6-fluoroalkyl-2,3-dihydropyridazine compounds, and preparation method and application thereof

Abstract

The application discloses a 6-fluoroalkyl-2,3-dihydro pyridazine compound and a preparation method and application thereof, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: performing [3+3] cycloaddition reaction on fluoroalkyl bromo hydrazone and vinyl sulfonium ylide in an organic solvent under alkaline conditions; and the 6-fluoroalkyl-2,3-dihydro pyridazine compound is obtained after the reaction is completed. The compound provided by the application has aggregation-induced emission (Aggregation-Induced Emission, AIE) performance, is a potential fluorescent material, and the synthesis method has the characteristics of easy availability of reaction raw materials, simple operation, mild reaction conditions and good reaction yield, and is beneficial to popularization and application.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and particularly relates to a 6-fluoroalkyl-2,3-dihydropyridazine compound, its preparation method and application. Background Technology

[0002] Dihydropyridazines are a class of six-membered heterocyclic compounds containing N-N bonds. Their structural units are widely found in biologically active molecules. These compounds play important roles in anti-inflammation, treatment of heart diseases in humans and animals, and anticancer activity. Therefore, dihydropyridazines are widely used in the pharmaceutical and pesticide fields. Due to the significant applications of dihydropyridazines in medicine, agriculture, and materials science, their synthesis has been explored over the past few decades. Currently, the synthetic methods for dihydropyridazines include the following:

[0003] (a) Condensation reaction of hydrazine with 1,4-dicarbonyl compounds and their analogues to synthesize dihydropyridazine compounds

[0004] This method is a traditional synthetic method for dihydropyridazine compounds, among which common 1,4-dicarbonyl compounds include 1,4-diones ( J. Org. Chem. 2016, 81 Compounds such as γ-keto esters (8112-8120.) and γ-keto esters. For example, in 2013, Kohno's group reported the condensation cyclization reaction of chiral γ-keto esters with hydrazine hydrate to synthesize five chiral 4,5-dihydropyridazine compounds ( , 8112-8120.) Tetrahedron 2013, 69 (1658-1662.). The advantage of this method is its high enantioselectivity; the disadvantages are the use of chiral compounds as raw materials, resulting in high prices and synthesis costs, and a limited number of substrates (only five compounds were synthesized). Furthermore, the reaction uses explosive hydrazine hydrate as a raw material, requiring harsh reaction conditions and high temperatures. It is worth noting that this condensation reaction can also be used to synthesize dihydropyridazine compounds containing fluoroalkyl groups. For example, in 2009, Hao Jian's research group reported the synthesis of 3-fluoroalkyl-4,5-dihydropyridazinone compounds (…). Tetrahedron ,2009, 65 (4212-4219). The advantage of this synthetic method is the high yield; the disadvantage is that it uses toluene as a solvent and the reflux reaction temperature is high.

[0005] (II) Synthesis of dihydropyridazine compounds via cyclization reaction

[0006] This method is a major synthetic approach for dihydropyridazine compounds that has emerged in recent years. It primarily synthesizes these compounds through cyclization reactions involving hydrazones and azoolefins, such as [3+3] and [4+2] reactions. The specific method is as follows:

[0007] (1) Synthesis of dihydropyridazine compounds via hydrazone-mediated [3+3] cyclization: In 2015, the Siddiqui group reported a method for synthesizing dihydropyridazine compounds via the [3+3] cyclization reaction of hydrazones with α,β-unsaturated aldehydes under I2 catalysis. RSC Adv. 2015 , 5, 52355-52360 . The advantages of this method include mild reaction conditions, simple operation, and excellent yield; the disadvantage is that it uses toxic I₂ as a catalyst. This synthetic method can also be used to synthesize dihydropyridazine compounds containing trifluoromethyl groups. For example, in 2013, Rueping's group first reported... A method for preparing 3-trifluoromethyl-1,4-dihydropyridazine compounds by cyclization reaction of trifluoromethylhydrazone and cinnamaldehyde under acid catalysis. Angew. Chem. Int. Ed. 2013 , 52, (8008-8011.). The advantages of this method are that the raw materials are readily available and the operation is simple. It is an asymmetric catalytic reaction. The main limitations are that the substrate application range is narrow and the reaction time is long.

[0008] In 2020, Hu Yulai's research group reported a compound containing trifluoromethyl groups. N A method for synthesizing 3-trifluoromethyl-1,6-dihydropyridazine compounds via intramolecular cyclization of ′-homoallylhydrazide ( J. Org. Chem. 2020, 85 (12304-12314). The advantage of this method is its high yield; the disadvantage is that it uses stoichiometric amounts of copper acetate in the reaction, resulting in a relatively high reaction temperature. It is worth noting that this paper is the first to report that dihydropyridazine compounds containing trifluoromethyl groups possess aggregation-induced emission (AIE) properties, making them potential fluorescent materials.

[0009] (2) Synthesis of dihydropyridazine compounds via [4+2] cyclization reaction involving azoolefins: In 2020, the Gong Ping research group reported a method for efficiently constructing 1,4-dihydropyridazine compounds under alkaline conditions through a [4+2] Diels-Alder reaction of an azoolefin generated in situ with an enamine ketone. Org. Chem. Front. 2020 , 7,(2307-2312.). The advantages of this method are that it requires no catalyst, yields excellent results, and can be scaled up to gram size, providing a practical and reliable route for the synthesis of heterocyclic compounds. This synthetic method can also be used to synthesize dihydropyridazine compounds containing fluoroalkyl groups. For example, in 2023, Li Xingguang's research group first reported a method for synthesizing 1,4-dihydropyridazine compounds containing fluoroalkyl groups via a [4+2] cyclization reaction of azoolefins with fluoroalkyl-containing imine sulfonyl ylides. Chem. Commun. 2023, 59 (12495-12498). The advantages of this method are mild conditions, no need for metal catalysts, and a wide range of applicable substrates; the disadvantage is that the organic solvent CCl4 used is not environmentally friendly.

[0010] In summary, a great deal of research has been conducted on the synthesis methods of dihydropyridazine compounds in the existing technology, and each synthesis method has different characteristics and limitations.

[0011] Furthermore, with the development of organofluorine chemistry, it has been recognized that introducing fluoroalkyl groups into organic molecules can significantly alter the chemical, physical, and biological properties of the parent compound, such as acidity / basicity, bioavailability, metabolic stability, and lipophilicity. However, synthetic methods for dihydropyridazine compounds containing fluoroalkyl groups (mainly trifluoromethyl or difluoromethyl) are rarely reported. To date, only four papers have reported synthetic methods for dihydropyridazine compounds containing trifluoromethyl or difluoromethyl groups (see above for details). In particular, the number of reported syntheses of dihydropyridazine compounds substituted with difluoromethyl is extremely small. Therefore, further exploration of new synthetic methods for these compounds is essential.

[0012] Halogenated hydrazones, as precursors of nitrile imines, have been widely used in the synthesis of various heterocyclic compounds (References: Chem. Rev. 1993, 93, 2731, Chem. Rev. 2015, 115 (e.g., 5366-5412). Cycloaddition reactions involving trifluoromethyl nitrile imines generated in situ from trifluoromethyl halohydrazones under the action of a base have proven to be one of the most powerful methods for synthesizing nitrogen-containing heterocyclic compounds containing trifluoromethyl groups (References: ). Chem. Rev. 2021, 121 , 1670-1715; Chin. J. Org. Chem. 2023, 43 (e.g., 3257-3267). In contrast, difluoromethyl halogenated hydrazones participate in fewer cycloaddition reactions. Existing techniques mainly focus on the [3+2] cycloaddition reactions of difluoromethyl halogenated hydrazones with dipolarophilic compounds such as carbon-carbon double or triple bonds, successfully yielding difluoromethyl-substituted pyrazole or pyrazoline compounds (References: ). J. Org. Chem 2022, 87 498.; Asian J. Org. Chem 2022, e202200438.; Chin. J. Org. Chem 2024, 44 , 1226-1239; J. Org. Chem. 2024, 89 , 10066-10076.; J. Org. Chem 2024, 89 (e.g., 10591-10602). However, it is noteworthy that the [3+3] cycloaddition reaction involving difluoromethyl halohydrazones has not been reported. Furthermore, vinylthioylides, as stable ylide reagents, are important precursors in organic transformations and play a crucial role in the synthesis of various drug molecules. Simultaneously, the electron-deficient olefin moiety in vinylthioylide molecules can form metal carbenes with metals under metal catalysis, leading to XH (X = C, N, O, S) insertion reactions; and, under metal catalysis, vinylthioylides can also undergo cyclization reactions with pyridines, alkynes, cycloenones, primary amines, etc., to synthesize nitrogen-containing heterocyclic compounds and aromatic compounds (see review literature: Chem. Commun. , 2023, 59 (12411). However, to date, the cyclization reaction of vinylthioylides with halohydrazones has not been reported. Summary of the Invention

[0013] To address the aforementioned technical problems, this invention proposes a 6-fluoroalkyl-2,3-dihydropyridazine compound, its preparation method, and its applications.

[0014] To achieve the above objectives, the present invention provides the following technical solution:

[0015] A 6-fluoroalkyl-2,3-dihydropyridazine compound, with the structural formula shown in formula (I):

[0016]

[0017] (I);

[0018] Wherein, the R f It is CF2H or CF3;

[0019] The Ar 1 It is any one of phenyl, 4-methoxyphenyl, 2-naphthyl and 4-chlorophenyl.

[0020] The Ar 2 It is phenyl or 4-chlorophenyl.

[0021] More preferably, the structural formula of the 6-fluoroalkyl-2,3-dihydropyridazine compound is as follows:

[0022]

[0023] A method for preparing a 6-fluoroalkyl-2,3-dihydropyridazine compound includes the following steps:

[0024] A fluoroalkyl bromide hydrazone and a vinyl thioyl ylide were subjected to a [3+3] cycloaddition reaction in an organic solvent under alkaline conditions to obtain the 6-fluoroalkyl-2,3-dihydropyridazine compound.

[0025] Preferably, the molar ratio of the vinyl thioyl ylide, the fluoroalkyl bromide hydrazone, and the base is 1.0:1.5:1.5.

[0026] Preferably, the general structural formula of the fluoroalkyl brominated hydrazone is:

[0027] ;

[0028] Wherein, the R f It is CF2H or CF3;

[0029] The Ar 1 It is any one of phenyl, 4-methoxyphenyl, 2-naphthyl and 4-chlorophenyl.

[0030] More preferably, the fluoroalkyl brominated hydrazone is difluoromethyl brominated hydrazone or trifluoromethyl brominated hydrazone.

[0031] Preferably, the general structural formula of the vinyl thioyl ylide is:

[0032] ;

[0033] Wherein, the Ar 2 It is phenyl or 4-chlorophenyl.

[0034] Preferably, the alkali includes any one of Na2CO3, K2CO3, Cs2CO3, and NaHCO3.

[0035] More preferably, the alkali is Na2CO3.

[0036] Preferably, the organic solvent includes dichloromethane and toluene.

[0037] More preferably, the organic solvent is dichloromethane.

[0038] Preferably, the [3+3] cycloaddition reaction is carried out at a temperature of 25 °C for a reaction time of 24-98 h, more preferably 98 h.

[0039] Preferably, after the [3+3] cycloaddition reaction is completed, column chromatography separation is also included;

[0040] The eluent used in the column chromatography separation is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of (15-8):1.

[0041] More preferably, the reaction route for the synthesis of the 6-fluoroalkyl-2,3-dihydropyridazine is as follows:

[0042]

[0043] Specifically, the following steps are included:

[0044] Vinyl thioyl ylide (1.0 equiv.), fluoroalkyl bromide hydrazone (1.5 equiv.), base (1.5 equiv.), and 2 mL of organic solvent were added to a Schlenk reaction tube to obtain a mixture. The mixture was stirred at 25 °C for 24–96 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography using silica gel as the stationary phase and petroleum ether (PE) and ethyl acetate (EA) as eluents (PE∶EA = (15–8)∶1, v / v) to obtain the 6-fluoroalkyl-2,3-dihydropyridazine compound.

[0045] Compared with the prior art, the present invention has the following advantages and technical effects:

[0046] This invention provides a novel method for synthesizing 6-fluoroalkyl-2,3-dihydropyridazine compounds via a [3+3] cycloaddition reaction using vinylthioylide reagents and fluoroalkyl brominated hydrazones as starting materials. This method features readily available reactants, simple operation, mild reaction conditions, and good yields. It also achieves a [3+3] cycloaddition reaction involving difluoromethyl brominated hydrazones, providing a new route for the synthesis of six-membered nitrogen-containing heterocyclic compounds containing difluoromethyl groups. The 6-fluoroalkyl-2,3-dihydropyridazine compounds synthesized using this method are further processed... 1 H NMR, 13 C NMR, 19 The product was detected by high-resolution NMR mass spectrometry and was found to be a pure target compound with high purity. It also exhibited aggregation-induced emission (AIE) properties, making it a potential fluorescent material. Attached Figure Description

[0047] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings:

[0048] Figure 1The methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylic acid (3a) obtained in Example 1 1 H NMR spectrum;

[0049] Figure 2 The methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylic acid (3a) obtained in Example 1 13 C NMR spectrum;

[0050] Figure 3 The methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylic acid (3a) obtained in Example 1 19 F NMR spectrum;

[0051] Figure 4 This is a high-resolution mass spectrometry monitoring image of methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylic acid (3a) obtained in Example 1;

[0052] Figure 5 The methyl 6-(difluoromethyl)-2-(4-methoxyphenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid ester (3b) obtained in Example 2 1 H NMR spectrum;

[0053] Figure 6 The methyl 6-(difluoromethyl)-2-(4-methoxyphenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid ester (3b) obtained in Example 2 13 C NMR spectrum;

[0054] Figure 7 The methyl 6-(difluoromethyl)-2-(4-methoxyphenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid ester (3b) obtained in Example 2 19 F NMR spectrum;

[0055] Figure 8 This is a high-resolution mass spectrometry monitoring image of methyl 6-(difluoromethyl)-2-(4-methoxyphenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid (3b) obtained in Example 2;

[0056] Figure 9 The methyl 6-(difluoromethyl)-2-(2-naphthyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid (3c) obtained in Example 3 1 H NMR spectrum;

[0057] Figure 10The methyl 6-(difluoromethyl)-2-(2-naphthyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid (3c) obtained in Example 3 13 C NMR spectrum;

[0058] Figure 11 The methyl 6-(difluoromethyl)-2-(2-naphthyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid (3c) obtained in Example 3 19 F NMR spectrum;

[0059] Figure 12 This is a high-resolution mass spectrometry monitoring image of methyl 6-(difluoromethyl)-2-(2-naphthyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid (3c) obtained in Example 3;

[0060] Figure 13 The methyl 6-(difluoromethyl)-2-(4-chlorophenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid ester (3d) obtained in Example 4 1 H NMR spectrum;

[0061] Figure 14 The methyl 6-(difluoromethyl)-2-(4-chlorophenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid ester (3d) obtained in Example 4 13 C NMR spectrum;

[0062] Figure 15 The methyl 6-(difluoromethyl)-2-(4-chlorophenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid ester (3d) obtained in Example 4 19 F NMR spectrum;

[0063] Figure 16 This is a high-resolution mass spectrometry monitoring image of methyl 6-(difluoromethyl)-2-(4-chlorophenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid (3d) obtained in Example 4;

[0064] Figure 17 The methyl 6-(trifluoromethyl)-2-phenyl-4-(4-chlorophenyl)-2,3-dihydropyridazine-3-carboxylic acid (3e) obtained in Example 5 1 H NMR spectrum;

[0065] Figure 18 The methyl 6-(trifluoromethyl)-2-phenyl-4-(4-chlorophenyl)-2,3-dihydropyridazine-3-carboxylic acid (3e) obtained in Example 5 13 C NMR spectrum;

[0066] Figure 19The methyl 6-(trifluoromethyl)-2-phenyl-4-(4-chlorophenyl)-2,3-dihydropyridazine-3-carboxylic acid (3e) obtained in Example 5 19 F NMR spectrum;

[0067] Figure 20 This is a high-resolution mass spectrometry monitoring image of methyl 6-(trifluoromethyl)-2-phenyl-4-(4-chlorophenyl)-2,3-dihydropyridazine-3-carboxylic acid (3e) obtained in Example 5;

[0068] Figure 21 The fluorescence characterization diagram of methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a) obtained in Example 1;

[0069] Where, a is an image of the solid powder under visible and ultraviolet light (365 nm); b is an image of 3a under different water contents ( f w The fluorescence emission spectrum at 0-90%) was obtained with an excitation wavelength of 332 nm; c is the curve of fluorescence intensity at the maximum emission wavelength (520 nm) as a function of water content.

[0070] Figure 22 The fluorescence characterization diagram of methyl 6-(difluoromethyl)-2-(4-methoxyphenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid (3b) obtained in Example 2;

[0071] Where, a is an image of the solid powder under visible and ultraviolet light (365 nm); b is an image of 3b under different water contents ( f w The fluorescence emission spectrum at 0-90%) was obtained with an excitation wavelength of 331 nm; c is the curve of fluorescence intensity at the maximum emission wavelength (560 nm) as a function of water content.

[0072] Figure 23 The fluorescence characterization diagram of methyl 6-(difluoromethyl)-2-(2-naphthyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid (3c) obtained in Example 3;

[0073] Where, a is an image of the solid powder under visible and ultraviolet light (365 nm); b is an image of 3c under different water contents ( f w The fluorescence emission spectrum at 0-90%) was obtained with an excitation wavelength of 332 nm; c is the curve of fluorescence intensity at the maximum emission wavelength (535 nm) as a function of water content.

[0074] Figure 24The fluorescence characterization diagram of methyl 6-(difluoromethyl)-2-(4-chlorophenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid (3d) obtained in Example 4;

[0075] Where, a is an image of the solid powder under visible and ultraviolet light (365 nm); b is a 3D image of the powder under different water contents (…). f w The fluorescence emission spectrum at 0-90%) was obtained with an excitation wavelength of 328 nm; c is the curve of fluorescence intensity at the maximum emission wavelength (523 nm) as a function of water content.

[0076] Figure 25 The fluorescence characterization diagram of methyl 6-(trifluoromethyl)-2-phenyl-4-(4-chlorophenyl)-2,3-dihydropyridazine-3-carboxylic acid (3e) obtained in Example 5;

[0077] Where, a is an image of the solid powder under visible and ultraviolet light (365 nm); b is an image of 3e at different water contents ( f w The fluorescence emission spectrum at 0-90%) was obtained with an excitation wavelength of 335 nm; c is the curve of fluorescence intensity at the maximum emission wavelength (522 nm) as a function of water content. Detailed Implementation

[0078] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0079] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0080] Unless otherwise specified, all raw materials used in the embodiments of this invention were purchased through commercial channels;

[0081] Among them, difluoromethyl bromide hydrazone was prepared according to the literature Han T, Wang KH, Yang M, et al. Synthesis of Difluoromethylated Pyrazoles by the [3+2] CycloadditionReaction of Difluoroacetohydrazonoyl Bromides[J].The Journal of Organic Chemistry, 2022(1):87.DOI:10.1021 / acs.joc.1c02521.

[0082] Trifluoromethyl bromide hydrazone was prepared according to the literature Mlostoń, Grzegorz, Urbaniak K, Utecht G, et al. Trifluoromethylated 2,3-dihydro-1,3,4-thiadiazoles via the regioselective[3+2]-cycloadditions of fluorinated nitrile imines with aryl, hetaryl, and ferrocenyl thioketones[J]. Journal of Fluorine Chemistry, 2016:147-154.DOI:10.1016 / j.jfluchem.2016.10.018.

[0083] Unless otherwise specified, room temperature or normal temperature in this invention refers to 25±3℃.

[0084] Example 1

[0085] The synthesis of methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylic acid (3a) is described below:

[0086] ;

[0087] Specifically, the following steps are included:

[0088] Will( Z )-4-(dimethyloxo-λ 6 Methyl 3-(thionyl)-3-phenylbut-2-enoate (75.9 mg, 0.30 mmol, 1.0 equiv.), N′-Phenylacetyl difluoromethyl bromide hydrazone (111.6 mg, 0.45 mmol, 1.5 equiv.), Na2CO3 (47.7 mg, 0.45 mmol, 1.5 equiv.), and 2 mL of dichloromethane (DCM) were added to a 10 mL Schlenk reaction tube to obtain a mixture. This mixture was stirred at 25 °C for 98 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents (PE:EA = 15:1, v / v). 71.8 mg of a yellow solid, 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylic acid methyl ester (3a), was obtained in 70% yield with a purity >99%.

[0089] The synthesized methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylic acid (3a) was subjected to... 1 HNMR, 13 C NMR, 19 F NMR high-resolution mass spectrometry detection (such as F NMR detection) Figure 1-4 As shown in the figure, it can be concluded that the product is a pure target compound. The corresponding characterization data of the product are as follows:

[0090] 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.2 Hz, 2H), 7.47-7.38 (m, 7H), 7.14-7.10 (m, 1H), 6.80 (s, 1H), 6.36 (t, J = 54.8 Hz, 1H), 5.94 (s, 1H), 3.68 (s, 3H).

[0091] 13 C{ 1 H NMR (150 MHz, CDCl3) δ 169.4, 144.9, 138.8 (t, J C-F = 28.8 Hz),135.3, 130.3, 129.5, 129.2, 128.9, 126.2, 123.5, 116.2, 114.4 (t, J C-F = 234.2Hz), 109.6, 57.6, 52.8.

[0092] 19F NMR (376 MHz, CDCl3) δ -114.83 (d, J = 54.9 Hz), -114.84 (d, J = 54.9Hz).

[0093] HRMS (ESI): m / z calcd for C 19 H 17 F2N2O2[M + H ] ＋ 343.12526, found 343.12521.

[0094] Example 2

[0095] The synthesis of methyl 6-(difluoromethyl)-2-(4-methoxyphenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid (3b) is described below:

[0096] ;

[0097] Specifically, the following steps are included:

[0098] Will( Z )-4-(dimethyloxo-λ 6 Methyl 3-(thionyl)-3-phenylbut-2-enoate (75.9 mg, 0.30 mmol, 1.0 equiv.), N ′-p-methoxyphenyl difluoromethyl bromide hydrazone (125.6 mg, 0.45 mmol, 1.5 equiv.), Na2CO3 (47.7 mg, 0.45 mmol, 1.5 equiv.), and 2 mL of dichloromethane (DCM) were added to a 10 mL Schlenk reaction tube to obtain a mixture. This mixture was stirred at 25 °C for 96 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents (PE:EA=8:1) to obtain 71.5 mg of a yellow solid, 6-(difluoromethyl)-2-(4-methoxyphenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid methyl ester (3b), with a yield of 64% and a purity of >99%.

[0099] The synthesized methyl 6-(difluoromethyl)-2-(4-methoxyphenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid (3b) was subjected to... 1 H NMR, 13 C NMR, 19 F NMR high-resolution mass spectrometry detection (such as F NMR detection) Figure 5-8As shown in the figure, it can be concluded that the product is a pure target compound. The corresponding characterization data of the product are as follows:

[0100] 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.2 Hz, 2H), 7.46-7.39 (m, 3H),7.31 (d, J = 9.2 Hz, 2H), 6.93 (d, J = 9.2 Hz, 2H), 6.80 (s, 1H), 6.35 (t, J = 54.8Hz, 1H), 5.87 (s, 1H), 3.81 (s, 3H), 3.68 (s, 3H).

[0101] 13 C{ 1 H NMR (150 MHz, CDCl3) δ 169.6, 156.3, 139.0, 138.1 (t, J C-F = 29.0Hz), 135.4, 129.3, 128.9, 126.8, 126.1, 118.1, 114.6 (t, J C-F = 233.9 Hz),114.4, 109.5, 58.3, 55.6, 52.7.

[0102] 19 F NMR (376 MHz, CDCl3) δ -114.35 (d, J = 54.9 Hz);

[0103] HRMS (ESI): m / z calcd for C 20 H 19 F2N2O3[M + H] ＋ 373.1358, found 373.1358.

[0104] Example 3

[0105] The synthesis of methyl 6-(difluoromethyl)-2-(2-naphthyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid (3c) is described below:

[0106] ;

[0107] The specific synthesis process is as follows:

[0108] Will( Z )-4-(dimethyloxo-λ 6 Methyl 3-(thionyl)-3-phenylbut-2-enoate (75.9 mg, 0.30 mmol, 1.0 equiv.), N ′-2-Naphthyldifluoromethylbromohydrazone (134.6 mg, 0.45 mmol, 1.5 equiv.), Na2CO3 (47.7 mg, 0.45 mmol, 1.5 equiv.), and 2 mL of dichloromethane (DCM) were added to a 10 mL Schlenk reaction tube to obtain a mixture. This mixture was stirred at 25 °C for 98 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents (PE:EA=10:1) to obtain 61.2 mg of a yellow solid, 6-(difluoromethyl)-2-(2-naphthyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid methyl ester (3c), with a yield of 52% and a purity of >99%.

[0109] The synthesized methyl 6-(difluoromethyl)-2-(2-naphthyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid (3c) was subjected to... 1 H NMR, 13 C NMR, 19 F NMR high-resolution mass spectrometry detection (such as F NMR detection) Figure 9-12 As shown in the figure, it can be concluded that the product is a pure target compound. The corresponding characterization data of the product are as follows:

[0110] 1 H NMR (400 MHz, CDCl3) δ 7.89-7.78 (m, 6H), 7.53-7.39 (m, 6H), 6.84 (s,1H), 6.42 (t, J = 54.8 Hz, 1H), 6.11 (s, 1H), 3.69 (s, 3H).

[0111] 13 C{ 1 H NMR (150 MHz, CDCl3) δ 169.4, 142.7, 138.8 (t, J C-F= 28.8 Hz),135.3, 133.8, 130.7, 130.2, 129.6, 129.4, 129.0, 127.6, 127.5, 126.8, 126.2,124.8, 117.4, 114.4 (t, J C-F = 233.9 Hz), 111.2, 109.7, 57.8, 52.8.

[0112] 19 F NMR (376 MHz, CDCl3) δ -114.84 (d, J = 54.1 Hz), -114.88 (d, J = 54.1Hz).

[0113] HRMS (ESI): m / z calcd for C 23 H 19 F2N2O2[M + H] + 393.1409, found 393.1404.

[0114] Example 4

[0115] The synthesis of methyl 6-(difluoromethyl)-2-(4-chlorophenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid (3d) is described below:

[0116] ;

[0117] Specifically, the following steps are included:

[0118] Will( Z )-4-(dimethyloxo-λ 6 Methyl 3-(thionyl)-3-phenylbut-2-enoate (75.9 mg, 0.30 mmol, 1.0 equiv.), N′-p-chlorophenyl difluoromethyl bromide hydrazone (127.6 mg, 0.45 mmol, 1.5 equiv.), Na2CO3 (47.7 mg, 0.45 mmol, 1.5 equiv.), and 2 mL of dichloromethane (DCM) were added to a 10 mL Schlenk reaction tube to obtain a mixture, which was stirred at 25 °C for 94 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents (PE:EA=10:1) to obtain 59.0 mg of a yellow solid, 6-(difluoromethyl)-2-(4-chlorophenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid methyl ester (3d), with a yield of 52% and a purity of >99%.

[0119] The synthesized methyl 6-(difluoromethyl)-2-(4-chlorophenyl)-4-phenyl-2,3-dihydropyridazine-3-carboxylic acid (3d) was subjected to... 1 H NMR, 13 C NMR, 19 F NMR high-resolution mass spectrometry detection (such as F NMR detection) Figure 13-16 As shown in the figure, the results indicate that the product is a pure target compound. The corresponding characterization data of the product are as follows:

[0120] 1 H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.0 Hz, 2H), 7.46-7.39 (m, 7H), 6.80 (s, 1H), 6.33 (t, J = 54.8 Hz, 1H), 5.88 (s, 1H), 3.67 (s, 3H);

[0121] 13 C{ 1 ¹H NMR (150 MHz, CDCl₃): δ 169.1, 143.6, 139.2 (t, J C-F = 29.3 Hz),135.2, 131.0, 129.7, 129.2, 129.0, 128.7, 126.2, 117.3, 114.3 (t, J C-F = 234.3Hz), 109.6, 57.6, 52.9;

[0122] 19 F NMR (376 MHz, CDCl3): δ -115.15 (dd, J = 54.9, 20.3 Hz);

[0123] HRMS (ESI): m / z calcd for C 19 H 16 ClF2N2O2[M + H] + 377.0863, found 377.0862.

[0124] Example 5

[0125] Synthesis of methyl 6-(trifluoromethyl)-2-phenyl-4-(4-chlorophenyl)-2,3-dihydropyridazine-3-carboxylic acid (3e)

[0126] The synthesis route is as follows:

[0127] ;

[0128] Specifically, the following steps are included:

[0129] Will( Z )-4-(dimethyloxo-λ 6 Methyl thioninate (86.0 mg, 0.30 mmol, 1.0 equiv.)-3-(4-chlorophenyl)but-2-enoate N ′-Phenylacetyltrifluoromethylbromohydrazone (120.1 mg, 0.24 mmol, 1.2 equiv.), Na2CO3 (47.7 mg, 0.45 mmol, 1.5 equiv.), and 2 mL of dichloromethane (DCM) were added to a 10 mL Schlenk tube to obtain a mixture. This mixture was stirred at 25 °C for 98 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents (PE:EA = 10:1) to obtain 66.4 mg of a yellow solid, 6-(trifluoromethyl)-2-phenyl-4-(4-chlorophenyl)-2,3-dihydropyridazine-3-carboxylic acid methyl ester (3e), with a yield of 56% and a purity of >99%.

[0130] The synthesized methyl 6-(trifluoromethyl)-2-phenyl-4-(4-chlorophenyl)-2,3-dihydropyridazine-3-carboxylic acid (3e) was subjected to... 1 H NMR, 13 C NMR, 19 F NMR, high-resolution mass spectrometry detection (such as F NMR, high-resolution mass spectrometry detection) Figure 17-20 As shown in the figure, the results indicate that the product is a pure target compound. The corresponding characterization data of the product are as follows:

[0131] 1 H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.8 Hz, 2H), 7.43-7.40 (m, 6H), 7.19-7.140 (m, 1H), 6.71 (s, 1H), 5.90 (s, 1H), 3.70 (s, 3H).

[0132] 13 C{ 1 ¹H NMR (150 MHz, CDCl₃): δ 169.1, 144.6, 135.7, 133.8 (q, J C-F = 36.0Hz), 133.5, 129.3, 129.2, 127.9, 127.5, 124.2, 121.4 (q, J C-F = 270 Hz), 116.7,109.9, 57.4, 53.0.

[0133] 19 F NMR (376 MHz, CDCl3): δ -67.25 (s);

[0134] HRMS (ESI): m / z calcd for C 19 H 15 ClF3N2O2[M + H ] ＋ 395.0769, found 395.0770.

[0135] Example 6

[0136] The synthesis of methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a) differed from that in Example 1 in that the base Na2CO3 (47.7 mg, 0.45 mmol, 1.5 equiv.) was replaced with cesium carbonate (146.6 mg, 0.45 mmol, 1.5 equiv.). All other process steps and parameters were the same as in Example 1, yielding 50.3 mg of a yellow solid, methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a), with a yield of 49% and a purity >99%.

[0137] Example 7

[0138] The synthesis of methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a) differed from that in Example 1 in that the base Na2CO3 (47.7 mg, 0.45 mmol, 1.5 equiv.) was replaced with potassium carbonate (62.2 mg, 0.45 mmol, 1.5 equiv.). All other process steps and parameters were the same as in Example 1, yielding 51.4 mg of a yellow solid, methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a), with a yield of 50% and a purity >99%.

[0139] Example 8

[0140] The synthesis of methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a) differed from that in Example 1 in that the base Na2CO3 (47.7 mg, 0.45 mmol, 1.5 equiv.) was replaced with NaHCO3 (37.8 mg, 0.45 mmol, 1.5 equiv.). All other process steps and parameters were the same as in Example 1, yielding 49.0 mg of yellow solid methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a) with a yield of 48% and a purity >99%.

[0141] Example 9

[0142] The synthesis of methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a) differed from that in Example 1 in that the solvent dichloromethane was replaced with toluene. All other process steps and parameters were the same as in Example 1, yielding 50.6 mg of yellow solid methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a) with a yield of 49% and a purity of >99%.

[0143] Comparative Example 1

[0144] The synthesis of methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a) differed from that in Example 1 in that the base Na2CO3 (47.7 mg, 0.45 mmol, 1.5 equiv.) was replaced with triethylamine (Et3N) (45.5 mg, 0.45 mmol, 1.5 equiv.). All other process steps and parameters were the same as in Example 1, yielding 34.9 mg of a yellow solid, methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a), with a yield of 34% and a purity >99%. It can be seen that compared to Example 1, the yield was significantly reduced by simply changing the base to Et3N.

[0145] Comparative Example 2

[0146] The synthesis of methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a) differed from that in Example 1 in that the solvent dichloromethane was replaced with tetrahydrofuran (THF). All other process steps and parameters were the same as in Example 1, yielding 31.8 mg of a yellow solid, methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a), with a yield of 31% and a purity >99%. It can be seen that compared to Example 1, the yield was significantly reduced by simply changing the solvent to THF.

[0147] Comparative Example 3

[0148] The synthesis of methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a) differed from that in Example 1 in that the solvent dichloromethane was replaced with 1,4-dioxane. All other process steps and parameters were the same as in Example 1, yielding 23.7 mg of a yellow solid, methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a), with a yield of 23% and a purity >99%. It can be seen that compared to Example 1, the yield was significantly reduced by simply changing the solvent to 1,4-dioxane.

[0149] Comparative Example 4

[0150] The synthesis of methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a) differed from that in Example 1 in that the solvent dichloromethane was replaced with acetonitrile (CH3CN). All other process steps and parameters were the same as in Example 1, yielding 39.0 mg of a yellow solid, methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a), with a yield of 38% and a purity >99%. It can be seen that compared to Example 1, the yield was significantly reduced by simply changing the solvent to CH3CN.

[0151] Comparative Example 5

[0152] The synthesis of methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a) differed from Comparative Example 4 in that the molar ratio of vinyl thioylide, fluoroalkyl bromide hydrazone, and base was replaced from 1.0:1.5:1.5 to 1.0:1.0:1.0. All other process steps and parameters remained the same as in Comparative Example 4, yielding 18.5 mg of a yellow solid, methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a), with a yield of 18% and a purity >99%. It can be seen that compared to Comparative Example 4, the yield was significantly reduced by simply changing the molar ratio of vinyl thioylide, fluoroalkyl bromide hydrazone, and base to 1.0:1.0:1.0.

[0153] Comparative Example 6

[0154] The synthesis of methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a) differed from that of Comparative Example 4 in that the molar ratio of vinyl thioylide, fluoroalkyl bromide hydrazone, and base was replaced from 1.0:1.5:1.5 to 1.0:2.0:2.0. All other process steps and parameters were the same as those in Comparative Example 4, yielding 28.2 mg of yellow solid methyl 6-(difluoromethyl)-2,4-diphenyl-2,3-dihydropyridazine-3-carboxylate (3a) with a yield of 27% and a purity of >99%.

[0155] Compared with Comparative Example 4, the yield was significantly reduced when only the molar ratio of vinylthioylide, fluoroalkyl bromide hydrazone and base was changed to 1.0:2.0:2.0.

[0156] Aggregation-induced emission (AIE) is a unique photophysical phenomenon characterized by certain molecules exhibiting little or no luminescence in dispersed states (e.g., low-concentration solutions), but significantly enhanced luminescence in aggregated or solid-state states. Since its first report in 2001, this phenomenon has attracted widespread attention from researchers due to its significant application potential in fields such as bioimaging, fluorescence sensing, liquid crystal displays, and organic light-emitting diode (OLED) lighting. Aggregate. 2020, 1 , 6-18.; Angew. Chem. Int. Ed. 2020, 59 , 9888 -9907.; Chem. Soc. Rev., 2023 , 52, 6715-6753.).

[0157] Application Example 1

[0158] The fluorescence spectra of compounds 3a-3e obtained in Examples 1-5 are as follows: Figure 21-25 As shown, compounds 3a-3e are all yellow in the solid state and emit bright yellow fluorescence under 365 nm ultraviolet light. Figure 21 Part A of the middle section - Figure 25 (Part a). Meanwhile, using tetrahydrofuran as a good solvent and water as a poor solvent, compounds 3a-3e were tested at different water contents ( f w Fluorescence emission in a tetrahydrofuran / water mixed solution (10-90%). The results show that when the water content... f w When the concentration was 90%, compounds 3a-3e showed obvious aggregation, and the fluorescence intensity was significantly enhanced, emitting green fluorescence. Figure 21 Part B of the middle section - Figure 25 Part b, and Figure 21 Part C - Figure 25 (Part C)

[0159] The above test results indicate that 6-fluoroalkyl-2,3-dihydropyridazine compounds have a significant aggregation-induced emission effect, making them a promising luminescent material for research.

[0160] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A 6-fluoroalkyl-2,3-dihydropyridazine compound, characterized in that, The structural formula is shown as formula (I): （I）； wherein R is selected from the group consisting of f CF2H or CF3; The Ar 1 It is any one of phenyl, 4-methoxyphenyl, 2-naphthyl, and 4-chlorophenyl; said Ar 2 is phenyl or 4-chlorophenyl.

2. A process for the preparation of 6-fluoroalkyl-2,3-dihydro pyridazines as claimed in claim 1, wherein, The method comprises the following steps: The [3+3] cycloaddition reaction of fluoralkyl bromohydrin and vinyl sulfonium ylide is carried out in an organic solvent under alkaline conditions, and the 6-fluoralkyl-2,3-dihydropyridazine compound is obtained after the reaction is completed; The general structural formula of the fluoralkyl bromohydrin is: ； wherein R is selected from the group consisting of f CF2H or CF3; The Ar 1 It is any one of phenyl, 4-methoxyphenyl, 2-naphthyl, and 4-chlorophenyl; The general structural formula of the vinyl sulfonium ylide is: ； wherein Ar is phenyl or 4-chlorophenyl. 2 is phenyl or 4-chlorophenyl.

3. A process for the preparation of a 6-fluoroalkyl-2,3-dihydro pyridazine compound according to claim 2, characterized in that, The molar ratio of the vinyl sulfonium ylide, the fluoralkyl bromohydrin and the base is 1.0:1.5:1.

5.

4. The process for the preparation of 6-fluoroalkyl-2,3-dihydro pyridazines according to claim 3, characterized in that, The base comprises any one of Na2CO3, K2CO3, Cs2CO3 and NaHCO3.

5. The process for the preparation of 6-fluoroalkyl-2,3-dihydro pyridazines according to claim 2, characterized in that, The organic solvent comprises dichloromethane and toluene.

6. A process for the preparation of a 6-fluoroalkyl-2,3-dihydro pyridazine compound according to claim 2, characterized in that, The temperature of the [3+3] cycloaddition reaction is 25°C, and the reaction time is 24-98h.

7. A process for the preparation of a 6-fluoroalkyl-2,3-dihydro pyridazine compound according to claim 2 or 6, characterized in that, After the [3+3] cycloaddition reaction is completed, column chromatography separation is further included. The eluent used in the column chromatography separation is a mixed solution obtained by mixing petroleum ether and ethyl acetate at a volume ratio of (15-8):

1.

8. The 6-fluoralkyl-2,3-dihydropyridazine compound in claim 1 is applied to a fluorescent material.

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