A fluorine alkyl substituted furan quinazoline compound and a preparation method thereof

Abstract

The application provides a method for defluorocyclization reaction of perfluoroalkyl tetrahydronaphthalenone and amidine compound and cobalt-1,3-dicarbonyl complex under the promotion condition of cesium carbonate, and a series of fluorine alkyl substituted furan quinazoline compounds are synthesized. The strategy is free from the dependence on multi-step pre-functionalization and transition metal catalysis in the traditional synthesis path. In the reaction process, six carbon-fluorine bonds at three perfluoroalkyl carbon sites of the polyfluoroalkyl ketone are continuously broken, five carbon-carbon / carbon-nitrogen / carbon-oxygen bonds and two heterocycles are constructed through one-pot method, the accurate synthesis of the fluorine alkyl substituted furan quinazoline compound is realized, and the method has the characteristics of mild condition, good functional group tolerance, simple post-treatment, green step, low pollution and high economic benefit; and the obtained compound shows certain inhibition activity on human malignant melanoma (A-375) cells.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to a fluoroalkyl-substituted furan quinazoline compound and its preparation method. Background Technology

[0002] Heterocyclic compounds are a class of advantageous structural skeletons, widely found in various natural products, drugs, pesticides, functional materials, chelated ligands, and other compounds (J. Med. Chem., 2014, 57, 5845-5859). Among them, quinazolines and furans have consistently attracted attention due to their unique physicochemical properties and biological activities. Polycyclic heteroaromatic compounds that integrate the quinazoline skeleton and furan ring into the same molecule are a research hotspot: the attractiveness of quinazoline-furan fused compounds stems from the synergistic effect of the inherent properties of the two structural units, which can synergistically regulate key parameters such as metabolic stability, lipophilicity, and pKa value, thereby profoundly affecting the overall function and biological activity of the molecule. Notably, the U.S. Food and Drug Administration (FDA) has approved several quinazoline-furan hybrids for marketing as anti-tumor and sympathetic nerve blockers, with typical examples including lapatinib and prazosin.

[0003] Typically, peripheral functionalization of existing heterocyclic compounds is performed first, followed by the construction of intermolecular carbon-carbon bonds to link different (hetero)aromatic segments. This method is a powerful tool for connecting various structural units (Chem. Soc. Rev., 2021, 50, 8903-8953). However, this method has many drawbacks: it requires multiple steps to prepare active precursors (such as organometallic reagents, organohalides, and pseudohalides), relies on expensive transition metal catalysts / ligands, has poor functional group compatibility, requires relatively harsh reaction conditions, and is difficult to efficiently construct structural analog libraries.

[0004] In summary, to address the aforementioned issues, defluorination multicomponent reactions (MCRs) have become an effective strategy for the efficient assembly of various fluorinated and fluoroalkyl dominant skeletal heterocycles. Heterocycles that can be prepared include isoxazoles, triazoles, pyrimidines, pyridines, dihydropyridines, dihydrofurans, and furans. Compared to traditional multicomponent reactions, this defluorination reaction mode, through selective carbon-fluorine bond functionalization, can transform readily available fluorinated synthetic building blocks into difficult-to-prepare heterocyclic skeletons. It not only introduces valuable functional groups but also retains locally fluorinated substituents at regiospecific positions. However, the deep modification of polyfluoroalkyl compounds inherently presents challenges in terms of reactivity and selectivity, for reasons including: (1) sp 3 (1) The dissociation energy of the hybrid carbon-fluorine bond is high; (2) The properties of multiple fluorine atoms adjacent to different carbon sites are similar; (3) Under transition metal catalysis or harsh reaction conditions, other CX bonds will undergo competitive breaking (Org. Chem. Front., 2022, 9, 2013-2055).

[0005] Here, we report our research on the three-component cyclization reaction of perfluoroalkyl tetrahydronaphthone, amidine compounds, and cobalt-1,3-dicarbonyl complexes. Notably, this defluorination multicomponent reaction is a novel reaction not reported in the literature and has significant advantages: (1) The reaction can construct five new CC, CN, C=N, and CO bonds in a one-pot process to assemble two heterocyclic systems; (2) The reaction can achieve the modular synthesis of the uniquely structured 4-(furan-2-yl)quinazoline and can precisely introduce fluoroalkyl substituents; (3) The reaction exhibits high chemoselectivity for the continuous activation of six aliphatic CF bonds on three sterically blocked perfluoroalkyl carbons, expanding the application scenarios of defluorination of perfluoroalkyl tetrahydronaphthone (iScience, 2020, 23, 101259); (4) Tris(acetylacetone)cobalt[Co(acac)3] can be used as a multifunctional 1,3-dicarbonyl equivalent to undergo a [3+2] cyclization reaction with perfluoroalkenyl chains. Despite the attractiveness of this reaction mode, the involvement of multiple reactants and the competitive two-component condensation reaction between fluoroalkyl ketones and amidines pose challenges to the feasibility of the reaction (Synthesis, 2020, 52, 273-280). Summary of the Invention

[0006] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0007] In view of the problems existing in the above and / or prior art, the present invention is proposed.

[0008] One object of the present invention is to provide a fluoroalkyl-substituted furanylquinazoline compound.

[0009] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a fluoroalkyl-substituted furan quinazoline compound, the structural formula of which is shown in Formula I;

[0010]

[0011] Among them, R 1 Selected from one of methoxy, methyl, halogen, and phenyl;

[0012] R 2 Selected from methyl and halogen-substituted phenyl groups;

[0013] R 3 Selected from thiophene, pyridine, phenyl groups containing methoxy, ethoxy, methyl, trifluoromethyl, and halogen-substituted compounds;

[0014] R 4 Selected from methyl and ethyl;

[0015] R 5 Selected from one of ethyl, phenyl halogen-substituted phenyl, and methoxy-substituted phenyl;

[0016] C n F 2n+1 Selected from one of trifluoromethyl, heptafluoropropyl, undecylfluoropentyl, and pentadecylfluoroheptyl; n = 1-7.

[0017] 2. The method for preparing a fluoroalkyl-substituted furanylquinazoline compound as described in claim 1, characterized in that: it comprises,

[0018] The six C(sp) groups at three carbon sites on the fluoroalkyl chain were selectively activated in N-methylpyrrolidone solvent with the aid of cesium carbonate, using compounds of formula III (amidines), perfluoroalkyl tetrahydronaphthones of formula II, and cobalt-1,3-dicarbonyl complexes of formula IV. 3 The -F bond undergoes a defluorination cyclization reaction to yield the compound shown in Formula I;

[0019] The chemical structural formula of the perfluoroalkyl tetrahydronaphthone is shown in formula (II) below:

[0020]

[0021] In Equation II, R 1 R 2 With Equation I, R 1 R 2 Consistent correspondence; C n F 2n+1 Selected from one of trifluoromethyl, heptafluoropropyl, undecylfluoropentyl, and pentadecylfluoroheptyl; n = 1-7.

[0022] The chemical structural formula of the amidine compound is shown in formula (III) below:

[0023]

[0024] In Equation III, R 3 With Equation I, R 3 The correspondence is consistent.

[0025] The chemical structural formula of the cobalt-1,3-dicarbonyl complex is shown in formula (IV) below:

[0026]

[0027] Wherein, R in equation IV 4 R 5 With Equation I, R4 R 5 The correspondence is consistent.

[0028] In a preferred embodiment of the preparation method of the perfluoroalkyl tetrahydronaphthone of the present invention, the perfluoroalkyl tetrahydronaphthone comprises 2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone, 7-fluoro-2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone, 7-methyl-2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone, 2-(perfluorobutyl)-7-phenyl-1,2,3,4-tetrahydronaphthone, 7-methoxy-2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone, 7-chloro-2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone, 7-bromo-2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone, etc. One of the following: (fluorobutyl)-1,2,3,4-tetrahydronaphthone, 6-methoxy-2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone, 5-methoxy-2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone, 4-(3,4-dichlorophenyl)-2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone, 4-methyl-2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone, 2-(perfluorohexyl)-1,2,3,4-tetrahydronaphthone, 2-(perfluorooctyl)-1,2,3,4-tetrahydronaphthone, and 2-(perfluorodecyl)-1,2,3,4-tetrahydronaphthone;

[0029] The amidine compounds include one of the following: benzylamine hydrochloride, 4-fluorobenzylamine hydrochloride, 4-methylbenzylamine hydrochloride, 4-methoxybenzylamine hydrochloride, 4-trifluoromethylbenzylamine hydrochloride, 4-pyridinemimidine hydrochloride, 4-chlorobenzylamine hydrochloride, 4-bromobenzylamine hydrochloride, 3-bromobenzylamine hydrochloride, 2-ethoxybenzylamine hydrochloride, and thiophene-2-mimidine hydrochloride;

[0030] The cobalt-1,3-dicarbonyl complexes include cobalt(III) acetylacetonate, tris(1,6-diethylhexane-2,4-diketoic acid) cobalt(III), tris(1,3,5-triphenylpentane-2,4-diketoic acid) cobalt(III), tris(1,3,5-tri(4-chlorophenyl)pentane-2,4-diketoic acid) cobalt(III) and tris(1,3,5-tris(4-methoxyphenyl)pentane-2,4-diketoic acid) cobalt(III).

[0031] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted furan quinazoline compound of the present invention, the molar ratio of the perfluoroalkyl tetrahydronaphthone, the amidine compound, and the cobalt-1,3-dicarbonyl complex is 1:1.75-3.0:1.0-3.75; preferably, the molar ratio is 1:1.75:2.5.

[0032] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted furanylquinazoline compound of the present invention, the solvent includes one of dimethyl sulfoxide, N,N-dimethylformamide and N-methylpyrrolidone; preferably, the solvent is N-methylpyrrolidone.

[0033] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted furan quinazoline compound of the present invention, the defluorination cyclization reaction is carried out at a temperature of 50–90°C; preferably, the reaction temperature is 70°C.

[0034] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted furan quinazoline compound of the present invention, the defluorination cyclization reaction is carried out for a reaction time of 12-48 h; preferably, the reaction time is 24 h.

[0035] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted furan quinazoline compound of the present invention, the molar ratio of the perfluoroalkyl tetrahydronaphthone, tetrabutylammonium bromide, cesium carbonate and magnesium sulfate is 1:5.0-11.0:5.5-11.5:1.5-4.5, and preferably 1:5.0:9.5:2.5.

[0036] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted furanylquinazoline compound of the present invention, the base includes cesium carbonate, potassium carbonate, cesium fluoride, potassium phosphate, and sodium hydroxide; preferably, the base is cesium carbonate.

[0037] In summary, the optimal reaction equation for this invention is as follows:

[0038]

[0039] Compared with the prior art, the present invention has the following beneficial effects:

[0040] This invention provides a method for the defluorination and cyclization reaction of perfluoroalkyl tetrahydronaphthones, amidine compounds, and cobalt-1,3-dicarbonyl complexes under cesium carbonate-promoted conditions, synthesizing a series of fluoroalkyl-substituted furanoquinazoline compounds. This strategy eliminates the dependence of traditional synthetic routes on multi-step pre-functionalization and transition metal catalysis. During the reaction, the six carbon-fluorine bonds at the three perfluoroalkyl carbon sites of the polyfluoroalkyl ketone are successively broken, ultimately constructing five carbon-carbon / carbon-nitrogen / carbon-oxygen bonds and two heterocycles in a one-pot process. This achieves the precise synthesis of fluoroalkyl-substituted furanoquinazoline compounds, featuring mild conditions, good functional group tolerance, simple post-processing, green procedures, low pollution, and high economic benefits. Furthermore, the obtained compounds exhibit certain inhibitory activity against human malignant melanoma (A-375) cells. Attached Figure Description

[0041] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein:

[0042] Figure 1 The hydrogen spectrum of the target product aaa in Example 1 of this invention;

[0043] Figure 2 The fluorine spectrum of the target product aaa in Example 1 of this invention;

[0044] Figure 3 The carbon spectrum of the target product aaa in Example 1 of this invention;

[0045] Figure 4 The proton spectrum of the target product baa in Example 2 of this invention;

[0046] Figure 5 The fluorine spectrum of the target product baa in Example 2 of this invention;

[0047] Figure 6 The carbon spectrum of the target product baa in Example 2 of this invention;

[0048] Figure 7 The proton spectrum of Caa, the target product of Example 3 of this invention;

[0049] Figure 8 The fluorine spectrum of Caa, the target product of Example 3 of the present invention;

[0050] Figure 9 The carbon spectrum of Caa, the target product of Example 3 of the present invention;

[0051] Figure 10 The proton spectrum of the target product daa in Example 4 of this invention;

[0052] Figure 11 The fluorine spectrum of the target product daa in Example 4 of this invention;

[0053] Figure 12 The carbon spectrum of the target product daa in Example 4 of this invention;

[0054] Figure 13 The proton spectrum of the target product eaa in Example 5 of this invention;

[0055] Figure 14 The fluorine spectrum of the target product eaa in Example 5 of this invention;

[0056] Figure 15The carbon spectrum of the target product eaa in Example 5 of this invention;

[0057] Figure 16 The proton spectrum of the target product aba in Example 6 of this invention;

[0058] Figure 17 The fluorine spectrum of the target product aba in Example 6 of this invention;

[0059] Figure 18 The carbon spectrum of the target product aba in Example 6 of this invention;

[0060] Figure 19 The proton spectrum of the target product ACA in Example 7 of this invention;

[0061] Figure 20 The fluorine spectrum of the target product ACA in Example 7 of this invention;

[0062] Figure 21 The carbon spectrum of the target product ACA in Example 7 of this invention;

[0063] Figure 22 The proton spectrum of the target product ada in Example 8 of this invention;

[0064] Figure 23 The fluorine spectrum of the target product ada in Example 8 of this invention;

[0065] Figure 24 The carbon spectrum of the target product ada in Example 8 of this invention;

[0066] Figure 25 The proton spectrum of the target product aea in Example 9 of this invention;

[0067] Figure 26 The fluorine spectrum of the target product aea in Example 9 of this invention;

[0068] Figure 27 The carbon spectrum of the target product aea in Example 9 of this invention;

[0069] Figure 28 The proton spectrum of the target product afa in Example 10 of this invention;

[0070] Figure 29 The fluorine spectrum of the target product afa in Example 10 of this invention;

[0071] Figure 30 The carbon spectrum of the target product afa in Example 10 of this invention;

[0072] Figure 31 The proton spectrum of the target product aab in Example 11 of this invention;

[0073] Figure 32 The fluorine spectrum of the target product aab in Example 11 of this invention;

[0074] Figure 33 The carbon spectrum of the target product aab in Example 11 of this invention;

[0075] Figure 34 The proton spectrum of the target product aac in Example 12 of this invention;

[0076] Figure 35 The fluorine spectrum of the target product aac in Example 12 of this invention;

[0077] Figure 36 The carbon spectrum of the target product aac in Example 12 of this invention;

[0078] Figure 37 The proton spectrum of the target product aad in Example 13 of this invention;

[0079] Figure 38 The fluorine spectrum of the target product aad in Example 13 of this invention;

[0080] Figure 39 The carbon spectrum of the target product aad in Example 13 of this invention;

[0081] Figure 40 The proton spectrum of the target product aae in Example 14 of this invention;

[0082] Figure 41 The fluorine spectrum of the target product aae in Example 14 of this invention;

[0083] Figure 42 The carbon spectrum of the target product aae in Example 14 of this invention; Detailed Implementation

[0084] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0085] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0086] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0087] The amidine compounds used in the examples were prepared according to the methods reported in the references (Angew. Chem. Int. Ed., 2017, 56, 1338-1341; Chem. Commun., 2018, 54, 12722-12725; iScience, 2020, 23, 101259).

[0088] The amidine compounds used in the examples were prepared according to the method reported in the reference (Adv. Synth. Catal., 2023, 365, 1801-1805);

[0089] The cobalt-1,3-dicarbonyl complex used in the examples was prepared by the method reported in the reference (Bull. Korean Chem. Soc., 2010, 31, 891-895).

[0090] Example 1

[0091] (1) A solution of 2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone (0.0728 g, 0.2 mmol, 1 equiv.), benzamide hydrochloride (0.0548 g, 0.35 mmol, 1.75 equiv.), cobalt(III) acetylacetonate (0.1781 g, 0.5 mmol, 2.5 equiv.), tetrabutylammonium bromide (0.3224 g, 1.0 mmol, 5.0 equiv.), anhydrous magnesium sulfate (0.0602 g, 0.5 mmol, 2.5 equiv.), and cesium carbonate (0.6191 g, 1.9 mmol, 9.5 equiv.) in N-methylpyrrolidone (3 mL) was stirred at 70 °C under nitrogen protection for 24 hours.

[0092] (2) After the reaction in step (1) is completed, the product is quenched with saturated ammonium chloride (20 mL) solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (10 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1 / 40 to 1 / 20. Finally, 39.2 mg of the target product aaa is obtained.

[0093] The target product aaa was characterized as follows: Figure 1 As shown in Figures 2 and 3, the result is: a yellow solid;

[0094] 1H NMR (400MHz, CDCl3): δ 9.56-9.49 (m, 1H), 8.79 (ddd, J=8.0, 3.7, 2.2Hz, 2H), 7.99-7.92 (m, 1H), 7.89-7.78 (m, 4H), 7.62-7.53 (m, 3H), 2.69 (s, 3H), 2.63 (s, 3H)ppm.

[0095] 19 F NMR (376MHz, CDCl3): δ-54.54 (s, 3F)ppm.

[0096] 13 C NMR (100MHz, CDCl3): δ 194.0, 160.4, 159.4, 154.6, 152.4, 149.3, 137.8, 135.3, 131.1, 130.8, 130.5, 129.4, 128.84, 128.79, 128.2, 128.0, 125.4, 122.2, 122.0 (q, J=269.3Hz), 121.3, 120.2, 116.1 (q, J=37.4Hz), 30.9, 14.6ppm.

[0097] HRMS(m / z): calcd for C 26 H 18 F3N2O2[M+H] + 447.1315, found: 447.1306.

[0098] Characterization data revealed that the obtained reaction product was 1-(2-methyl-5-(2-phenylbenzo[h]quinazolin-4-yl)-4-(trifluoromethyl)furan-3-yl)acetone (purity > 98%), and the structural formula of this compound is:

[0099]

[0100] The product yield was calculated to be 44%.

[0101] Example 2

[0102] (1) A solution of 7-fluoro-2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone (0.0764 g, 0.2 mmol, 1 equiv.), benzamide hydrochloride (0.0548 g, 0.35 mmol, 1.75 equiv.), cobalt(III) acetylacetonate (0.1781 g, 0.5 mmol, 2.5 equiv.), tetrabutylammonium bromide (0.3224 g, 1.0 mmol, 5.0 equiv.), anhydrous magnesium sulfate (0.0602 g, 0.5 mmol, 2.5 equiv.), and cesium carbonate (0.6191 g, 1.9 mmol, 9.5 equiv.) in N-methylpyrrolidone (3 mL) was stirred at 70 °C under nitrogen protection for 24 hours.

[0103] (2) After the reaction in step (1) is completed, the product is quenched with saturated ammonium chloride (20 mL) solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (10 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1 / 40 to 1 / 20. Finally, 28.8 mg of the target product baa is obtained.

[0104] The target product baa was characterized as follows: Figure 4 As shown in Figures 5 and 6, the result is: a yellow solid;

[0105] 1 H NMR (400MHz, CDCl3): δ 9.08 (dd, J=10.0, 2.8Hz, 1H), 8.78-8.75 (m, 2H), 7.92 (dd, J=8.7, 5.4Hz, 1H), 7.83 (d, J=9.0Hz, 1H), 7.76 (d, J=9.1Hz, 1H), 7.60-7.55 (m, 4H), 2.69 (s, 3H), 2.63 (s, 3H)ppm.

[0106] 19 F NMR (376MHz, CDCl3): δ-54.56 (s, 3F), -110.45 (td, J=8.9, 6.0Hz, 1F) ppm.

[0107] 13C NMR (100MHz, CDCl3): δ 194.0, 163.4, 160.9, 160.4, 159.4, 154.9, 151.7 (q, J=4.6Hz), 137.5, 132.3 (d, J=8.9Hz), 132.0, 131.2, 130.4 (d, J=8.4Hz), 128.9 (d, J=7.8 Hz), 128.6, 123.3, 122.3, 122.0 (q, J=268.9Hz), 120.6 (d, J=2.4Hz), 120.4, 120.1, 119.8, 110.3 (d, J=22.9Hz), 30.9 (d, J=2.7Hz), 14.6ppm.

[0108] HRMS(m / z): calcd for C 26 H 17 F4N2O2[M+H] + 465.1221, found: 465.1229.

[0109] Characterization data revealed that the obtained reaction product was 1-(5-(9-fluoro-2-phenylbenzo[h]quinazolin-4-yl)-2-methyl-4-(trifluoromethyl)furan-3-yl)acetone (purity > 98%), and the structural formula of this compound is:

[0110]

[0111] The product yield was calculated to be 31%.

[0112] Example 3

[0113] (1) A solution of 7-methyl-2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone (0.0756 g, 0.2 mmol, 1 equiv.), benzamide hydrochloride (0.0548 g, 0.35 mmol, 1.75 equiv.), cobalt(III) acetylacetonate (0.1781 g, 0.5 mmol, 2.5 equiv.), tetrabutylammonium bromide (0.3224 g, 1.0 mmol, 5.0 equiv.), anhydrous magnesium sulfate (0.0602 g, 0.5 mmol, 2.5 equiv.), and cesium carbonate (0.6191 g, 1.9 mmol, 9.5 equiv.) in N-methylpyrrolidone (3 mL) was stirred at 70 °C under nitrogen protection for 24 hours.

[0114] (2) After the reaction in step (1) is completed, the mixture is quenched with saturated ammonium chloride (20 mL) solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (10 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1 / 40 to 1 / 20. Finally, 36.1 mg of the target product caa is obtained.

[0115] The target product caa was characterized as follows: Figure 7 As shown in Figures 8 and 9, the result is: yellow oily substance;

[0116] 1 H NMR (400MHz, CDCl3): δ 9.26 (dd, J=1.8, 1.0Hz, 1H), 8.81-8.77 (m, 2H), 7.81 (dd, J=8.6, 5.7Hz, 2H), 7.71 (d, J=9.1Hz, 1H), 7.65 (dd, J=8.2, 1.8Hz, 1H), 7.62-7.53 (m, 3H), 2.71 (s, 3H), 2.69 (s, 3H), 2.63 (s, 3H)ppm.

[0117] 19 F NMR (376MHz, CDCl3): δ-54.54 (s, 3F)ppm.

[0118] 13 C NMR (100MHz, CDCl3): δ 194.0, 160.2, 159.3, 154.6, 152.2, 149.4 (q, J=4.5Hz), 138.2, 137.9, 133.4, 132.5, 131.0, 130.5, 129.3, 128.8 3, 128.79, 128.0, 124.8, 122.2, 122.0 (q, J=268.7Hz), 120.4, 120.2, 116.1 (q, J=37.7Hz), 30.8, 22.2, 14.6ppm.

[0119] HRMS(m / z): calcd for C 27 H 20 F3N2O2[M+H] + 461.1471, found: 461.1466.

[0120] Characterization data revealed that the obtained reaction product was 1-(2-methyl-5-(9-methyl-2-phenylbenzo[h]quinazolin-4-yl)-4-(trifluoromethyl)furan-3-yl)acetone (purity > 98%), and the structural formula of this compound is:

[0121]

[0122] The product yield was calculated to be 39%.

[0123] Example 4

[0124] (1) A solution of 2-(perfluorobutyl)-7-phenyl-1,2,3,4-tetrahydronaphthone (0.0881 g, 0.2 mmol, 1 equiv.), benzamide hydrochloride (0.0548 g, 0.35 mmol, 1.75 equiv.), cobalt(III) acetylacetonate (0.1781 g, 0.5 mmol, 2.5 equiv.), tetrabutylammonium bromide (0.3224 g, 1.0 mmol, 5.0 equiv.), anhydrous magnesium sulfate (0.0602 g, 0.5 mmol, 2.5 equiv.), and cesium carbonate (0.6191 g, 1.9 mmol, 9.5 equiv.) in N-methylpyrrolidone (3 mL) was stirred at 70 °C under nitrogen protection for 24 hours.

[0125] (2) After the reaction in step (1) is completed, the product is quenched with saturated ammonium chloride (20 mL) solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (10 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1 / 40 to 1 / 20. Finally, 33.3 mg of the target product daa is obtained.

[0126] The target product daa was characterized as follows: Figure 10 As shown in Figures 11 and 12, the result is: a yellow solid;

[0127] 1H NMR (400MHz, CDCl3): δ 9.71 (d, J=1.9Hz, 1H), 8.81-8.78 (m, 2H), 8.07 (dd, J=8.3, 1.9Hz, 1H), 7.99 (d, J=8.3Hz, 1H), 7.90- 7.85(m, 3H), 7.82-7.77(m, 1H), 7.62-7.55(m, 5H), 7.51-7.44(m, 1H), 2.70(s, 3H), 2.64(s, 3H)ppm.

[0128] 1 9 F NMR (376MHz, CDCl3): δ-54.52 (s, 3F)ppm.

[0129] 13 C NMR (100MHz, CDCl3): δ 194.0, 160.4, 159.4, 154.7, 152.5, 149.4 (q, J=4.4Hz), 140.9, 140.8, 137.8, 134.4, 131.1, 130.8, 130.0, 129.2, 129.0, 128.9, 1 28.7, 128.0, 127.8, 123.4, 122.2, 122.0 (q, J=268.8Hz), 121.8, 121.2, 120.5, 116.6 (q, J=34.8Hz), 30.9 (d, J=2.9Hz), 14.6ppm.

[0130] HRMS(m / z): calcd for C 32 H 22 F3N2O2[M+H] + 523.1628, found: 523.1630.

[0131] Characterization data revealed that the obtained reaction product was 1-(5-(2,9-diphenylbenzo-M-quinazolin-4-yl)-2-methyl-4-(trifluoromethyl)furan-3-yl)acetone (purity > 98%), and the structural formula of this compound is:

[0132]

[0133] The product yield was calculated to be 32%.

[0134] Example 5

[0135] (1) A solution of 7-methoxy-2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone (0.0788 g, 0.2 mmol, 1 equiv.), benzamide hydrochloride (0.0548 g, 0.35 mmol, 1.75 equiv.), cobalt(III) acetylacetonate (0.1781 g, 0.5 mmol, 2.5 equiv.), tetrabutylammonium bromide (0.3224 g, 1.0 mmol, 5.0 equiv.), anhydrous magnesium sulfate (0.0602 g, 0.5 mmol, 2.5 equiv.), and cesium carbonate (0.6191 g, 1.9 mmol, 9.5 equiv.) in N-methylpyrrolidone (3 mL) was stirred at 70 °C under nitrogen protection for 24 hours.

[0136] (2) After the reaction in step (1) is completed, the product is quenched with saturated ammonium chloride (20 mL) solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (10 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1 / 20 to 1 / 8. Finally, 30.3 mg of the target product eaa is obtained.

[0137] The target product eaa was characterized as follows: Figure 13 As shown in Figures 14 and 15, the result is: a white solid;

[0138] 1 H NMR (400MHz, DMSO-D6): δ 8.87 (d, J=2.7Hz, 1H), 8.78-8.75 (m, 2H), 7.86-7.77 (m, 2H), 7.65 (d, J=9.0Hz, 1H), 7.6 1-7.54 (m, 3H), 7.45 (dd, J=8.7, 2.7Hz, 1H), 4.13 (s, 3H), 2.69 (s, 3H), 2.63 (s, 3H)ppm.

[0139] 1 9 F NMR (376MHz, DMSO-D6): δ-54.55 (s, 3F)ppm.

[0140] 13C NMR (100MHz, DMSO-D6): δ 194.0, 159.9, 159.5, 159.3, 154.7, 151.6, 149.5 (q, J=4.2Hz), 137.9, 132.1, 131.0, 130.1, 129.7, 129.0, 128.8, 128 .7, 122.2, 122.0 (q, J=268.6Hz), 121.6, 120.6, 118.7, 116.1 (d, J=37.8Hz), 105.2, 55.8, 30.8 (d, J=2.6Hz), 14.6ppm.

[0141] HRMS(m / z): C 27 H 20 F3N2O3[M+H] + 477.1421, found: 477.1427.

[0142] Characterization data revealed that the obtained reaction product was 1-(5-(9-methoxy-2-phenylbenzo[h]quinazolin-4-yl)-2-methyl-4-(trifluoromethyl)furan-3-yl)acetone (purity > 98%), and the structural formula of this compound is:

[0143]

[0144] The product yield was calculated to be 72%.

[0145] Example 6

[0146] (1) A solution of 2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone (0.0728 g, 0.2 mmol, 1 equiv.), 4-fluorobenzoamidine hydrochloride (0.0611 g, 0.35 mmol, 1.75 equiv.), cobalt(III) acetylacetonate (0.1781 g, 0.5 mmol, 2.5 equiv.), tetrabutylammonium bromide (0.3224 g, 1.0 mmol, 5.0 equiv.), anhydrous magnesium sulfate (0.0602 g, 0.5 mmol, 2.5 equiv.), and cesium carbonate (0.6191 g, 1.9 mmol, 9.5 equiv.) in N-methylpyrrolidone (3 mL) was stirred at 70 °C under nitrogen protection for 24 hours.

[0147] (2) After the reaction in step (1) is completed, the mixture is quenched with saturated ammonium chloride (20 mL) solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (10 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1 / 40 to 1 / 20. Finally, 38.9 mg of the target product aba is obtained.

[0148] The target product aba was characterized as follows: Figure 16 As shown in Figures 17 and 18, the result is: a white solid;

[0149] 1 H NMR (400MHz, CDCl3): δ 9.50-9.43 (m, 1H), 8.82-8.73 (m, 2H), 7.96-7.91 (m, 1H), 7.87-7.77 (m, 4H), 7.27-7.22 (m, 2H), 2.69 (s, 3H), 2.62 (s, 3H)ppm.

[0150] 19 F NMR (376MHz, CDCl3): δ-54.55 (s, 3F), -109.88--109.96 (m, 1F)ppm.

[0151] 13 C NMR (100MHz, CDCl3): δ 194.0, 166.3, 163.8, 159.5, 159.3, 154.6, 152.5, 149.3 (q, J=4.0Hz), 135.4, 134.04 (d, J=2.7Hz), 131.0, 130.9 (d, J=2.1 Hz), 130.4, 129.4, 128.2, 128.0, 125.4, 122.3, 122.0 (q, J=268.5Hz), 121.3, 120.1, 115.8 (d, J=21.6Hz), 30.9, 14.6ppm.

[0152] HRMS(m / z): calcd for C 26 H 17 F4N2O2[M+H] + 465.1221, found: 465.1220.

[0153] Characterization data revealed that the obtained reaction product was 1-(5-(2-(4-fluorophenyl)benzo[h]quinazolin-4-yl)-2-methyl-4-(trifluoromethyl)furan-3-yl)acetone (purity > 98%), and the structural formula of this compound is:

[0154]

[0155] The product yield was calculated to be 42%.

[0156] Example 7

[0157] (1) A solution of 2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone (0.0728 g, 0.2 mmol, 1 equiv.), 4-methylbenzoamide hydrochloride (0.0597 g, 0.35 mmol, 1.75 equiv.), cobalt(III) acetylacetonate (0.1781 g, 0.5 mmol, 2.5 equiv.), tetrabutylammonium bromide (0.3224 g, 1.0 mmol, 5.0 equiv.), anhydrous magnesium sulfate (0.0602 g, 0.5 mmol, 2.5 equiv.), and cesium carbonate (0.6191 g, 1.9 mmol, 9.5 equiv.) in N-methylpyrrolidone (3 mL) was stirred at 70 °C under nitrogen protection for 24 hours.

[0158] (2) After the reaction in step (1) is completed, the product is quenched with saturated ammonium chloride (20 mL) solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (10 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1 / 40 to 1 / 20. Finally, 21.3 mg of the target product aca is obtained.

[0159] The target product aca was characterized as follows: Figure 19 As shown in Figures 20 and 21, the result is: a yellow solid;

[0160] 1 H NMR (400MHz, CDCl3): δ 9.53-9.47 (m, 1H), 8.70-8.65 (m, 2H), 7.93 (dt, J=5.6, 3.2Hz, 1H), 7.87-7.80 (m, 3H) , 7.78 (d, J=9.1Hz, 1H), 7.40-7.36 (m, 2H), 2.69 (s, 3H), 2.63 (s, 3H), 2.47 (s, 3H)ppm.

[0161] 19 F NMR (376MHz, CDCl3): δ-54.55 (s, 3F)ppm.

[0162] 13 C NMR (100MHz, CDCl3): δ 194.0, 160.6, 159.3, 154.6, 152.4, 149.5 (q, J=4.6Hz), 141.4, 135.4, 135.2, 130.7, 130.5, 129.6, 129.1 , 128.8, 128.1, 127.9, 125.44, 125.38, 122.2, 122.0 (q, J=268.3Hz), 121.3, 120.1, 30.8, 21.7, 14.6ppm.

[0163] HRMS(m / z): calcd for C 27 H 20 F3N2O2[M+H] + 461.1471, found: 461.1468.

[0164] Characterization data revealed that the obtained reaction product was 1-(5-(2-(p-tolyl)benzo[h]quinazolin-4-yl)-2-methyl-4-(trifluoromethyl)furan-3-yl)acetone (purity > 98%), and the structural formula of this compound is:

[0165]

[0166] The product yield was calculated to be 23%.

[0167] Example 8

[0168] (1) A solution of 2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone (0.0728 g, 0.2 mmol, 1 equiv.), 4-methoxybenzomidazine hydrochloride (0.0653 g, 0.35 mmol, 1.75 equiv.), cobalt(III) acetylacetonate (0.1781 g, 0.5 mmol, 2.5 equiv.), tetrabutylammonium bromide (0.3224 g, 1.0 mmol, 5.0 equiv.), anhydrous magnesium sulfate (0.0602 g, 0.5 mmol, 2.5 equiv.), and cesium carbonate (0.6191 g, 1.9 mmol, 9.5 equiv.) in N-methylpyrrolidone (3 mL) was stirred at 70 °C under nitrogen protection for 24 hours.

[0169] (2) After the reaction in step (1) is completed, the product is quenched with saturated ammonium chloride (20 mL) solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (10 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1 / 40 to 1 / 20. Finally, 19.0 mg of the target product ada is obtained.

[0170] The target product ada was characterized as follows: Figure 22 As shown in Figures 23 and 24, the result is: a yellow solid;

[0171] 1 H NMR (400MHz, CDCl3): δ 9.51-9.46 (m, 1H), 8.76-8.71 (m, 2H), 7.95-7.90 (m, 1H), 7.84-7.79 (m, 3H), 7.7 7(d, J=9.1Hz, 1H), 7.12-7.05(m, 2H), 3.93(s, 3H), 2.68(s, 3H), 2.62(s, 3H)ppm.

[0172] 19 F NMR (376MHz, CDCl3): δ-54.54 (s, 3F)ppm.

[0173] 13 C NMR (100MHz, CDCl3): δ 194.0, 162.2, 160.3, 159.3, 154.5, 152.5, 149.5, 135.4, 130.7, 130.6, 130.5(2C), 128.8, 128.1, 127. 8, 125.4, 122.2, 122.0 (q, J=268.3Hz), 121.4, 119.8, 116.0 (q, J=37.2Hz), 114.2, 55.6, 30.9, 14.6ppm.

[0174] HRMS(m / z): calcd for C 27 H 20 F3N2O3[M+H] + 477.1421, found: 477.1420.

[0175] Characterization data revealed that the obtained reaction product was 1-(5-(2-(4-methoxyphenyl)benzo[h]quinazolin-4-yl)-2-methyl-4-(trifluoromethyl)furan-3-yl)acetone (purity > 98%), and the structural formula of this compound is:

[0176]

[0177] The product yield was calculated to be 20%.

[0178] Example 9

[0179] (1) A solution of 2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone (0.0728 g, 0.2 mmol, 1 equiv.), 4-trifluoromethylbenzoamide hydrochloride (0.0786 g, 0.35 mmol, 1.75 equiv.), cobalt(III) acetylacetonate (0.1781 g, 0.5 mmol, 2.5 equiv.), tetrabutylammonium bromide (0.3224 g, 1.0 mmol, 5.0 equiv.), anhydrous magnesium sulfate (0.0602 g, 0.5 mmol, 2.5 equiv.), and cesium carbonate (0.6191 g, 1.9 mmol, 9.5 equiv.) in N-methylpyrrolidone (3 mL) was stirred at 70 °C under nitrogen protection for 24 hours.

[0180] (2) After the reaction in step (1) is completed, the product is quenched with saturated ammonium chloride (20 mL) solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (10 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1 / 40 to 1 / 20. Finally, 40.4 mg of the target product aea is obtained.

[0181] The target product aea was characterized as follows: Figure 25 As shown in Figures 26 and 27, the result is: a white solid;

[0182] 1 H NMR (400MHz, CDCl3): δ9.51-9.45(m, 1H), 8.88(d, J=8.8Hz, 2H), 7.98-7.93(m , 1H), 7.90 (d, J=9.1Hz, 1H), 7.88-7.79 (m, 5H), 2.70 (s, 3H), 2.64 (s, 3H)ppm.

[0183] 19F NMR (376MHz, CDCl3): δ-54.57 (s, 3F), -62.56 (s, 3F)ppm.

[0184] 13 C NMR (100MHz, CDCl3): δ 194.0, 159.4, 158.9, 154.7, 152.5, 149.1 (q, J=4.6Hz), 141.1, 135.4, 132.5 (q, J=32.4Hz), 131.0, 130.4, 130.1, 129.0, 128.3, 128 .2, 125.7 (d, J=4.4Hz), 125.4, 123.0, 122.3, 122.0 (q, J=268.9Hz), 121.2, 120.6, 116.4 (q, J=37.5Hz), 30.9 (d, J=2.9Hz), 14.6ppm.

[0185] HRMS(m / z): calcd for C 27 H 17 F6N2O2[M+H] + 515.1189, found: 515.1187.

[0186] Characterization data revealed that the obtained reaction product was 1-(2-methyl-5-(2-(4-(trifluoromethyl)phenyl)benzo[h]quinazolin-4-yl)-4-(trifluoromethyl)furan-3-yl)acetone (purity > 98%), and the structural formula of this compound is:

[0187]

[0188] The product yield was calculated to be 39%.

[0189] Example 10

[0190] (1) A solution of 2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone (0.0728 g, 0.2 mmol, 1 equiv.), 4-pyridinebenzamide hydrochloride (0.0552 g, 0.35 mmol, 1.75 equiv.), cobalt(III) acetylacetonate (0.1781 g, 0.5 mmol, 2.5 equiv.), tetrabutylammonium bromide (0.3224 g, 1.0 mmol, 5.0 equiv.), anhydrous magnesium sulfate (0.0602 g, 0.5 mmol, 2.5 equiv.), and cesium carbonate (0.6191 g, 1.9 mmol, 9.5 equiv.) in N-methylpyrrolidone (3 mL) was stirred at 70 °C under nitrogen protection for 24 hours.

[0191] (2) After the reaction in step (1) is completed, the product is quenched with saturated ammonium chloride (20 mL) solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (10 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1 / 40 to 1 / 20. Finally, 20.8 mg of the target product afa is obtained.

[0192] The target product afa was characterized as follows: Figure 28 As shown in 29 and 30, the result is: brown oily;

[0193] 1 H NMR (400MHz, CDCl3): δ 9.53-9.49 (m, 1H), 8.89 (s, 2H), 8.66 (s, 2H), 8.01-7.95 (m, 2H), 7.90-7.86 (m, 3H), 2.70 (s, 3H), 2.64 (s, 3H)ppm.

[0194] 19 F NMR (376MHz, CDCl3): δ-54.57 (s, 3F)ppm.

[0195] 13 C NMR (100MHz, CDCl3): δ 193.9, 167.4, 161.9, 159.5, 158.1, 154.8, 152.5, 150.3, 149.8, 148.9 (d, J=4.6Hz), 146.1, 145.4, 135. 4, 131.2, 130.6, 130.3, 128.3 (d, J=2.8Hz), 125.4, 121.9 (q, J=268.4Hz), 121.2, 119.7, 24.2, 14.6ppm.

[0196] HRMS(m / z): calcd for C 25 H 17 F3N3O2[M+H] + 448.1267, found: 448.1263.

[0197] Characterization data revealed that the obtained reaction product was 1-(5-(2-(4-pyridyl)benzo[h]quinazolin-4-yl)-2-methyl-4-(trifluoromethyl)furan-3-yl)acetone (purity > 98%), and the structural formula of this compound is:

[0198]

[0199] The product yield was calculated to be 23%.

[0200] Example 11

[0201] (1) A solution of 2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone (0.0728 g, 0.2 mmol, 1 equiv.), benzamide hydrochloride (0.0548 g, 0.35 mmol, 1.75 equiv.), tris(1,6-diethylhexane-2,4-diketoic acid)cobalt(III) (0.2132 g, 0.5 mmol, 2.5 equiv.), tetrabutylammonium bromide (0.3224 g, 1.0 mmol, 5.0 equiv.), anhydrous magnesium sulfate (0.0602 g, 0.5 mmol, 2.5 equiv.), and cesium carbonate (0.6191 g, 1.9 mmol, 9.5 equiv.) in N-methylpyrrolidone (3 mL) was stirred at 70 °C under nitrogen protection for 24 hours.

[0202] (2) After the reaction in step (1) is completed, the product is quenched with saturated ammonium chloride (20 mL) solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (10 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1 / 40 to 1 / 20. Finally, 23.6 mg of the target product aab is obtained.

[0203] The target product aab was characterized as follows: Figure 31 As shown in Figures 32 and 33, the result is: a yellow solid;

[0204] 1 H NMR (400MHz, CDCl3): δ 9.55-9.49(m, 1H), 8.83-8.78(m, 2H), 7.94(dt, J=5.4, 3.2Hz, 1H), 7.88-7.81(m, 4H), 7.63-7.52(m , 3H), 3.01 (q, J=7.6Hz, 2H), 2.93 (q, J=7.2Hz, 2H), 1.38 (t, J=7.5Hz, 3H), 1.26 (t, J=7.2Hz, 3H)ppm.

[0205] 19 F NMR (376MHz, CDCl3): δ-54.42 (s, 3F)ppm.

[0206] 13 C NMR (100MHz, CDCl3): δ198.2, 162.4, 160.4, 154.4, 152.5, 149.6 (q, J=4.9Hz), 137.9, 135.3, 131.0, 130.8, 130.6, 129.4, 12 8.9, 128.8, 128.1, 127.9, 125.5, 122.1 (q, J=271.1Hz), 121.7, 121.3, 120.0, 116.1, 36.6 (d, J=2.4Hz), 21.6, 12.7, 8.4ppm.

[0207] HRMS(m / z): calcd for C 28 H 22 F3N2O2[M+H] + 475.1628, found: 475.1621.

[0208] Characterization data revealed that the obtained reaction product was 1-(2-ethyl-5-(2-phenylbenzo[h]quinazolin-4-yl)-4-(trifluoromethyl)furan-3-yl)prop-1-one (purity > 98%), and the structural formula of this compound is:

[0209]

[0210] The product yield was calculated to be 25%.

[0211] Example 12

[0212] (1) A solution of 2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone (0.0728 g, 0.2 mmol, 1 equiv.), benzamide hydrochloride (0.0548 g, 0.35 mmol, 1.75 equiv.), tris(1,3,5-triphenylpentane-2,4-diketoacid)cobalt(III) (0.2712 g, 0.5 mmol, 2.5 equiv.), tetrabutylammonium bromide (0.3224 g, 1.0 mmol, 5.0 equiv.), anhydrous magnesium sulfate (0.0602 g, 0.5 mmol, 2.5 equiv.), and cesium carbonate (0.6191 g, 1.9 mmol, 9.5 equiv.) in N-methylpyrrolidone (3 mL) was stirred at 70 °C under nitrogen protection for 24 hours.

[0213] (2) After the reaction in step (1) is completed, the product is quenched with saturated ammonium chloride (20 mL) solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (10 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1 / 40 to 1 / 20. Finally, 42.6 mg of the target product aac is obtained.

[0214] The target product aac was characterized as follows: Figure 34 As shown in Figures 35 and 36, the result is: a yellow solid;

[0215] 1 H NMR (400MHz, CDCl3): δ 9.54-9.50 (m, 1H), 8.85-8.81 (m, 2H), 8.08 (d, J=9.1Hz, 1H), 8.03-7.99 (m, 2H), 7.96-7.92 (m, 1 H), 7.91-7.87(m, 1H), 7.85-7.81(m, 2H), 7.71-7.65(m, 1H), 7.62-7.55(m, 5H), 2.47(s, 3H)ppm.

[0216] 19 F NMR (376MHz, CDCl3): δ-54.60 (s, 3F)ppm.

[0217] 13 C NMR (100MHz, CDCl3): δ 190.4, 160.4, 156.1, 153.8, 152.7, 150.0 (q, J=4.2Hz), 137.9, 137.7, 135.3, 134.1, 131.0, 130.7, 130.6, 129.8, 129.3, 128.9, 128.84, 128.81, 128.1, 127.9, 127.1, 125.5, 121.8 (q, J=269.2Hz), 121.5, 119.6, 118.3 (q, J=37.6Hz), 13.7ppm.

[0218] HRMS(m / z): calcd for C 31 H 20 F3N2O2[M+H] + 509.1471, found: 509.1476.

[0219] Characterization data revealed that the obtained reaction product was (2-methyl-5-(2-phenylbenzo[h]quinazolin-4-yl)-4-(trifluoromethyl)furan-3-yl)(phenyl)methyl ketone (purity > 98%), and the structural formula of this compound is:

[0220]

[0221] The product yield was calculated to be 42%.

[0222] Example 13

[0223] (1) A solution of 2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone (0.0728 g, 0.2 mmol, 1 equiv.), benzamide hydrochloride (0.0548 g, 0.35 mmol, 1.75 equiv.), tris(1,3,5-tris(4-chlorophenyl)pentane-2,4-diketo acid)cobalt(III) (0.3229 g, 0.5 mmol, 2.5 equiv.), tetrabutylammonium bromide (0.3224 g, 1.0 mmol, 5.0 equiv.), anhydrous magnesium sulfate (0.0602 g, 0.5 mmol, 2.5 equiv.), and cesium carbonate (0.6191 g, 1.9 mmol, 9.5 equiv.) in N-methylpyrrolidone (3 mL) was stirred at 70 °C under nitrogen protection for 24 hours.

[0224] (2) After the reaction in step (1) is completed, the product is quenched with saturated ammonium chloride (20 mL) solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (10 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1 / 40 to 1 / 20. Finally, 41.5 mg of the target product aad is obtained.

[0225] The target product aad was characterized as follows: Figure 37 As shown in 38 and 39, the result is: yellow oily;

[0226] 1 H NMR (400MHz, CDCl3): δ 9.56-9.50 (m, 1H), 8.83-8.78 (m, 2H), 8.08 (d, J=9.1Hz, 1H), 7.98-7.89 (m, 4H), 7.87-7.83 (m, 2H), 7.60-7.52 (m, 5H), 2.49 (s, 3H)ppm.

[0227] 19 F NMR (376MHz, CDCl3): δ-54.48 (s, 3F)ppm.

[0228] 13 C NMR (100MHz, CDCl3): δ 189.2, 164.3, 160.4, 156.2, 153.7, 140.7, 137.9, 136.1, 135.3, 131.6, 131.3, 131.13, 131.07, 130.8, 129 .3, 129.1, 128.9, 128.8, 128.7, 128.5, 128.1, 128.0, 121.6 (q, J=268.1Hz), 125.5, 121.5, 119.7, 13.7ppm.

[0229] HRMS(m / z): calcd for C 31 H 19 ClF3N2O2[M+H] + 543.1082, found: 543.1078.

[0230] Characterization data revealed that the obtained reaction product was (4-chlorophenyl)(2-methyl-5-(2-phenylbenzo[h]quinazolin-4-yl)4-(trifluoromethyl)furan-3-yl) methyl ketone (purity > 98%), and the structural formula of this compound is:

[0231]

[0232] The product yield was calculated to be 38%.

[0233] Example 14

[0234] (1) A solution of 2-(perfluorobutyl)-1,2,3,4-tetrahydronaphthone (0.0728 g, 0.2 mmol, 1 equiv.), benzamide hydrochloride (0.0548 g, 0.35 mmol, 1.75 equiv.), tris(1,3,5-tris(4-methoxyphenyl)pentane-2,4-diketoacid)cobalt(III) (0.3163 g, 0.5 mmol, 2.5 equiv.), tetrabutylammonium bromide (0.3224 g, 1.0 mmol, 5.0 equiv.), anhydrous magnesium sulfate (0.0602 g, 0.5 mmol, 2.5 equiv.), and cesium carbonate (0.6191 g, 1.9 mmol, 9.5 equiv.) in N-methylpyrrolidone (3 mL) was stirred at 70 °C under nitrogen protection for 24 hours.

[0235] (2) After the reaction in step (1) is completed, the product is quenched with saturated ammonium chloride (20 mL) solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (10 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1 / 40 to 1 / 20. Finally, 42.9 mg of the target product aae is obtained.

[0236] The target product aae was characterized as follows: Figure 40 As shown in Figures 41 and 42, the result is: yellow oily substance;

[0237] 1 H NMR (400MHz, CDCl3): δ 9.56-9.50 (m, 1H), 8.86-8.79 (m, 2H), 8.10 (d, J=9.1Hz, 1H), 8.02-7.98 (m, 2H), 7.97-7.92 (m, 1H), 7.89 (d, J=9.1Hz, 1H), 7.85-7.81 (m, 2H), 7.61-7.53 (m, 3H), 7.06-7.00 (m, 2H), 3.93 (s, 3H), 2.47 (s, 3H)ppm.

[0238] 19 F NMR (376MHz, CDCl3): δ-54.72 (s, 3F)ppm.

[0239] 13 C NMR (100MHz, CDCl3): δ 188.9, 164.5, 160.3, 155.2, 153.8, 152.7, 149.7 (q, J=3.9Hz), 137.9, 135.3, 132.3, 131.0, 130.7, 130.6, 130.5, 129.3, 128.8 (2C), 128.1, 127.9, 125.5, 121.9 (q, J=268.8Hz), 121.6, 119.6, 116.3, 114.2, 114.0, 55.8, 13.6ppm.

[0240] HRMS(m / z): calcd for C 32 H 22 F3N2O3[M+H] + 539.1577, found: 539.1575.

[0241] Characterization data revealed that the obtained reaction product was (4-methoxyphenyl)(2-methyl-5-(2-phenylbenzo[h]quinazolin-4-yl)-4-(trifluoromethyl)furan-3-yl) methyl ketone (purity > 98%), and the structural formula of this compound is:

[0242]

[0243] The product yield was calculated to be 40%.

[0244] Example 15

[0245] Example 15 is basically the same as Example 1, except that in step (1), tetrabutylammonium bromide (TBAB) is used as additive I, dimethyl sulfoxide is used as solvent, the reaction time is 12 h at 70 °C, and the base is different, as shown in Table 1 below:

[0246] Table 1

[0247] <![CDATA[K2CO3(9.5)]]> 20 CsF(19) 27 <![CDATA[K3PO4(9.5)]]> 27 NaOH (9.5%) trace <![CDATA[Cs2CO3(9.5)]]> 41

[0248] As can be seen from Table 1, under the same reaction conditions, the reaction yield is lower than that of cesium carbonate (Cs2CO3) when potassium carbonate (K2CO3), cesium fluoride (CsF), potassium phosphate (K3PO4), or sodium hydroxide (NaOH) are used as bases.

[0249] Example 16

[0250] Example 16 is basically the same as Example 1, except that in step (1), cesium carbonate (Cs2CO3) is used as the base, TBAB is used as additive I, dimethyl sulfoxide is used as the solvent, the reaction time is 12 hours, and the temperature is different, as shown in Table 3 below:

[0251] Table 2

[0252] 50 2 70 30 90 17

[0253] As can be seen from Table 2, under the same reaction conditions, the reaction yield is lower at 50℃ and 90℃ than at 70℃.

[0254] Example 17

[0255] Example 17 is basically the same as Example 1, except that in step (1), cesium carbonate (Cs2CO3) is used as the base, dimethyl sulfoxide is used as the solvent, the reaction time is 12 hours at 70°C, and additive I is different, as shown in Table 4 below:

[0256] Table 3

[0257]

[0258]

[0259] As can be seen from Table 3, under the same reaction conditions, the reaction yield is lower than that of tetrabutylammonium bromide (TBHDPB), tetramethylammonium bromide (TMAB), benzyltriethylammonium bromide (BTEAB), phenyltrimethylammonium tribromide (PTMAB), or 18-crown-6 (18-Crown-6) as additive I.

[0260] Example 18

[0261] Example 18 is basically the same as Example 1, except that in step (1), cesium carbonate (Cs2CO3) is used as the base, tetrabutylammonium bromide (TBAB) is used as additive I, dimethyl sulfoxide is used as the solvent, the reaction time is 12h, and the reaction temperature is 70℃. Additive II is also different, as shown in Table 5 below:

[0262] Table 4

[0263] As can be seen from Table 4, under the same reaction conditions, magnesium chloride (MgCl2), zinc chloride (ZnCl2), calcium chloride (CaCl2), indium chloride (InCl3), and molecular sieves... When lithium chloride (LiCl), lithium tetrafluoroborate (LiBF4), and magnesium carbonate (MgCO3) are used as additives II, the reaction yield is lower than that of anhydrous magnesium sulfate (MgSO4).

[0264] Example 19

[0265] Example 19 is basically the same as Example 1, except that in step (1), cesium carbonate (Cs2CO3) is used as the base, tetrabutylammonium bromide (TBAB) is used as additive I, and anhydrous magnesium sulfate (MgSO4) is used as additive II. The reaction time is 24 hours at 70°C, and the reaction solvent is different, as shown in Table 2 below:

[0266] Table 5

[0267] DMSO 19 DMF 24 NMP 44

[0268] As can be seen from Table 5, under the same reaction conditions, the reaction yield is 19% when dimethyl sulfoxide (DMSO) is used as the solvent and 24% when N,N-dimethylformamide (DMF) is used as the solvent. The above reaction yields are not as high as those when N-methylpyrrolidone is used as the solvent.

[0269] Example 20

[0270] Example 20 is basically the same as Example 1, except that the reaction time is different in step (1), as shown in Table 6 below:

[0271] Table 6

[0272] 12 35 24 44 36 30 48 34

[0273] As can be seen from Table 6, under the same reaction conditions, shortening or increasing the reaction time is detrimental to the reaction; when the reaction time is 24 hours, the reaction yield is 44%.

[0274] Example 21

[0275] Example 21 is basically the same as Example 1, except that the perfluoroalkyl tetrahydronaphthone used in step (1) is different. The specific target products obtained are shown in Table 7 below:

[0276] Table 7

[0277]

[0278]

[0279] Example 22

[0280] Example 22 is basically the same as Example 1, except that the amidine compound is different in step (1). The specific target products obtained are shown in Table 8 below:

[0281] Table 8

[0282]

[0283]

[0284] Application Example 23

[0285] The activity of the compounds was tested using the A-375 (human malignant melanoma) cell line, following the methods reported in the literature (Bioorg. Med. Chem. 2012, 20, 6980-7001; Eur. J. Med. Chem. 2017, 137, 351-364).

[0286] (a) Selected test compounds:

[0287] Compound aaa: 1-(2-methyl-5-(2-phenylbenzo[h]quinazolin-4-yl)-4-(trifluoromethyl)furan-3-yl) ethyl ketone;

[0288] Compound caa: 1-(2-methyl-5-(9-methyl-2-phenylbenzo[h]quinazolin-4-yl)-4-(trifluoromethyl)furan-3-yl) ethyl ketone;

[0289] Compound eaa: 1-(5-(9-methoxy-2-phenylbenzo[h]quinazolin-4-yl)-2-methyl-4-(trifluoromethyl)furan-3-yl) ethyl ketone;

[0290] Compound ACA: l-(5-(2-(p-tolyl)benzo[h]quinazolin-4-yl)-2-methyl-4-(trifluoromethyl)furan-3-yl)acetone;

[0291] Compound ada: 1-(5-(2-(4-methoxyphenyl)benzo[h]quinazolin-4-yl)-2-methyl-4-(trifluoromethyl)furan-3-yl) ethyl ketone;

[0292] Compound aab: 1-(2-ethyl-5-(2-phenylbenzo[h]quinazolin-4-yl)-4-(trifluoromethyl)furan-3-yl)prop-1-one;

[0293] Compound aac: (2-methyl-5-(2-phenylbenzo[h]quinazolin-4-yl)-4-(trifluoromethyl)furan-3-yl)(phenyl)methyl ketone.

[0294] (II) DMSO Mother Liquor

[0295] Compound aaa, 8.93 mg accurately weighed and dissolved in 1 mL of DMSO, yielded 20 mM.

[0296] Compound caa, 9.21 mg accurately weighed, was dissolved in 1 mL of DMSO to obtain 20 mM.

[0297] Compound eaa, 9.53 mg accurately weighed, was dissolved in 1 mL of DMSO to obtain 20 mM.

[0298] Compound aca, 9.21 mg accurately weighed, was dissolved in 1 mL of DMSO to obtain 20 mM.

[0299] Compound ada was accurately weighed at 9.53 mg and dissolved in 1 mL of DMSO to obtain 20 mM.

[0300] Compound aab, 9.49 mg was accurately weighed and dissolved in 1 mL of DMSO to obtain 20 mM.

[0301] Compound aac, 10.17 mg was accurately weighed and dissolved in 1 mL of DMSO to give 20 mM.

[0302] (III) Concentration Examination

[0303] The inhibitory effects of concentrations of 500, 250, 100, 50, 25, 10, 5, 2.5, and 1 μM on cells were investigated. The sensitivity of different concentrations of various chemicals to cell viability and toxicity was measured using a CCK-8 assay, and the IC50 was calculated.

[0304] (iv) Co-training time

[0305] After co-culturing the drug-containing solution with cells for 24-36 hours, the cells were tested using a CCK8 assay, with six replicates per sample.

[0306] (V) The A-375 activity values ​​of the tested compounds aaa, baa, caa, daa, eaa, aba, aca, ada, aea, aab, and aac are shown in Table 8 below:

[0307] Table 9

[0308]

[0309]

[0310] As can be seen from the table, the IC50 values ​​of compounds aaa, caa, eaa, aca, ada, aab and aac are 216 μm, 185 μm, 69 μm, 67 μm, 30 μm, 131 μm and 108 μm, respectively. Compound ada showed the best function in inhibiting the activity of human malignant melanoma (A-375) cells.

[0311] This invention provides a method for the defluorination and cyclization reaction of perfluoroalkyl tetrahydronaphthones, amidine compounds, and cobalt-1,3-dicarbonyl complexes under cesium carbonate-promoted conditions, synthesizing a series of fluoroalkyl-substituted furanoquinazoline compounds. This strategy eliminates the dependence of traditional synthetic routes on multi-step prefunctionalization and transition metal catalysis. During the reaction, the six carbon-fluorine bonds at the three perfluoroalkyl carbon sites of the polyfluoroalkyl ketone are successively broken, ultimately constructing five carbon-carbon / carbon-nitrogen / carbon-oxygen bonds and two heterocycles in a one-pot process. This achieves the precise synthesis of fluoroalkyl-substituted furanoquinazoline compounds, featuring mild conditions, good functional group tolerance, simple post-processing, green procedures, low pollution, and high economic benefits.

[0312] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A fluoroalkyl-substituted furanylquinazoline compound, characterized in that: Its structural formula is shown in Formula I; Among them, R 1 Selected from one of methoxy, methyl, halogen, and phenyl; R 2 Selected from methyl and halogen-substituted phenyl groups; R 3 Selected from thiophene, pyridine, phenyl groups containing methoxy, ethoxy, methyl, trifluoromethyl, and halogen-substituted compounds; R 4 Selected from methyl and ethyl; R 5 Choose one of white ethyl, halogen-substituted phenyl, and methoxy-substituted phenyl; C n F 2n+1 Selected from one of trifluoromethyl, heptafluoropropyl, undecylfluoropentyl, and pentadecylfluoroheptyl; n = 1-7.

2. The method for preparing a fluoroalkyl-substituted furanylquinazoline compound as described in claim 1, characterized in that, The method includes the following steps: (1) Perfluoroalkyl tetrahydronaphthone, amidine compounds, a cobalt-1,3-dicarbonyl complex, tetrabutylammonium bromide, cesium carbonate, and anhydrous magnesium sulfate were added to N-methylpyrrolidone and stirred at 70°C for 24 h; wherein, The chemical structural formula of the perfluoroalkyl tetrahydronaphthone is shown in formula (II) below: In Equation II, R 1 R 2 With Equation I, R 1 R 2 Consistent; C n F 2n+1 Selected from one of trifluoromethyl, heptafluoropropyl, undecylfluoropentyl, and pentadecylfluoroheptyl; n = 1-7. The chemical structural formula of the amidine compound is shown in formula (III) below: In Equation III, R 3 With Equation I, R 3 The correspondence is consistent. The chemical structural formula of the cobalt-1,3-dicarbonyl complex is shown in formula (IV) below: In Equation IV, R 4 R 5 With Equation I, R 4 R 5 The correspondence is consistent. (2) After the reaction is completed, the reaction products are quenched and extracted in sequence. The combined organic phases are washed, dried and concentrated in sequence to obtain crude product. The crude product is purified to obtain fluoroalkyl-substituted furan quinazoline compound.

3. The method for preparing the fluoroalkyl-substituted furanylquinazoline compound as described in claim 2, characterized in that, In step (1), the molar ratio of the perfluoroalkyl tetrahydronaphthone, amidine compound and cobalt-1,3-dicarbonyl complex is 1:1.75-3.0:1.0-3.

75.

4. The method for preparing the fluoroalkyl-substituted furanylquinazoline compound as described in claim 2, characterized in that, In step (1), the solvent includes one of dimethyl sulfoxide, N,N-dimethylformamide and N-methylpyrrolidone.

5. The method for preparing the fluoroalkyl-substituted furanylquinazoline compound as described in claim 2, characterized in that, In step (1), the reaction temperature is 50–90°C.

6. The method for preparing the fluoroalkyl-substituted furanylquinazoline compound as described in claim 2, characterized in that, In step (1), the reaction time is 12 to 48 hours.

7. The method for preparing the fluoroalkyl-substituted furanylquinazoline compound as described in claim 2, characterized in that, In step (1), the molar ratio of the perfluoroalkyl tetrahydronaphthone, tetrabutylammonium bromide, cesium carbonate and magnesium sulfate is 1:5.0-11.0:5.5-11.5:1.5-4.

5.

8. The method for preparing the fluoroalkyl-substituted furanylquinazoline compound as described in claim 2, characterized in that, In step (1), the alkali includes cesium carbonate, potassium carbonate, cesium fluoride, potassium phosphate, and sodium hydroxide.

9. The use of the fluoroalkyl-substituted furanylquinazoline compound of claim 1 in the preparation of an active inhibitor of human malignant melanoma cells.

Images