Method for synthesizing 5, 6-dihydropyridazine derivative
The synthesis of 5,6-dihydropyridazine derivatives via visible light-promoted radical cyclization reaction solves the problem of the need for transition metal catalysts in existing technologies, achieving efficient and concise synthesis of dihydropyridazine derivatives and improving synthesis efficiency and purity.
Patent Information
- Application Number
- CN202511880342.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-13
- Publication Date
- 2026-02-13
AI Technical Summary
Existing methods for synthesizing 3-phenyl-4-(2,2,2-trifluoroethyl)diazahexacycles and their derivatives require transition metal catalysts or complex trifluoromethyl reagents, and the reaction conditions are complex, with many byproducts and low efficiency.
A visible light-promoted radical cyclization reaction was adopted, using (E)-N'-benzylidene-N-(but-3-en-1-yl)acetylhydrazine derivative and sodium trifluoromethanesulfinate in dimethyl sulfoxide solvent, with 4CzIPN as the photocatalyst, and the reaction was carried out under 420-430 nm light irradiation, simplifying the reaction system and avoiding metal catalysts.
It enables highly selective and high-yield synthesis under mild conditions, with fewer byproducts, lower energy consumption, wider applicability, good functional group tolerance, and simplifies reaction steps and reduces costs.
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Figure CN121517366A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of compound synthesis technology, and particularly relates to the field of synthesis technology of dihydropyridazine derivatives. Background Technology
[0002] Dihydropyridazine and other nitrogen-containing saturated / partially saturated heterocycles are important structural units for many bioactive molecules and drug leads. Compared with simple aromatic rings or linear skeletons, these nitrogen-containing heterocycles are more stereochemical and diverse in spatial configuration. On the one hand, this facilitates specific three-dimensional interactions with receptors and enzyme targets; on the other hand, they can serve as "saturated isosteres" or "conformation-locking units" for various aromatic heterocycles, optimizing the preferred conformation and stereochemical arrangement of molecules. Literature reports show that the dihydropyridazine skeleton is widely found in nonsteroidal progesterone receptor ligands, potent cardiotonic drugs, influenza neuraminidase inhibitors, and various antitumor, antibacterial, and central nervous system active molecules, and can serve as an important synthetic intermediate for constructing more complex heterocyclic systems. Therefore, developing mild and efficient methods to introduce diverse functional groups into this core not only enriches the structural diversity of nitrogen-containing heterocycles but also provides an important skeletal foundation for the discovery and optimization of novel drug lead molecules.
[0003] The introduction of fluorine has become a common structural modification strategy in modern medicinal chemistry, with many marketed small molecule drugs containing at least one fluorine atom or fluorinated alkyl segment. Introducing strong electron-withdrawing and hydrophobic fluorinated groups such as CF3 into aza-cores like dihydropyridazine can significantly modulate their pharmacological properties: on the one hand, by altering the molecule's polarity, pKa, and lipid-water partition coefficient, water solubility, lipid solubility, and membrane permeability can be optimized, thereby improving oral bioavailability, metabolic stability, and prolonging in vivo half-life; on the other hand, the bioelectronic effects and conformational directing effects of fluorinated groups and CF bonds can reshape the non-covalent interactions between ligands and target proteins, improving conformational matching and thus enhancing efficacy and selectivity. Studies have shown that various trifluoromethylated or difluoroalkylated dihydropyridazine derivatives exhibit excellent antitumor and anti-infective activities, along with superior pharmacokinetic characteristics. Appropriate fluorination modification provides an important means for optimizing the activity and improving the drug-likeness of this type of aza-core.
[0004] In 2024, Yu's research group reported a photocatalytically promoted polyfluoroalkylation-cyclization reaction for constructing various trifluoromethyl or difluoromethyl-substituted dihydropyridazine derivatives. This method uses trifluoromethylthiamium salt as the trifluoromethyl source and achieves the reaction under UV irradiation and at room temperature, obtaining medium to high yields under mild conditions without the need for high temperatures or strong chemical oxidants.
[0005]
[0006] In 2025, Wu's research group reported a copper-catalyzed radical cascade reaction for the synthesis of various trifluoromethyl-substituted five-membered nitrogen heterocycles. This method uses 1-(trifluoromethyl)-1,2-benzyl-3(1H)-one as the trifluoromethyl source, achieving the cyclization reaction under copper and high-temperature catalysis.
[0007]
[0008] Currently, methods for 3-phenyl-4-(2,2,2-trifluoroethyl)diazahexacyclic compounds and their derivatives typically require transition metal catalysts or complex trifluoromethyl reagents. Summary of the Invention
[0010] In view of this, the present invention discloses a method for synthesizing 5,6-dihydropyridazine derivatives by a visible light-promoted radical cyclization reaction, wherein (E)-N'-benzylidene-N-(but-3-en-1-yl)acetylhydrazine derivative and sodium trifluoromethanesulfinate are reacted in a solvent under photocatalyst and light irradiation conditions to obtain the product.
[0011] In a specific embodiment of the present invention, the solvent is dimethyl sulfoxide.
[0012] In a specific embodiment of the present invention, the photocatalyst is 4CzIPN.
[0013] In a specific embodiment of the present invention, the wavelength of the light is 420-430nm.
[0014] In a specific embodiment of the present invention, the structural formula of the (E)-N'-benzylidene-N-(but-3-en-1-yl)acetylhydrazine derivative is as follows: Where R is methyl, methoxy, iodine or chlorine.
[0015] This invention is carried out under mild conditions, with a simple reaction system, high method selectivity and yield, no other complex byproducts, and easy achievement of high purity; the substrate has a wide range of applicability and good functional group tolerance; few byproducts and low energy consumption. This invention uses visible light catalysis to achieve free radical cyclization, using sodium trifluoromethanesulfinate as the starting material and dimethyl sulfoxide as the solvent system. The reaction conditions are simple and the reaction efficiency is high. Attached Figure Description
[0016] Figure 1 It is the compound of Example 1 1 H NMR spectrum.
[0017] Figure 2 It is the compound of Example 1 13 C10 NMR spectrum.
[0018] Figure 3It is the compound of Example 1 19 F NMR spectrum.
[0019] Figure 4 It is the compound of Example 2 1 H NMR spectrum.
[0020] Figure 5 It is the compound of Example 2 13 C10 NMR spectrum.
[0021] Figure 6 It is the compound of Example 2 19 F NMR spectrum.
[0022] Figure 7 It is the compound of Example 3 1 H NMR spectrum.
[0023] Figure 8 It is the compound of Example 3 13 C10 NMR spectrum.
[0024] Figure 9 It is the compound of Example 3 19 F NMR spectrum.
[0025] Figure 10 It is the compound of Example 4 1 H NMR spectrum.
[0026] Figure 11 It is the compound of Example 4 13 C10 NMR spectrum.
[0027] Figure 12 It is the compound of Example 4 19 F NMR spectrum.
[0028] Figure 13 It is the compound of Example 5 1 H NMR spectrum.
[0029] Figure 14 It is the compound of Example 5 13 C10 NMR spectrum.
[0030] Figure 15 It is the compound of Example 5 19 F NMR spectrum. Detailed Implementation
[0031] The experimental equipment of this invention includes a reaction tube, a magnetic stirrer, an LED lamp, and a magnetic stirring device.
[0032] The present invention involves reacting (E)-N'-benzyl-N-(but-3-en-1-yl)acetylhydrazine derivative and sodium trifluoromethanesulfinate in dimethyl sulfoxide solvent, using 4CzIPN as a photocatalyst. The reaction is irradiated with light at a wavelength of 420-430 nm, and the reaction progress is monitored by thin-layer chromatography until complete. Finally, the mixture is purified by silica gel column chromatography (petroleum ether: ethyl acetate) to obtain a compound with general formula 3. The reaction equation is as follows:
[0033] .
[0034] Wherein: R is selected from any one of methyl, methoxy, iodine, and chlorine.
[0035] Example 1
[0036] In a reaction tube, 1a (0.2 mmol), 2a (0.6 mmol), 4CzIPN (2 mol%), dimethyl sulfoxide (2 mL), and a magnetic ball were added sequentially. The reaction was carried out under air irradiation with a 420-430 nm LED lamp at room temperature for 6 h. The reaction progress was monitored by thin-layer chromatography until complete. Finally, the compound 3aa was purified by silica gel column chromatography in 74% yield. The reaction equation is as follows:
[0037] .
[0038] The product spectral data are as follows:
[0039] 1 H NMR (600 MHz, CDCl3) δ 7.77-7.75 (m, 2 H), 7.46-7.44 (m, 3 H), 4.51-4.48 (m, 1 H ), 3.42-3.39 (m, 1 H), 3.28-3.23 (m, 1 H), 2.45 (s, 3 H), 2.40-2.35 (m, 1 H), 2.28-2.19 (m, 2 H), 2.00-1.96 (m, 1 H).
[0040] 13 C NMR (150 MHz, CDCl3) δ 172.5, 146.2, 135.3, 129.6, 128.7, 126.28(q, J = 266.1 Hz, 1 C), 125.7, 35.2 (q, J = 27.7 Hz, 1 C), 34.5, 25.1 (q, J =2.5 Hz, 1 C), 21.3, 21.3.
[0041] 19 F NMR (565 MHz, CDCl3) δ -63.9 (t, J = 10.7 Hz).
[0042] Example 2
[0043] 1b (0.2 mmol), 2a (0.6 mmol), 4CzIPN (2 mol%), dimethyl sulfoxide (2 mL), and a magnetic ball were added sequentially to a reaction tube. The reaction was carried out under air conditions, irradiated with a 420-430 nm LED lamp, and at room temperature for 6 h. The reaction progress was monitored by thin-layer chromatography until complete. Finally, the compound 3ba was purified by silica gel column chromatography in 50% yield. The reaction equation is as follows:
[0044] .
[0045] The product spectral data are as follows:
[0046] 1 H NMR (600 MHz, CDCl3) δ 7.64 (d, J = 8.4 Hz, 2 H), 7.25 (d, J = 7.8Hz, 2 H), 4.50-4.48 (m, 1 H), 3.39-3.37 (m, 1 H), 3.26-3.21 (m, 1 H), 2.44 (s, 3 H), 2.41 (s, 3 H), 2.39-2.32 (m, 1 H), 2.27-2.18 (m, 2 H), 2.00-1.94 (m, 1 H).
[0047] 13 C NMR (150 MHz, CDCl3) δ 172.4, 146.3, 139.8, 132.5, 129.6, 126.4(q, J = 276.2 Hz, 1 C), 125.6, 35.2 (q, J = 27.7 Hz, 1 C), 34.5, 25.1 (q, J =2.6 Hz, 1 C), 21.3, 21.3, 21.3.
[0048] 19 F NMR (565 MHz, CDCl3) δ -63.9 (t, J = 10.5 Hz).
[0049] Example 3
[0050] 1c (0.2 mmol), 2a (0.6 mmol), 4CzIPN (2 mol%), dimethyl sulfoxide (2 mL), and a magnetic ball were added sequentially to a reaction tube. The reaction was carried out under air irradiation with a 420-430 nm LED lamp at room temperature for 6 h. The reaction progress was monitored by thin-layer chromatography until complete. Finally, the compound 3ca was purified by silica gel column chromatography in 80% yield. The reaction equation is as follows:
[0051] .
[0052] The product spectrum is as follows:
[0053] 1 H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 8.4 Hz, 2 H), 7.41 (d, J = 9.0Hz, 2 H), 4.52-4.50 (m, 1 H), 3.36-3.33 (m, 1 H), 3.25-3.20 (m, 1 H), 2.44 (s, 3 H), 2.35-2.19 (m, 3 H), 2.00-1.94 (m, 1 H).
[0054] 13 C NMR (150 MHz, CDCl3) δ 172.4, 145.0, 135.6, 133.8, 129.1, 126.9,126.2 (q, J = 276.1 Hz, 1 C) 35.2 (q, J = 27.8 Hz, 1 C), 34.5, 25.1 (q, J =2.4 Hz, 1 C), 21.3, 21.2.
[0055] 19 F NMR (565 MHz, CDCl3) δ -63.9 (t, J = 10.7 Hz).
[0056] Example 4
[0057] 1d (0.2 mmol), 2a (0.6 mmol), 4CzIPN (2 mol%), dimethyl sulfoxide (2 mL), and a magnetic ball were added sequentially to a reaction tube. The reaction was carried out under air irradiation with a 420-430 nm LED lamp at room temperature for 6 h. The reaction progress was monitored by thin-layer chromatography until complete. Finally, the compound 3da was purified by silica gel column chromatography in 59% yield. The reaction equation is as follows:
[0058] .
[0059] The product spectrum is as follows:
[0060] 1 H NMR (600 MHz, CDCl3) δ 7.70 (d, J = 9.0 Hz, 2 H), 6.97 (d, J = 9.0Hz, 2 H), 4.51-4.48 (m, 1 H), 3.87 (s, 3 H), 3.38-3.35 (m, 1 H), 3.24-3.19(m, 1H), 2.44(s, 3H), 2.39-2.33(m, 1H), 2.27-2.20(m, 2H), 1.99-1.93(m, 1H).
[0061] 13 C NMR (150 MHz, CDCl3) δ 172.3, 160.8, 146.0, 127.8, 127.1, 126.4(q, J = 276.2 Hz, 1 C) 114.2, 55.4, 35.2 (q, J = 27.7 Hz, 1 C),34.4, 25.1 (q,J = 2.6 Hz, 1 C), 21.3, 21.3.
[0062] 19 F NMR (565 MHz, CDCl3) δ -63.9 (t, J = 10.7 Hz).
[0063] Example 5
[0064] 1e (0.2 mmol), 2a (0.6 mmol), 4CzIPN (2 mol%), dimethyl sulfoxide (2 mL), and a magnetic ball were added sequentially to a reaction tube. The reaction was carried out under air irradiation with a 420-430 nm LED lamp at room temperature for 6 h. The reaction progress was monitored by thin-layer chromatography until complete. Finally, the compound 3ea was purified by silica gel column chromatography in 79% yield. The reaction equation is as follows:
[0065] .
[0066] The product spectrum is as follows:
[0067] 1H NMR (600 MHz, CDCl3) δ 7.95 (d, J = 7.8 Hz, 1 H), 7.46-7.43 (m, 1H), 7.24-7.23 (m, 1 H), 7.15-7.12 (m, 1 H), 4.10-4.06 (m, 1 H), 3.75-3.71 (m,1 H), 3.20-3.16 (m, 1 H), 2.34 (s, 3 H), 2.28-2.07 (m, 4 H).
[0068] 13 C NMR (150 MHz, CDCl3) δ 172.6, 149.9, 141.5, 140.0, 130.4, 129.3,128.4, 126.1 (q, J = 276.1 Hz, 1 C), 97.3, 35.8, 34.8 (q, J = 28.2 Hz, 1 C), 29.8 (q, J = 2.7 Hz, 1 C), 22.3, 21.3.
[0069] 19 F NMR (565 MHz, CDCl3) δ -63.7 (t, J = 10.7 Hz).
[0070] Comparative example
[0071] The existing method for preparing 5,6-dihydropyridazine and its derivatives involves dissolving (E)-N'-benzylene-N-(but-3-en-1-yl)acetylhydrazine and its derivative (0.2 mmol) and trifluoromethylthiamethylene salt (0.3 mmol) in dimethyl sulfoxide (2 mL) under a nitrogen atmosphere, followed by the addition of Ru(bpy)3Cl2·6 H2O (2 mol%). The reaction is carried out under a 20 W UV lamp (400–410 nm) with stirring at room temperature for 16 hours. After the reaction is complete, the product is purified by silica gel column chromatography.
[0072]
[0073] Compared to this method, this invention uses 4CzIPN as a photocatalyst, avoiding the use of metals as photocatalysts, making it more environmentally friendly; secondly, the reaction uses sodium trifluoromethanesulfonate as the source of trifluoromethyl groups, eliminating the need to synthesize trifluoromethylthiamethylene salt, reducing time and economic costs; finally, the reaction itself requires less time, further improving efficiency.
Claims
1. A method for synthesizing 5,6-dihydropyridazine derivatives, characterized in that, The product was obtained by reacting (E)-N'-benzylidene-N-(but-3-en-1-yl)acetylhydrazine derivative and sodium trifluoromethanesulfinate in a solvent under photocatalysis and light irradiation.
2. The method for synthesizing 5,6-dihydropyridazine derivatives according to claim 1, characterized in that, The solvent is dimethyl sulfoxide.
3. The method for synthesizing 5,6-dihydropyridazine derivatives according to claim 1, characterized in that, The photocatalyst is 4CzIPN.
4. The method for synthesizing 5,6-dihydropyridazine derivatives according to claim 1, characterized in that, The wavelength of the light is 420-430nm.
5. The method for synthesizing 5,6-dihydropyridazine derivatives according to claim 1, characterized in that, The structural formula of the (E)-N'-benzylene-N-(but-3-en-1-yl)acetylhydrazine derivative is: Where R is methyl, methoxy, iodine or chlorine.