Method for photocatalytic synthesis of 5-substituted pyrazolo [4, 3-d] pyrimidine-7 (6H)-ketone derivative

Abstract

The invention belongs to the technical field of organic synthesis, and particularly discloses a method for photocatalytic synthesis of a 5-substituted pyrazolo [4, 3-d] pyrimidine-7 (6H)-ketone derivative, which comprises the following steps: mixing 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-formamide and an aldehyde compound in a solvent, carrying out light irradiation at a certain temperature, and carrying out a reaction for 2-4 hours to obtain the 5-substituted pyrazolo [4, 3-d] pyrimidine-7 (6H)-ketone derivative. Under the combined action of a photocatalyst and alkali, carrying out aerobic oxidation reaction to synthesize the 5-substituted pyrazolo [4, 3-d] pyrimidine-7 (6H)-ketone derivative as shown in a formula III; according to the present invention, the cheap and easily available aldehyde compound is adopted as the raw material, the reaction condition is mild, the operation is simple, the selectivity and the yield of the product are high, the metal catalysis reaction is avoided, the use of the noble metal and the toxic reagent is avoided, and the wide industrial application prospect is provided, and the green chemical development idea is met.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, relates to the synthesis of pharmaceutical and chemical intermediates, and particularly relates to a method for photocatalytic aerobic oxidation synthesis of 5-substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one and its derivatives. Background Art

[0002] Pyrazolo[4,3-d]pyrimidin-7(6H)-one is a class of important nitrogen-containing heterocyclic compounds, formed by the fusion of a pyrazole ring and a pyrimidinone ring, and widely exists in natural products and synthetic drugs. Due to its good pharmacological activities, pyrazolopyrimidinone plays a very important role in biochemistry and living cells, and is widely used and studied as a phosphodiesterase inhibitor, adenosine antagonist, cytokinin antagonist, corticotropin-releasing factor antagonist, antifungal agent, antitumor agent, etc. The marketed drug sildenafil is the most common pyrazolo[4,3-d]pyrimidine compound, and is currently clinically used for the treatment of male erectile dysfunction (ED) and pulmonary arterial hypertension.

[0003]

[0004] Many reports have been made on the synthesis methods of pyrazolo[4,3-d]pyrimidin-7(6H)-one compounds. Most traditional synthesis methods use compounds such as 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide, aldehydes, benzoyl chloride, α-keto acids, styrene, and benzylamines as raw materials. However, most of these methods require noble metals, excessive oxidants, and high-temperature conditions, resulting in low product yields and poor substrate applicability. (J. Org. Chem., 2015, 80, 6915 - 6921; Bioorg. Med. Chem. Lett., 2012, 22, 5063 - 5066; ChemistrySelect, 2017, 2, 4963 - 4968; Chem. Commun., 2016, 52, 10245 - 10248; J. Heterocycl. Chem., 2005, 42, 1085 - 1093; Tetrahedron Lett., 2017, 58, 2889 - 2892; Org. Chem. Front., 2018, 5, 2734 - 2738.) In recent years, photocatalytic reactions have become a research hotspot in the field of synthetic chemistry due to their mild reaction conditions and good functional group compatibility, and have shown excellent application potential, which is an important alternative strategy to traditional transition metal-catalyzed reactions. In addition, molecular oxygen is considered an ideal terminal oxidant due to its abundance, low cost, environmental friendliness, and easy removal after oxidation. Therefore, it is of great significance to develop a simple and efficient new method for photocatalytic synthesis of pyrazolo[4,3-d]pyrimidin-7(6H)-one under mild conditions using molecular oxygen as the final oxidant. Summary of the Invention

[0005] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide a simple and efficient new method for photocatalytic synthesis of pyrazolo[4,3-d]pyrimidin-7(6H)-one under mild conditions using molecular oxygen as the final oxidant. The present invention uses aldehyde and 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide as the initial raw materials, 4CzIPN as the photocatalyst, DMSO as the solvent, and potassium tert-butoxide as the additive. The reaction conditions are mild and the post-treatment is simple. The synthesis of pyrazolo[4,3-d]pyrimidin-7(6H)-one and its derivatives is achieved with a relatively high yield, providing a new strategy for the synthesis of such compounds.

[0006] The present invention is achieved by the following technical solutions:

[0007] A method for photocatalytic synthesis of 5-substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one derivatives, comprising the following steps:

[0008] 4-Amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide shown in Formula I is mixed with the aldehyde compound shown in Formula II in a solvent. Under the combined action of a photocatalyst and a base, an aerobic oxidation reaction occurs under light irradiation and at a certain temperature to synthesize the 5-substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one derivative shown in Formula III;

[0009]

[0010] In the formula, R is selected from n-octyl, phenylpropyl, phenyl, 4-methylphenyl, 3-methylphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 4-isopropylphenyl, 4-isopropylphenyl, 4-methylthiophenyl, 4-nitrophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-bromophenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, 2-thienyl-, 2-pyridyl, 2-furyl or benzo[b]thiophen-2-yl.

[0011] A further improvement of the present invention is as follows:

[0012] The photocatalyst is one or a mixture of two or more of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN), 2,4,5,6-tetrakis(diphenylamino)-isophthalonitrile (4DPAIPN), 2,4,5,7-tetrabromofluorescein (Eosin Y), Rhodamine B, 9-mesityl-10-methylacridinium perchlorate (Acr-Mes-Me + ClO 4 - ), ruthenium(II) tris(2,2'-bipyridyl) dichloride (Ru(bpy) 3 Cl 2 ) or 9-fluorenone.

[0013] Furthermore, the solvent is one or a mixture of two or more of acetonitrile, ethanol, dimethyl sulfoxide, tetrahydrofuran, chlorobenzene, 1,2-dichloroethane, water or toluene.

[0014] Preferably, the solvent is dimethyl sulfoxide.

[0015] Furthermore, the base is one or a mixture of two or more of potassium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, potassium phosphate or triethylamine.

[0016] Preferably, the base is potassium tert-butoxide.

[0017] Furthermore, the light irradiation is one or a mixture of two or more of sunlight, red light, blue light, green light, purple light, infrared light or ultraviolet light.

[0018] Preferably, the light irradiation condition is blue light with a wavelength of 455 nm.

[0019] Further, the molar ratio of 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide, aldehyde compound, photocatalyst and base is (1 to 1.5):(1.0 to 1.2):(0.03 to 0.05):(0.1 to 0.2).

[0020] Further, the reaction temperature is 60 to 80 °C and the time is 12 to 24 h.

[0021] Further, after the reaction, a post-treatment process is included. The post-treatment process is specifically as follows: The reaction solution is washed with water, extracted with an organic solvent, and concentrated to obtain a crude product. The crude product is obtained as a pure product by column chromatography or recrystallization.

[0022] Further, the eluent for column chromatography is petroleum ether and dichloromethane, and the mixing ratio is petroleum ether:dichloromethane = 5:1 to 1:5;

[0023] and / or, the recrystallization solvent is methanol or ethanol or a mixture of the two.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0025] The synthesis method of the present invention uses aldehyde and 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide as starting materials, which are cheap and easily available. 4CzIPN is used as a photocatalyst, DMSO is used as a solvent, and potassium tert-butoxide is used as an additive. The reaction conditions are mild and the post-treatment is simple. The synthesis of pyrazolo[4,3-d]pyrimidin-7(6H)-one and its derivatives is achieved in a high yield, providing a new strategy for the synthesis of such compounds and having high research value and broad industrial application prospects. Specific Embodiments

[0026] The present invention will be introduced in detail below with reference to specific embodiments.

[0027] Example 1: Synthesis of 5-phenyl-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0028]

[0029] 4-Amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide (91.11 mg, 0.5 mmol), benzaldehyde (63.67 mg, 0.6 mmol), photocatalyst 4CzIPN (19.72 mg, 0.025 mmol), potassium tert-butoxide (5.61 mg, 0.05 mmol) and 2 mL of dimethyl sulfoxide were successively added to a 25 mL reaction tube. The mixture was reacted at 60 °C under irradiation with a blue LED (455 nm) for 16 h; then it was extracted with dichloromethane and washed three times with water. After that, the organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product; the crude product was purified by column chromatography (petroleum ether and dichloromethane = 2:1) to obtain 110 mg of a pure light yellow solid, with a yield of 82%. 1 HNMR(400MHz,DMSO-d 6 )δ12.43(s,1H),8.07(d,J=5.6Hz,2H),7.53(s,3H),4.15(s,3H),2.80(t,J=7.0Hz,2H),1.77(dd,J=14.1,7.0Hz,2H),0.95(t,J=7.0Hz,3H). 13 C NMR(101MHz,DMSO)δ155.12,150.56,145.42,138.33,133.35,131.12,128.99,127.98,124.80,38.31,27.64,22.16,14.35.

[0030] Example 2: Synthesis of 5-(4-methylphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0031]

[0032] 4-Amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide (91.11 mg, 0.5 mmol), 4-methylbenzaldehyde (72.09 mg, 0.6 mmol), photocatalyst 4CzIPN (19.72 mg, 0.025 mmol), potassium tert-butoxide (11.22 mg, 0.1 mmol) and 2 mL of dimethyl sulfoxide were successively added to a 25 mL reaction tube. The mixture was reacted at 60 °C under irradiation with a blue LED (455 nm) for 16 h; then it was extracted with dichloromethane and washed three times with water. After that, the organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product; the crude product was purified by column chromatography (petroleum ether and dichloromethane = 2:1) to obtain 118.58 mg of a pure light yellow solid, with a yield of 84%. 1HNMR(400MHz, DMSO) δ 12.35 (s, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 4.15 (s, 3H), 2.80 (t, J = 7.5 Hz, 2H), 2.38 (s, 3H), 1.84–1.70 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13 C NMR(101MHz, DMSO) δ 155.14, 150.56, 145.32, 141.02, 138.40, 130.57, 129.57, 127.88, 124.74, 38.31, 27.63, 22.15, 21.39, 14.35.

[0033] Example 3: Synthesis of 5-(4-Isopropylphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0034]

[0035] 4-Amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide (91.11 mg, 0.5 mmol), 4-isopropylbenzaldehyde (88.92 mg, 0.6 mmol), photocatalyst 4CzIPN (19.72 mg, 0.025 mmol), potassium tert-butoxide (5.61 mg, 0.05 mmol) and 2 mL of dimethyl sulfoxide were successively added to a 25 mL reaction tube. The mixture was reacted under irradiation with blue LED (455 nm) at 60 °C for 16 h; then it was extracted with dichloromethane, washed three times with water, and then the organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product; the crude product was purified by column chromatography (petroleum ether and dichloromethane = 3:1) to obtain 131.92 mg of a light yellow solid pure product with a yield of 85%. 1 H NMR(400MHz, DMSO) δ 12.35 (s, 1H), 8.00 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 4.15 (s, 3H), 2.95 (hept, J = 6.9 Hz, 1H), 2.79 (t, J = 7.5 Hz, 2H), 1.82–1.71 (m, 2H), 1.23 (d, J = 6.9 Hz, 6H), 0.95 (t, J = 7.4 Hz, 3H). 1313C NMR (101 MHz, DMSO) δ 155.13, 151.70, 150.56, 145.31, 138.41, 131.01, 128.02, 126.91, 124.71, 38.29, 33.78, 27.64, 24.09, 22.13, 14.34.

[0036] Example 4: Synthesis of 5-(3,4-dimethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0037]

[0038] 4-Amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide (91.11 mg, 0.5 mmol), 3,4-dimethoxybenzaldehyde (99.7 mg, 0.6 mmol), photocatalyst 4CzIPN (19.72 mg, 0.025 mmol), potassium tert-butoxide (5.61 mg, 0.05 mmol) and 2 mL of dimethyl sulfoxide were successively added to a 25 mL reaction tube. The mixture was reacted under irradiation with a blue LED (455 nm) at 60 °C for 16 h; then it was extracted with dichloromethane, washed three times with water, and then the organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product; the crude product was purified by column

[0039] chromatography (petroleum ether and dichloromethane = 2:1) to obtain 147.77 mg of a pure white solid, with a yield of 90%. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 12.27 (s, 1H), 7.77–7.64 (m, 2H), 7.06 (d, J = 8.5 Hz, 1H), 4.14 (s, 3H), 3.84 (d, J = 15.4 Hz, 6H), 2.79 (t, J = 7.5 Hz, 2H), 1.84–1.70 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13 13C NMR (101 MHz, DMSO) δ 155.25, 151.32, 150.27, 148.84, 145.13, 138.47, 125.60, 124.53, 121.08, 111.80, 111.00, 56.04, 38.26, 27.61, 22.07, 14.35.

[0040] Example 5: Synthesis of 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0041]

[0042] 4-Amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide (91.11 mg, 0.5 mmol), 2-ethoxybenzaldehyde (90.1 mg, 0.6 mmol), photocatalyst 4CzIPN (19.72 mg, 0.025 mmol), potassium tert-butoxide (5.61 mg, 0.05 mmol) and 2 mL of dimethyl sulfoxide were successively added to a 25 mL reaction tube. The mixture was reacted under irradiation with a blue LED (455 nm) at 60 °C for 16 h; then it was extracted with dichloromethane, washed three times with water, and then the organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product; the crude product was purified by column chromatography (petroleum ether and dichloromethane = 1:1) to obtain 129.59 mg of a pure white solid product with a yield of 83%. 1 H NMR (400 MHz, CDCl 3 ) δ 11.13 (s, 1H), 8.46 (dd, J = 7.9, 1.6 Hz, 1H), 7.44 (t, J = 8.7 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 4.35–4.22 (m, 5H), 3.00–2.85 (m, 2H), 1.94–1.82 (m, 2H), 1.59 (t, J = 7.0 Hz, 3H), 1.03 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 156.47, 153.93, 148.38, 146.61, 138.71, 132.36, 131.03, 124.44, 121.81, 120.19, 112.88, 65.26, 38.16, 27.81, 22.39, 14.71, 14.08.

[0043] Example 6: Synthesis of 5-(4-methylthiophenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0044]

[0045] 4-Amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide (91.11 mg, 0.5 mmol), 4-methylthio benzaldehyde (91.33 mg, 0.6 mmol), photocatalyst 4CzIPN (19.72 mg, 0.025 mmol), potassium tert-butoxide (5.61 mg, 0.05 mmol) and 2 mL of dimethyl sulfoxide were successively added to a 25 mL reaction tube. The mixture was reacted under irradiation with a blue LED (455 nm) at 60 °C for 16 h; then it was extracted with dichloromethane and washed three times with water. After that, the organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product; the crude product was purified by column chromatography (petroleum ether and dichloromethane = 2:1) to obtain 125.76 mg of a pure white solid, with a yield of 80%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.36 (s, 1H), 8.03 (d, J = 7.2 Hz, 2H), 7.36 (d, J = 6.9 Hz, 2H), 4.15 (s, 3H), 2.90–2.71 (m, 2H), 1.77 (d, J = 6.9 Hz, 2H), 1.04–0.84 (m, 3H). 13 C NMR (101 MHz, DMSO) δ 155.10, 150.07, 145.31, 142.39, 138.35, 129.41, 128.25, 125.59, 124.70, 38.28, 27.64, 22.12, 14.63, 14.34.

[0046] Example 7: Synthesis of 5-(2-chlorophenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0047]

[0048] 4-Amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide (91.11 mg, 0.5 mmol), 2-chlorobenzaldehyde (84.34 mg, 0.6 mmol), photocatalyst 4CzIPN (19.72 mg, 0.025 mmol), potassium tert-butoxide (5.61 mg, 0.05 mmol) and 2 mL of dimethyl sulfoxide were successively added to a 25 mL reaction tube. The mixture was reacted under irradiation with a blue LED (455 nm) at 60 °C for 16 h; then it was extracted with dichloromethane and washed three times with water. After that, the organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product; the crude product was purified by column chromatography (petroleum ether and dichloromethane = 4:1) to obtain 113.54 mg of a pure light yellow solid, with a yield of 75%. 1 H NMR (400 MHz, DMSO-d6 ) δ 12.58 (s, 1H), 7.60 (dd, J = 7.8, 2.1 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.3 Hz, 1H), 4.17 (s, 3H), 2.75 (t, J = 7.5 Hz, 2H), 1.78–1.65 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO) δ 154.49, 149.83, 145.40, 137.99, 134.26, 132.27, 131.87, 131.58, 130.02, 127.62, 124.95, 38.35, 27.60, 22.26, 14.29.

[0049] Example 8: Synthesis of 5-(4-bromophenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0050]

[0051] 4-Amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide (91.11 mg, 0.5 mmol), 4-bromobenzaldehyde (111.01 mg, 0.6 mmol), photocatalyst 4CzIPN (19.72 mg, 0.025 mmol), potassium tert-butoxide (5.61 mg, 0.05 mmol) and 2 mL of dimethyl sulfoxide were successively added to a 25 mL reaction tube. The mixture was reacted under irradiation with blue LED (455 nm) at 60 °C for 16 h; then it was extracted with dichloromethane, washed three times with water, and then the organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product; the crude product was purified by column chromatography (petroleum ether and dichloromethane = 2:1) to obtain 142.36 mg of a white solid pure product with a yield of 82%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.47 (s, 1H), 8.01 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 4.15 (s, 3H), 2.79 (t, J = 7.5 Hz, 2H), 1.82–1.71 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO) δ 154.99, 149.56, 145.49, 138.15, 132.47, 131.95, 129.96, 124.85, 124.79, 38.31, 27.62, 22.13, 14.35.

[0052] Example 9: Synthesis of 5-(2-furyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0053]

[0054] 4-Amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide (91.11 mg, 0.5 mmol), thiophene-2-carbaldehyde (67.29 mg, 0.6 mmol), photocatalyst 4CzIPN (11.83 mg, 0.015 mmol), potassium tert-butoxide (5.61 mg, 0.05 mmol) and 2 mL of dimethyl sulfoxide were successively added to a 25 mL reaction tube. The mixture was reacted under irradiation with blue LED (455 nm) at 60 °C for 16 h; then it was extracted with dichloromethane, washed three times with water, and then the organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product; the crude product was purified by column chromatography (petroleum ether and dichloromethane = 1:1) to obtain 96.02 mg of a pure yellow solid, with a yield of 70%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.52 (s, 1H), 8.10 (d, J = 3.7 Hz, 1H), 7.76 (d, J = 5.0 Hz, 1H), 7.21–7.13 (m, 1H), 4.14 (s, 3H), 2.76 (t, J = 7.5 Hz, 2H), 1.82–1.67 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO) δ 154.71, 146.07, 145.00, 138.00, 137.90, 131.23, 128.72, 128.69, 124.63, 38.35, 27.61, 21.96, 14.33.

[0055] Example 10: Synthesis of 5-n-heptyl-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0056]

[0057] 4-Amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide (91.11 mg, 0.5 mmol), n-octanal (76.93 mg, 0.6 mmol), photocatalyst 4CzIPN (19.72 mg, 0.025 mmol), potassium tert-butoxide (5.61 mg, 0.05 mmol) and 2 mL of dimethyl sulfoxide were successively added to a 25 mL reaction tube. The mixture was reacted at 60 °C under irradiation with a blue LED (455 nm) for 16 h; then it was extracted with dichloromethane, washed three times with water, and then the organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product; the crude product was purified by column chromatography (petroleum ether and dichloromethane = 1:1) to obtain 74.05 mg of a light yellow solid pure product with a yield of 51%. 1 HNMR (400 MHz, DMSO-d 6 ) δ 12.07 (s, 1H), 4.10 (s, 3H), 2.71 (t, J = 7.5 Hz, 2H), 2.59–2.53 (m, 2H), 1.70 (tt, J = 13.4, 6.8 Hz, 4H), 1.26 (dd, J = 9.2, 5.4 Hz, 8H), 0.91 (t, J = 7.4 Hz, 3H), 0.85 (t, J = 6.8 Hz, 4H). 13 C NMR (101 MHz, DMSO) δ 155.08, 154.92, 144.48, 138.37, 124.67, 38.18, 34.36, 31.60, 28.80, 28.79, 27.57, 27.55, 22.49, 22.16, 14.38, 14.26.

[0058] Example 11

[0059] In this example, the photocatalyst was 2,4,5,7-tetrabromofluorescein (Eosin Y), and other operations were substantially the same as those in Example 1, which will not be elaborated here. 93.91 g of a light yellow solid pure product was obtained after purification with a yield of 70%.

[0060] Example 12

[0061] In this example, the solvent was toluene, and other operations were substantially the same as those in Example 1, which will not be elaborated here. 69.76 g of a light yellow solid pure product was obtained after purification with a yield of 52%.

[0062] Example 13

[0063] In this example, the base was potassium hydroxide, and other operations were substantially the same as those in Example 1, which will not be elaborated here. 85.86 g of a light yellow solid pure product was obtained after purification with a yield of 64%.

[0064] The above embodiments are only for illustrating the technical concept and features of the present invention, and the purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly, and shall not be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention shall be covered by the protection scope of the present invention.

Claims

1. A method for photocatalytic synthesis of 5-substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one derivatives, characterized in that: The following steps are involved: The 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide shown in formula I and the aldehyde compound shown in formula II are mixed in a solvent, and an aerobic oxidation reaction occurs under light and a certain temperature under the combined action of a photocatalyst and a base to synthesize a 5-substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one derivative shown in formula III; wherein R is selected from n-octyl, propylphenyl, phenyl, 4-methylphenyl, 3-methylphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 4-isopropylphenyl, 4-isopropylphenyl, 4-methylthiophenyl, 4-nitrophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-bromophenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, 2-thienyl, 2-pyridyl, 2-furyl or benzo[B]thiophene-2-yl.

2. The method for synthesizing 5-substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one derivatives by photocatalytic aerobic oxidation according to claim 1, characterized in that: The photocatalyst is one or a mixture of two or more of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, 2,4,5,6-tetrakis(diphenylamino)-isophthalonitrile, 2,4,5,7-tetrabromofluorescein, rhodamine B, 9-mesityl-10-methylacridine perchlorate, terpyridine ruthenium chloride or 9-fluorenone.

3. The method for synthesizing 5-substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one derivatives by photocatalytic aerobic oxidation according to claim 1, characterized in that: The solvent is one or a mixture of two or more of acetonitrile, ethanol, dimethyl sulfoxide, tetrahydrofuran, chlorobenzene, 1,2-dichloroethane, and parallel import toluene.

4. The method for synthesizing 5-substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one derivatives by photocatalytic aerobic oxidation according to claim 1, characterized in that: The base is one or a mixture of two or more of potassium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, potassium phosphate or triethylamine.

5. The method for synthesizing 5-substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one derivatives by photocatalytic aerobic oxidation according to claim 1, characterized in that: The light is one or a mixture of two or more of sunlight, red light, blue light, green light, purple light, infrared light or ultraviolet light.

6. The method for synthesizing 5-substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one derivatives by photocatalytic aerobic oxidation according to claim 1, characterized in that: The molar ratio of the 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide, the aldehyde compound, the photocatalyst and the base is (1-1.5):(1.0-1.2):(0.03-0.05):(0.1-0.2).

7. The method for synthesizing 5-substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one derivatives by photocatalytic aerobic oxidation according to claim 1, characterized in that: The illumination condition is blue light with a wavelength of 455nm; And / or, the solvent is dimethyl sulfoxide; And / or, the base is potassium tert-butoxide.

8. The method for synthesizing 5-substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one derivatives by photocatalytic aerobic oxidation according to claim 1, characterized in that: The reaction temperature is 60-80°C and the reaction time is 12-24 hours.

9. The method for synthesizing 5-substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one derivatives by photocatalytic aerobic oxidation according to claim 1, characterized in that: After the reaction is completed, a post-treatment process is preferably included, wherein the post-treatment process specifically comprises: washing the reaction solution with water, extracting with an organic solvent, and concentrating to obtain a crude product, and the crude product is subjected to column chromatography or recrystallization to obtain a pure product.

10. The method for synthesizing 5-substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one derivatives by photocatalytic aerobic oxidation according to claim 9, characterized in that: The eluents for the column chromatography are petroleum ether and dichloromethane, and the mixing ratio is petroleum ether: dichloromethane = 5:1 to 1:5; And / or, the recrystallization solvent is methanol or ethanol or a mixture of the two.

Images