Preparation method of tetrahydropyridazine derivatives

Abstract

This invention belongs to the technical field of preparing tetrahydropyridazine derivatives. The method provided by this invention is simple to operate and does not require an external metal catalyst. The target product contains both a diazoxide and a tetrahydropyridazine skeleton, making it a potential intermediate in the pharmaceutical and materials fields. This invention provides a method for preparing tetrahydropyridazine derivatives, which involves adding a compound having general formula 1, tert-butyl peroxide, and sodium bicarbonate to a solution of acetone, as shown in the following reaction equation:

Description

Technical Field

[0001] This invention belongs to the technical field of preparing tetrahydropyridazine derivatives. Background Technology

[0002] Tetrahydropyridazines, as a representative class of six-membered nitrogen-containing heterocyclic skeletons, possess high structural strain release potential, suitable electronic properties, and favorable derivatization space, thus attracting continuous attention in medicinal chemistry and synthetic methodology research. This core contains two ortho-nitrogen atoms, which can not only significantly regulate the basicity, polarity distribution, and conformational preference of the molecule, but also further influence its hydrogen bonding, dipole-dipole interactions, and hydrophobic recognition processes with biological targets through substituent modification, exhibiting strong pharmacophore embedding capabilities in lead compound design. Existing studies have shown that tetrahydropyridazines and their derivatives have demonstrated significant application potential in areas such as neuromodulation, anti-infection, cardiovascular active molecules, and receptor ligand development, making them important nitrogen-containing skeletons with both biological activity foundation and potential for later optimization. Meanwhile, introducing diverse functional groups around the tetrahydropyridazine skeleton is a key strategy for expanding its chemical and pharmacological spaces. Among these advancements, acetone radical-mediated functionalization offers a novel entry point for the later-stage editing of this scaffold: by selectively introducing a 2-oxopropyl fragment onto the tetrahydropyridazine scaffold, not only can the important pharmacodynamic structural unit of the carbonyl group be embedded while maintaining the original heterocycle recognition framework, but its strong dipole characteristics and further transformation potential can also be leveraged to achieve synergistic regulation of molecular polarity, lipid-water partitioning, metabolic stability, and target binding modes. More importantly, this carbonyl side chain can be further transformed through reduction, reductive amination, condensation, or cyclization to rapidly construct a diverse molecular library. Therefore, acetone radical-mediated tetrahydropyridazine modification not only has methodological significance but also provides a programmable synthetic module for the discovery and optimization of active molecules. Thus, developing acetone radical-mediated transformation targeting the tetrahydropyridazine scaffold not only enriches the methods for constructing and functionalizing this type of nitrogen-containing heterocycle but also holds promise for providing new molecular editing tools for its in-depth application in medicinal chemistry.

[0003] In 2025, Ji's research group reported a metal-free radical cascade nitration / cyclization reaction for the synthesis of nitro-substituted diazacyclic compounds from N-homoallylacetylhydrazine derivatives. This method uses readily available and inexpensive sodium nitrite as the nitro source and potassium persulfate as the oxidant. The reaction is carried out in acetonitrile solvent at 110 °C for 6 hours, successfully constructing nitro-substituted diazacyclic structures in moderate to good yields. This reaction provides a simple, metal-free one-pot synthetic strategy for the construction of nitro-substituted tetrahydropyridazine bioactive molecules.

[0004]

[0005] In 2025, Ji's research group reported a practical copper-catalyzed strategy for the amination and cyclization of non-activated alkenes. This method uses O-benzoylhydroxylamine as an alkylamine precursor to initiate a radical cascade process. Through the reaction of N-alkenyl-N'-(E)-benzylacetylhydrazine derivatives with O-benzoylhydroxylamine, a variety of structurally diverse tetrahydropyridazine skeletons were successfully constructed. This method yields the target amination of tetrahydropyridazine products in good yields, providing an efficient and simple synthetic route for the construction of tetrahydropyridazine bioactive molecules.

[0006] Summary of the Invention

[0007] The purpose of this invention is to enable acetone radicals to attack terminal double bonds under high temperature and oxidant catalysis, using N-alkenyl-N'-(E)-benzylidene acetylhydrazine as a substrate to achieve intramolecular cyclization reaction.

[0008] This invention provides a method for preparing a tetrahydropyridazine derivative, comprising adding a compound having general formula 1, tert-butyl peroxide, and sodium bicarbonate to a solution of acetone, as shown in the following reaction equation: .

[0009] Further, R is hydrogen, 4-methyl, 4-methoxy, 2,5-dimethoxy, 2-iodine, or 4-chloro.

[0010] Furthermore, the reaction temperature is 120°C.

[0011] Furthermore, the reaction time is 8 hours.

[0012] Furthermore, the mass ratio of the compound having general formula 1 to tert-butyl peroxide is 1:4.

[0013] Furthermore, the mass ratio of the compound having general formula 1, tert-butyl peroxide, and sodium bicarbonate is 2:8:5.

[0014] The method provided by this invention is simple to operate and requires no external metal catalyst. The target product contains both azahexane and tetrahydropyridazine skeletons, making it a potential intermediate in the pharmaceutical and materials fields. Attached Figure Description

[0015] Figure 1 This is the hydrogen spectrum of the product from Example 1.

[0016] Figure 2 This is the carbon spectrum of the product from Example 1.

[0017] Figure 3 This is the hydrogen spectrum of the product from Example 2.

[0018] Figure 4 This is the carbon spectrum of the product from Example 2.

[0019] Figure 5 This is the hydrogen spectrum of the product from Example 3.

[0020] Figure 6 This is the carbon spectrum of the product from Example 3.

[0021] Figure 7 This is the hydrogen spectrum of the product from Example 4.

[0022] Figure 8 This is the carbon spectrum of the product from Example 4.

[0023] Figure 9 This is the hydrogen spectrum of the product from Example 5.

[0024] Figure 10 This is the carbon spectrum of the product from Example 5.

[0025] Figure 11 This is the hydrogen spectrum of the product from Example 6.

[0026] Figure 12 This is the carbon spectrum of the product from Example 6. Detailed Implementation

[0027] This invention discloses a method for synthesizing tetrahydropyridazine derivatives without transition metals. The method uses acetone as the solvent and source of free radicals in the reaction system, and achieves the synthesis of 1-acetyl-1,4,5,6-tetrahydropyridazine derivatives through initiation by tert-butyl peroxide. The reaction system is simple, the method has high selectivity and yield, a wide range of applicable substrates, and good functional group tolerance.

[0028] Example 1 In a reaction tube, 1a (0.2 mmol), tert-butyl peroxide (0.8 mmol), sodium bicarbonate (0.5 mmol), acetone 2a (3 mL), and a magnetic stir bar were added sequentially. The mixture was stirred at 120 °C for 8 hours, and the reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, the mixture was purified by silica gel column chromatography using petroleum ether / ethyl acetate (3:1) as the mobile phase to obtain compound 3aa in 80% yield. The reaction equation is as follows: .

[0029] Spectral data of the product compounds: 1H NMR (600 MHz, CDCl3) δ 7.81-7.79 (m, 2 H), 7.44-7.38 (m, 3 H), 4.39-4.36 (m, 1 H), 3.31-3.26 (m, 1 H), 3.07-3.03 (m, 1 H), 2.53 (t, J = 7.2Hz, 2H), 2.44 (s, 3H), 2.11 (s, 3H), 2.01-1.95 (m, 2H), 1.88-1.81 (m, 1H), 1.67-1.60 (m, 1H).

[0030] 13 C NMR (150 MHz, CDCl3) δ 207.6, 172.5, 149.6, 136.8, 129.2, 128.6,125.9, 40.2, 35.1, 30.0, 29.4, 25.4, 21.4, 20.9.

[0031] Example 2

[0032] In a reaction tube, 1b (0.2 mmol), tert-butyl peroxide (0.8 mmol), sodium bicarbonate (0.5 mmol), acetone 2a (3 mL), and a magnetic stir bar were added sequentially. The mixture was stirred at 120 °C for 8 hours, and the reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, the mixture was purified by silica gel column chromatography using petroleum ether / ethyl acetate (3:1) as the mobile phase to obtain compound 3ba in 79% yield. The reaction equation is as follows: .

[0033] Spectral data of the product compounds: 1 H NMR (600 MHz, CDCl3) δ 7.78-7.76 (m, 2 H), 7.40-7.38 (m, 2 H), 4.40-4.36 (m, 1 H), 3.28-3.23 (m, 1 H), 3.01-2.98 (m, 1 H), 2.56-2.53 (m, 2H), 2.43 (s, 3 H), 2.15 (s, 3 H), 2.00-1.94 (m, 2 H), 1.85-1.79 (m, 1 H), 1.62-1.56 (m, 1 H).

[0034] 13C NMR (150 MHz, CDCl3) δ 207.6, 172.4, 148.4, 135.1, 128.8, 127.2, 39.9, 34.9, 30.1, 29.3, 25.2, 21.4, 20.6.

[0035] Example 3

[0036] In a reaction tube, 1c (0.2 mmol), tert-butyl peroxide (0.8 mmol), sodium bicarbonate (0.5 mmol), acetone 2a (3 mL), and a magnetic stir bar were added sequentially. The mixture was stirred at 120 °C for 8 hours, and the reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, the mixture was purified by silica gel column chromatography using petroleum ether / ethyl acetate (3:1) as the mobile phase to obtain compound 3ca in 62% yield. The reaction equation is as follows: .

[0037] Spectral data of the product compounds: 1 H NMR (600 MHz, CDCl3) δ 7.69-7.67 (m, 2 H), 7.23-7.22 (m, 2 H), 4.39-4.35 (m, 1 H), 3.30-3.25 (m, 1 H), 3.03-3.00 (m, 1 H), 2.52 (t, J = 7.2Hz, 2 H), 2.44 (s, 3 H), 2.40 (s, 3 H), 2.12 (s, 3 H), 1.99-1.94 (m, 2 H), 1.87-1.81 (m, 1 H), 1.66-1.60 (m, 1 H).

[0038] 13 C NMR (150 MHz, CDCl3) δ 207.7, 172.5, 149.8, 139.3, 134.0, 129.3, 125.9, 40.3, 35.0, 30.0, 29.4, 25.5, 21.4, 21.3, 21.0.

[0039] Example 4

[0040] In a reaction tube, 1d (0.2 mmol), tert-butyl peroxide (0.8 mmol), sodium bicarbonate (0.5 mmol), acetone 2a (3 mL), and a magnetic stir bar were added sequentially. The mixture was stirred at 120 °C for 8 hours, and the reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, the mixture was purified by silica gel column chromatography using petroleum ether / ethyl acetate (3:1) as the mobile phase to obtain compound 3da in 69% yield. The reaction equation is as follows: .

[0041] Spectral data of the product compounds: 1 H NMR (600 MHz, CDCl3) δ 7.93-7.92 (m, 1 H), 7.42-7.39 (m, 1 H), 7.25-7.24 (m, 1 H), 7.10-7.07 (m, 1 H), 4.11-4.07 (m, 1 H), 3.64-3.60 (m, 1H), 2.83-2.79 (m, 1 H), 2.47-2.41 (m, 1 H), 2.38-2.35 (m, 1 H), 2.33 (s, 3H), 2.08-2.02 (m, 4 H), 1.89-1.84 (m, 1 H), 1.81-1.75 (m, 1 H), 1.62-1.56 (m,1 H).

[0042] 13 C NMR (150 MHz, CDCl3) δ 207.5, 172.6, 153.3, 142.7, 139.9, 129.9,129.6, 128.1, 97.1, 40.6, 36.0, 33.8, 29.9, 25.1, 22.1, 21.4.

[0043] Example 5

[0044] In a reaction tube, 1e (0.2 mmol), tert-butyl peroxide (0.8 mmol), sodium bicarbonate (0.5 mmol), acetone 2a (3 mL), and a magnetic stir bar were added sequentially. The mixture was stirred at 120 °C for 8 hours, and the reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, the mixture was purified by silica gel column chromatography using petroleum ether / ethyl acetate (3:1) as the mobile phase to obtain compound 3ea in 74% yield. The reaction equation is as follows: .

[0045] Spectral data of the product compounds: 1 H NMR (600 MHz, CDCl3) δ 7.77-7.74 (m, 2 H), 6.95-6.93 (m, 2 H), 4.38-4.35 (m, 1 H), 3.85 (s, 3 H), 3.28-3.23 (m, 1 H), 3.01-2.98 (m, 1 H),2.53 (t, J = 6.9 Hz, 2 H), 2.43 (s, 3 H), 2.13 (s, 3 H), 2.00-1.94 (m, 2 H), 1.85-1.79 (m, 1 H), 1.65-1.58 (m, 1 H).

[0046] 13 C NMR (150 MHz, CDCl3) δ 207.8, 172.4, 160.5, 149.6, 130.1, 129.3,128.4, 127.4, 113.9, 55.4, 40.2, 35.0, 30.1, 29.3, 25.3, 21.4, 20.8.

[0047] Example 6

[0048] In a reaction tube, 1f (0.2 mmol), tert-butyl peroxide (0.8 mmol), sodium bicarbonate (0.5 mmol), acetone 2a (3 mL), and a magnetic stir bar were added sequentially. The mixture was stirred at 120 °C for 8 hours, and the reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, the mixture was purified by silica gel column chromatography using petroleum ether / ethyl acetate (3:1) as the mobile phase to obtain compound 3fa in 68% yield. The reaction equation is as follows: .

[0049] Spectral data of the product compounds: 1 H NMR (600 MHz, CDCl3) δ 6.90-6.88 (m, 2 H), 6.86-6.84 (m, 1 H), 3.89-3.82 (m, 2 H), 3.81 (s, 3 H), 3.80 (s, 3 H), 3.09-3.04 (m, 1 H), 2.44-2.38 (m, 1 H), 2.36-2.30 (m, 4 H), 2.04-1.99 (m, 4 H), 1.81-1.69 (m, 2 H), 1.54-1.48 (m, 1 H).

[0050] 13 C NMR (150 MHz, CDCl3) δ 207.9, 172.3, 153.7, 152.4, 151.5, 128.3,116.1, 114.6, 112.2, 56.1, 55.8, 40.8, 36.7, 33.1, 29.8, 26.0, 22.5, 21.3.

[0051] Comparative example

[0052] Existing methods for preparing tetrahydropyridazine derivatives include: Using N-alkenyl-N'-(E)-benzylacetylhydrazine derivative (0.2 mmol) and sodium nitrite (0.4 mmol) as substrates, potassium persulfate (0.4 mmol) and acetonitrile (2 mL) were added as solvents, and the reaction was carried out at 110 °C for 6 hours. .

[0053] Compared to this method, the reaction conditions of this invention use acetone as both solvent and reaction substrate, and the reaction does not require the synthesis of other free radical donors, making it highly efficient and easy to operate.

Claims

1. A method for preparing tetrahydropyridazine derivatives, characterized in that, The compound having general formula 1, t-butyl peroxybenzoate and sodium bicarbonate are added to a solution of acetone and the reaction is carried out according to the following reaction scheme: .

2. The preparation method according to claim 1, characterized in that, The R is hydrogen, 4-methyl, 4-methoxy, 2,5-dimethoxy, 2-iodine, or 4-chloro.

3. The preparation method according to claim 1, characterized in that, The reaction temperature is 120°C.

4. The preparation method according to claim 1, characterized in that, The reaction time is 8 hours.

5. The preparation method according to claim 1, characterized in that, The mass ratio of the compound having general formula 1 to tert-butyl peroxide is 1:

4.

6. The preparation method according to claim 1, characterized in that, The mass ratio of the compound having general formula 1, tert-butyl peroxide, and sodium bicarbonate is 2:8:5.

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