield of 90%. The reaction formula is as follows:

[0068]

[0069] 3-nitro-2,5-diphenylpyrazolo[1,5-a]pyrimidin-7-amine: 1 HNMR(400MHz,DMSO-d6)δ8.51(s,2H),8.16(dd,J=7.5,2.1Hz,2H),7.75(dd,J=6.6,2.9Hz,2H),7.63-7.45(m,6H),6.97(s,1H); 13 CNMR(101MHz,DMSO)δ160.09,153.18,149.34,145.57,137.27,131.76,131.18,130.03,130.00,129.37,128.36,127.63,119.18,90.24.

[0070] Example 8 2-(3-chlorophenyl)-3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine

[0071] In this example, the preparation steps of 5-(4-bromophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine are as follows: Charge 2-(3-chlorophenyl)-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine (0.2 mmol, 0.0642 g), iron(III) nitrate nonahydrate (0.1 mmol, 0.0404 g), and trifluoroacetic acid (1 mL) into a 10 mL thick-walled pressure-resistant tube. Stir the mixture at room temperature for 1 hour. After the reaction is completed, quench the reaction solution with saturated sodium bicarbonate solution (10 mL), and extract the organic phase with ethyl acetate (15 mL × 3). Then dry the organic layer over anhydrous Na2SO4 and remove the solvent under reduced pressure. Finally, purify the crude product by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 1:1) to obtain the final product 2-(3-chlorophenyl)-3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine, 61.45 mg, with a yield of 84%. The reaction formula is as follows:

[0072]

[0073] 2-(3-chlorophenyl)-3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine: 1 HNMR (400 MHz, DMSO-d6) δ 8.55 (s, 2H), 8.18 - 8.13 (m, 2H), 7.83 (t, J = 1.9 Hz, 1H), 7.74 (dt, J = 7.5, 1.5 Hz, 1H), 7.63 - 7.54 (m, 5H), 6.98 (s, 1H); 13 CNMR (101 MHz, DMSO) δ 159.78, 151.20, 148.90, 145.03, 136.73, 133.34, 132.57, 130.78, 129.83, 129.45, 129.26, 128.92, 128.43, 127.19, 89.89.

[0074] Example 9 3-nitro-5-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-7-amine

[0075] In this example, the preparation steps of 5-(4-bromophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine are as follows: Charge 5-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-7-amine (0.2 mmol, 0.0433 g), iron(III) nitrate nonahydrate (0.1 mmol, 0.0404 g) and trifluoroacetic acid (1 mL) into a 10 mL thick-walled pressure-resistant tube, and stir the mixture at room temperature for 1 hour. After the reaction is completed, quench the reaction solution with saturated sodium bicarbonate solution (10 mL), and extract the organic phase with ethyl acetate (15 mL × 3). Then dry the organic layer over anhydrous Na2SO4 and remove the solvent under reduced pressure. Finally, purify the crude product by silica gel flash chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the final product 3-nitro-5-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-7-amine, 38.67 mg, with a yield of 74%. The reaction formula is as follows:

[0076]

[0077] 3-nitro-5-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-7-amine: 1 HNMR(400MHz,DMSO-d6)δ8.85(s,1H),8.48(s,2H),7.83(ddd,J=10.8,4.4,1.1Hz,2H),7.22(dd,J=5.1,3.7Hz,1H),6.83(s,1H); 13 CNMR(101MHz,DM SO)δ155.53,149.48,143.97,142.82,142.78,131.70,129.20,128.47,121.45,88.25.

[0078] Example 10 2-(tert-butyl)-3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine

[0079] In this example, the preparation steps of 5-(4-bromophenyl)-3-nitropyrazolo[1,5-a]pyrimidin-7-amine are as follows: Charge 2-(tert-butyl)-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine (0.2 mmol, 0.0533 g), iron(III) nitrate nonahydrate (0.1 mmol, 0.0404 g) and trifluoroacetic acid (1 mL) into a 10 mL thick-walled pressure-resistant tube, and stir the mixture at room temperature for 1 hour. After the reaction is completed, quench the reaction solution with saturated sodium bicarbonate solution (10 mL), and extract the organic phase with ethyl acetate (15 mL × 3). Then dry the organic layer with anhydrous Na2SO4 and remove the solvent under reduced pressure. Finally, purify the crude product by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 1:1) to obtain the final product 2-(tert-butyl)-3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine, 54.17 mg, with a yield of 87%. The reaction formula is as follows:

[0080]

[0081] 2-(tert-butyl)-3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine: 1 HNMR(400MHz,DMSO-d6)δ8.30(s,2H),8.14-8.07(m,2H),7.59-7.49(m,3H),6.90(s,1H),1.52(s,9H); 13 CNMR(101MHz,DMSO)δ160.77,159.98,149.05,146.65,137.36,131.07,129.30,127.59,120.28,89.81,34.99,28.40.

[0082] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention and are not intended to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and they should all be covered by the scope of the claims of the present invention.

Claims

1. A nitration method of 5-phenylpyrazolo[1,5-a]pyrimidin-7-amine, characterized in that, The method comprises the following steps: Add 5-phenylpyrazolo[1,5-a]pyrimidin-7-amine and Fe(NO3)3·9H2O into a reaction tube, add a solvent, after the reaction is completed, separate and purify the reaction solution to obtain the final product 3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine compound.

2. The method according to claim 1, characterized in that The reaction general formula of the method is: Among them, R 1 is a substituent at the 3-position of t-Bu or the benzene ring; R 2 is a substituent on the thiophene group or the benzene ring.

3. The method according to claim 2, wherein The R 1 When it is a substituent at the 3-position on the benzene ring, it is selected from H and Cl; the R 2 When it is a substituent on the benzene ring, it is selected from 4-H, 4-F, 4-Cl, 4-Br, 4-Me or 3-CF3.

4. The method according to claim 1, wherein The molar ratio of the 5-phenylpyrazolo[1,5-a]pyrimidin-7-amine to Fe(NO3)3·9H2O is 2:

1.

5. The method according to claim 1, wherein The solvent is trifluoroacetic acid.

6. The method according to claim 1, wherein The reaction time is 50 min - 60 min, and the reaction temperature is room temperature.

7. The method according to claim 1, characterized in that The specific steps of the separation are to quench the reaction solution with saturated sodium bicarbonate solution, extract with ethyl acetate three times, dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure. The specific steps of the purification are to purify the crude product by silica gel flash chromatography.

8. The method according to claim 7, wherein The ratio of petroleum ether / ethyl acetate in the silica gel flash chromatography is 1:

1.

9. 3-Nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine and its derivatives prepared by the method according to any one of claims 1-8.

10. Use of the 3-nitro-5-phenylpyrazolo[1,5-a]pyrimidin-7-amine and its derivatives according to claim 9 in the fields of synthetic chemistry and medicinal chemistry.

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