A fluoroalkyl-substituted pyridine compound and a method for preparing the same

Abstract

The application provides a method for defluorocyclization reaction of fluoroalkyl peroxide and benzylamine under the promotion of triethylenediamine and potassium phosphate, and synthesizes a series of fluoroalkyl pyridine compounds. 3 The reaction realizes precise synthesis of the fluoroalkyl-substituted pyridine compound by selectively activating six C(sp )‑F bonds of three carbon sites on the fluoroalkyl chain, has the characteristics of mild conditions, good functional group tolerance, simple post-treatment, green steps, low pollution and high economic benefits, and the obtained compound shows certain anti-human multiple myeloma cell (U266) activity, and can be used for preparing an active inhibitor for resisting human multiple myeloma cells.

Description

Technical Field

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

[0002] Pyridine is considered a preferred skeletal structure due to its ubiquitous presence in small molecule drugs and synthetic bioactive molecules, exhibiting broad biological activities. With the increasing importance of fluorinated compounds in the pharmaceutical and materials fields, developing efficient and precise fluorinated pyridine modification strategies has become a research hotspot (Chem. Soc. Rev., 2019, 48, 5033-5139). Traditional pyridine synthesis methods, such as the Hantzsch reaction, Pyridine synthesis and multi-molecular Chichibabin reactions often require stringent conditions and complex multi-step processes (Angew. Chem. Int. Ed. 2017, 56, 9660-9668). Furthermore, these methods have significant limitations, such as reliance on expensive transition metal catalysts, cumbersome operational procedures, and the use of environmentally sensitive reactants. Of particular note is the significant technical hurdle in the fluorination of the pyridine ring—due to the inherent electronic effects of the pyridine ring, direct fluorination and fluoroalkylation reactions can typically only proceed selectively at the ortho or para position, making meta-selective modification a long-standing technical challenge in this field (Angew. Chem. Int. Ed. 2023, 62, e202302941).

[0003] To address the aforementioned technical deficiencies, this invention innovatively develops a novel method for the synthesis of fluoroalkylpyridines. This method, through a base-promoted defluorination cyclization reaction of fluoroalkyl peroxides and benzylamine, successfully overcomes the technical bottleneck of traditional methods in terms of regioselectivity control. The technical solution of this invention has the following significant advantages: it eliminates the need for expensive metal catalysts, significantly reducing production costs; the reaction conditions are mild, allowing for efficient operation in an air atmosphere; and it uses triethylenediamine and potassium phosphate as bases, selectively activating C(sp) sites on specific carbon sites on the fluoroalkyl chain. 3 The )-F bond enables excellent chemoselectivity and regioselectivity; it has broad functional group compatibility and excellent atom economy; and the resulting compound exhibits certain anti-human multiple myeloma cell (U266) activity, which can be used to prepare an active inhibitor against human multiple myeloma cells. Summary of the Invention

[0004] 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.

[0005] In view of the problems existing in the above and / or prior art, the present invention is proposed.

[0006] One object of the present invention is to provide a fluoroalkyl-substituted pyridine compound.

[0007] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a fluoroalkyl-substituted pyridine compound, the structural formula of which is shown in Formula I;

[0008]

[0009] R is selected from one of methoxy, methyl, halogen, and ester groups;

[0010] C n F 2n+1 Selected from one of trifluoromethyl, heptafluoropropyl, nonafluorobutyl, undecylfluoropentyl, and pentadecylfluoroheptyl; n = 1-7.

[0011] 2. The method for preparing a fluoroalkyl-substituted pyridine compound as described in claim 1, characterized in that it comprises:

[0012] Using benzylamine as the nitrogen source and the fluoroalkyl peroxide shown in Formula II, in a solvent with the aid of triethylenediamine and potassium phosphate, the six C(sp) atoms at three carbon sites on the fluoroalkyl chain were selectively activated. 3 The -F bond undergoes a defluorination cyclization reaction to yield the compound shown in Formula I;

[0013]

[0014] In Equation II, R corresponds to R in Equation I;

[0015] In a preferred embodiment of the preparation method of the fluoroalkyl peroxide of the present invention, the fluoroalkyl peroxide comprises 1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexylbenzene, 1-[1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]-4-methoxybenzene, 4-[1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]-1,2-dimethoxybenzene, 1-[1- [1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]-4-methylbenzene, 1-[1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]-4-fluorobenzene, 1-[1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]-4-chlorobenzene, 1-[1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]-3-chlorobenzene, 1-[1- [(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]-2-chlorobenzene, 1-bromo-4-[1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]benzene, 4-[1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]ethyl benzoate, 1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,7,7,8,8,8-tridecylfluorooctylbenzene ...6-nonafluorohexyl]-2-chlorobenzene, 1-bromo-4-[1-(tert-butylperoxy)-3,3,4,4,5,5,6,6 One of the following: (butylperoxy)-3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-pentadecylfluorononylbenzene, 1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecylfluorodecylbenzene, and 1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-tetrafluorododecylbenzene.

[0016] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted pyridine compound of the present invention, the molar ratio of the fluoroalkyl peroxide to the benzylamine is 1:3.0 to 5.0; preferably, the molar ratio is 1:5.0.

[0017] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted pyridine compound of the present invention, the solvent includes one of acetonitrile, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N-methylpyrrolidone, tert-butanol, and water; preferably, the solvent is N-methylpyrrolidone.

[0018] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted pyridine compound of the present invention, the defluorination cyclization reaction is carried out at a temperature of room temperature to 60°C; preferably, the reaction temperature is 60°C.

[0019] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted pyridine compound of the present invention, the defluorination cyclization reaction is carried out for a reaction time of 6 to 12 hours; preferably, the reaction time is 12 hours.

[0020] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted pyridine compound of the present invention, the defluorination cyclization reaction is carried out in a nitrogen, oxygen, or air atmosphere; preferably, the reaction environment is an air atmosphere.

[0021] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted pyridine compound of the present invention, the molar ratio of the fluoroalkyl peroxide, the triethylenediamine, and the potassium phosphate is 1:1.5–3.5:1.5–3.5; preferably, the molar ratio is 1:3.5:3.5.

[0022] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted pyridine compound of the present invention, the base comprises a dual base consisting of triethylenediamine and cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium tert-butoxide, and potassium phosphate, respectively; preferably, the base is triethylenediamine and potassium phosphate.

[0023] The present invention further discloses the application of the above-mentioned fluoroalkyl-substituted pyridine compounds in the preparation of activity inhibitors of human multiple myeloma cells (U266).

[0024] In summary, the optimal reaction equation for this invention is as follows:

[0025]

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] This invention provides a method for the defluorination cyclization reaction of fluoroalkyl peroxides and benzylamine under the promoting conditions of triethylenediamine and potassium phosphate, synthesizing a series of fluoroalkylpyridine compounds. This reaction selectively activates the six C(sp) atoms at three carbon sites on the fluoroalkyl chain. 3 By exploiting the -F bond, the precise synthesis of fluoroalkyl-substituted pyridine compounds was achieved. This method features mild conditions, good functional group tolerance, simple post-processing, green steps, low pollution, and high economic benefits. Furthermore, the obtained compounds exhibit certain anti-human multiple myeloma cells (U266) activity and can be used to prepare active inhibitors against human multiple myeloma cells. Attached Figure Description

[0028] 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:

[0029] Figure 1 The proton spectrum of target product a in Example 1 of this invention;

[0030] Figure 2 The fluorine spectrum of target product a in Example 1 of this invention;

[0031] Figure 3 The carbon spectrum of target product a in Example 1 of this invention;

[0032] Figure 4 The proton spectrum of target product b in Example 2 of this invention;

[0033] Figure 5 The fluorine spectrum of target product b in Example 2 of the present invention;

[0034] Figure 6 The carbon spectrum of target product b in Example 2 of this invention;

[0035] Figure 7 The proton spectrum of target product c in Example 3 of this invention;

[0036] Figure 8 The fluorine spectrum of target product c in Example 3 of this invention;

[0037] Figure 9 The carbon spectrum of target product c in Example 3 of this invention;

[0038] Figure 10 The proton spectrum of the target product d in Example 4 of this invention;

[0039] Figure 11 The fluorine spectrum of the target product d in Example 4 of this invention;

[0040] Figure 12 The carbon spectrum of the target product d in Example 4 of this invention;

[0041] Figure 13 The proton spectrum of target product e in Example 5 of this invention;

[0042] Figure 14 The fluorine spectrum of target product e in Example 5 of this invention;

[0043] Figure 15 The carbon spectrum of target product e in Example 5 of this invention; Detailed Implementation

[0044] 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.

[0045] 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.

[0046] 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.

[0047] The fluoroalkyl peroxide used in the examples was prepared by the method reported in the reference (J.Org.Chem.2016, 81, 5878-5885.).

[0048] Example 1

[0049] (1) A solution of 1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexylbenzene (0.124 g, 0.3 mmol, 1 equiv.), benzylamine (0.16 mL, 1.5 mmol, 5 equiv.), triethylenediamine (0.118 mg, 1.05 mmol, 3.5 equiv.) and potassium phosphate (0.223 mg, 1.05 mmol, 3.5 equiv.) in N-methylpyrrolidone (2 mL) was stirred in air at 60 °C for 12 hours.

[0050] (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 / 10. Finally, 42.9 mg of target product a is obtained.

[0051] The target product a was characterized as follows: Figure 1 As shown in Figures 2 and 3, the result is: yellow oily substance;

[0052] 1H NMR (400MHz, CDCl3): δ 7.96-7.93 (m, 2H), 7.47-7.41 (m, 3H), 7.01 (d, J=2.2Hz, 1H), 6.81 (d, J=2.0Hz, 1H), 4.46 (s, 2H)ppm.

[0053] 19 F NMR (376MHz, CDCl3): δ-68.31 (s, 3F)ppm.

[0054] 13 C NMR (100MHz, CDCl3): δ 158.8, 154.4, 149.3 (q, J C-F =33.7Hz), 138.7, 129.5, 128.8(2C), 127.2(2C), 121.9(q, J C-F =274.5Hz), 107.8, 105.1 (q, J C-F =3.0Hz)ppm.

[0055] HRMS(m / z): calcd for C 12 H 10 F3N2 + [M+H] + 239.0791, found: 239.0799.

[0056] Characterization data revealed that the obtained reaction product was 2-phenyl-6-(trifluoromethyl)pyridine-4-amine (purity > 98%), and the structural formula of this compound is as follows:

[0057]

[0058] The product yield was calculated to be 60%.

[0059] Example 2

[0060] (1) A solution of 1-[1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]-4-methoxybenzene (0.133 g, 0.3 mmol, 1 equiv.), benzylamine (0.16 mL, 1.5 mmol, 5 equiv.), triethylenediamine (0.118 mg, 1.05 mmol, 3.5 equiv.) and potassium phosphate (0.223 mg, 1.05 mmol, 3.5 equiv.) in N-methylpyrrolidone (2 mL) was stirred in air at 60 °C for 12 hours.

[0061] (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, 35.6 mg of the target product b is obtained.

[0062] The target product b was characterized as follows: Figure 4 As shown in Figures 5 and 6, the result is: yellow oily substance;

[0063] 1 H NMR (400MHz, CDCl3): δ 7.93-7.89 (m, 2H), 6.97 (d, J=2.1Hz, 1H), 6.94 (d, J=1.3Hz, 2H), 6.76 (d, J=2.0Hz, 1H), 4.42 (s, 2H), 3.84 (s, 3H)ppm.

[0064] 19 F NMR (376MHz, CDCl3): δ-68.36 (s, 3F)ppm.

[0065] 13 C NMR (100MHz, CDCl3): δ 160.9, 158.5, 154.3, 149.0 (q, J C-F =33.7Hz), 131.2, 128.5 (2C), 121.9 (q, J C-F =274.1Hz), 114.1(2C), 106.9, 104.6(d, J C-F =3.2Hz), 55.5ppm.

[0066] HRMS(m / z): calcd for C 13 H 12 F3N2O + [M+H] + 269.0896, found: 269.0891.

[0067] Characterization data revealed that the obtained reaction product was 2-(4-methoxyphenyl)-6-(trifluoromethyl)pyridine-4-amine (purity > 98%), and the structural formula of this compound is:

[0068]

[0069] The product yield was calculated to be 44%.

[0070] Example 3

[0071] (1) A solution of 1-[1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]-4-methylbenzene (0.128 g, 0.3 mmol, 1 equiv.), benzylamine (0.16 mL, 1.5 mmol, 5 equiv.), triethylenediamine (0.118 mg, 1.05 mmol, 3.5 equiv.) and potassium phosphate (0.223 mg, 1.05 mmol, 3.5 equiv.) in N-methylpyrrolidone (2 mL) was stirred in air at 60 °C for 12 hours.

[0072] (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 / 10. Finally, 43.8 mg of the target product c is obtained.

[0073] The target product c was characterized as follows: Figure 7 As shown in Figures 8 and 9, the result is: yellow oily substance;

[0074] 1 H NMR (400MHz, CDCl3): δ 7.86-7.83 (m, 2H), 7.25 (d, J=8.0Hz, 2H), 6.97 (d, J=2.1Hz, 1H), 6.77 (d, J=2.0Hz, 1H), 4.44 (s, 2H), 2.39 (s, 3H)ppm.

[0075] 19 F NMR (376MHz, CDCl3): δ-68.30 (s, 3F)ppm.

[0076] 13 C NMR (100MHz, CDCl3): δ 158.8, 154.4, 149.0 (q, J C-F =33.2Hz), 139.6, 135.8, 129.5(2C), 127.0(2C), 121.9(q, J C-F =274.5Hz), 107.4, 104.8 (d, J C-F=3.2Hz), 21.4ppm.

[0077] HRMS(m / z): calcd for C 13 H 12 F3N2 + [M+H] + 253.0947, found: 253.0941.

[0078] Characterization data revealed that the obtained reaction product was 2-(4-methylphenyl)-6-(trifluoromethyl)pyridine-4-amine (purity > 98%), and the structural formula of this compound is:

[0079]

[0080] The product yield was calculated to be 58%.

[0081] Example 4

[0082] (1) A solution of 1-[1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]4-fluorobenzene (0.129 g, 0.3 mmol, 1 equiv.), benzylamine (0.16 mL, 1.5 mmol, 5 equiv.), triethylenediamine (0.118 mg, 1.05 mmol, 3.5 equiv.) and potassium phosphate (0.223 mg, 1.05 mmol, 3.5 equiv.) in N-methylpyrrolidone (2 mL) was stirred in air at 60 °C for 12 hours.

[0083] (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 / 10. Finally, 57.2 mg of the target product d is obtained.

[0084] The target product d was characterized as follows: Figure 10 As shown in Figures 11 and 12, the result is: a yellow solid; 1 H NMR (400MHz, CDCl3): δ 7.96-7.90 (m, 2H), 7.15-7.09 (m, 2H), 6.96 (d, J=2.0Hz, 1H), 6.80 (d, J=2.1Hz, 1H), 4.47 (s, 2H)ppm.

[0085] 19 F NMR (376MHz, CDCl3): δ-68.50 (s, 3F), -112.40 (s, 1F)ppm.

[0086] 13 C NMR (100MHz, CDCl3): δ 163.8 (d, J=248.7Hz), 157.8, 154.5, 149.2 (q, J C-F =33.7Hz), 134.8 (d, J) C-F =3.1Hz), 129.08 (d, J) C-F =8.4Hz), 121.8(q, J) C-F =274.4Hz), 115.7 (d, J = 21.6Hz), 107.4, 105.0 (q, J C-F =2.9Hz)ppm.

[0087] HRMS(m / z): calcd for C 12 H9F4N2 + [M+H] + 257.0696, found: 257.0697.

[0088] Characterization data revealed that the obtained reaction product was 2-(4-fluorophenyl)-6-(trifluoromethyl)pyridine-4-amine (purity > 98%), and the structural formula of this compound is:

[0089]

[0090] The product yield was calculated to be 74%.

[0091] Example 5

[0092] (1) A solution of ethyl 4-[1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]benzoate (0.145 g, 0.3 mmol, 1 equiv.), benzylamine (0.16 mL, 1.5 mmol, 5 equiv.), triethylenediamine (0.118 mg, 1.05 mmol, 3.5 equiv.) and potassium phosphate (0.223 mg, 1.05 mmol, 3.5 equiv.) in N-methylpyrrolidone (2 mL) was stirred in air at 60 °C for 12 hours.

[0093] (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, 66.8 mg of the target product e is obtained.

[0094] The target product e is characterized as follows: Figure 13 As shown in Figures 14 and 15, the result is: a white solid; 1 H NMR (400MHz, DMSO-D6): δ 8.06 (s, 4H), 7.26 (d, J=2.0Hz, 1H), 6.95 (d, J=1.9Hz, 1H), 6.76 (s, 2H), 4.33 (q, J=7.1Hz, 2H), 1.33 (t, J=7.1Hz, 3H) ppm.

[0095] 19 F NMR (376MHz, DMSO-D6): δ-67.20 (s, 3F)ppm.

[0096] 13 C NMR (100MHz, DMSO-D6): δ 165.5, 156.8, 155.6, 147.4 (q, J C-F =32.8Hz), 142.5, 130.3, 129.7(2C), 126.7(2C), 122.0(q, J C-F =274.3Hz), 107.3, 104.6, 60.9, 14.2ppm.

[0097] HRMS(m / z): calcd for C 15 H 14 F3N2O2 + [M+H] + 311.1002, found: 311.1006.

[0098] Characterization data revealed that the obtained reaction product was ethyl 4-(4-amino-6-(trifluoromethyl)pyridin-2-yl)benzoate (purity > 98%), and the structural formula of this compound is:

[0099]

[0100] The product yield was calculated to be 72%.

[0101] Example 6

[0102] Example 6 is basically the same as Example 1, except that in step (1), N-methylpyrrolidone is used as the solvent and the base is different, as shown in Table 1 below:

[0103] Table 1

[0104] alkali Yield (%) <![CDATA[DABCO(3.5)+Cs2CO3(3.5)]]> 59 <![CDATA[DABCO(3.5)+K2CO3(3.5)]]> 58 DABCO(3.5) + KOH(3.5) 56 <![CDATA[DABCO(3.5)+ t BuOLi(3.5)]]> 32 <![CDATA[DABCO(3.5)+K3PO4(3.5)]]> 60

[0105] As can be seen from Table 1, under the same reaction conditions, triethylenediamine (DABCO) reacts with cesium carbonate (Cs₂CO₃), potassium carbonate (K₂CO₃), potassium hydroxide (KOH), or lithium tert-butoxide (Cs₂CO₃). t When BuOLi is used as a base, the reaction yield is not as good as that of triethylenediamine (DABCO) and potassium phosphate (K3PO4).

[0106] Example 7

[0107] Example 7 is basically the same as Example 1, except that in step (1), triethylenediamine (DABCO) and cesium carbonate (Cs2CO3) are used as bases, and the reaction environment is different, as shown in Table 2 below:

[0108] Table 2

[0109]

[0110]

[0111] As can be seen from Table 2, under the same reaction conditions, nitrogen is the best reaction atmosphere among nitrogen, open flask, and oxygen atmospheres, and is close to that of air. Considering all factors, air atmosphere is the best choice.

[0112] Example 8

[0113] Example 8 is basically the same as Example 1, except that in step (1), triethylenediamine (DABCO) and cesium carbonate (Cs2CO3) are used as bases, and the reaction solvent is different at room temperature, as shown in Table 3 below:

[0114] Table 3

[0115] reaction solvent Yield (%) DMSO 48 DMF 40 THF 15 MeCN 29 EtOAc 13 <![CDATA[H2O]]> 2 <![CDATA[ t BuOH]]> 2 DMA 47

[0116] As can be seen from Table 3, under the same reaction conditions, using a solvent such as tert-butanol ( tThe yields were low when using BuOH, ethyl acetate (EtOAc), water (H2O), acetonitrile (MeCN), and tetrahydrofuran (THF); the yield was 48% when using dimethyl sulfoxide (DMSO); 40% when using N,N-dimethylformamide (DMF); and 47% when using N,N-dimethylacetamide (DMA). All of these yields were lower than those obtained with N-methylpyrrolidone as a solvent.

[0117] Example 9

[0118] Example 9 is basically the same as Example 1, except that in step (1), triethylenediamine (DABCO) and cesium carbonate (Cs2CO3) are used as bases, and N-methylpyrrolidone is used as solvent, and the temperature is different, as shown in Table 4 below:

[0119] Table 4

[0120] Temperature (°C) Yield (%) room temperature 56 40 58 50 56

[0121] As can be seen from Table 4, under the same reaction conditions, the reaction yield is lower at room temperature to 50℃ than at 60℃.

[0122] Example 10

[0123] Example 10 is basically the same as Example 1, except that the reaction time is different in step (1), as shown in Table 5 below:

[0124] Table 5

[0125] reaction time Yield (%) 12 60 8 0 6 0

[0126] As can be seen from Table 5, under the same reaction conditions, shortening the reaction time is detrimental to the reaction; when the reaction time is 12 hours, the reaction yield is 63%.

[0127] Example 11

[0128] Example 11 is basically the same as Example 1, except that the fluoroalkyl peroxide is different in step (1). The specific target products obtained are shown in Table 6 below:

[0129] Table 6

[0130]

[0131]

[0132] Application Examples

[0133] Preliminary anti-human multiple myeloma cell (U266) activity tests were performed on compounds a, d, e, f, g, h, k, l, m, and n obtained in the above implementation examples, and cell viability was determined by measuring ATP levels. The test method was as follows: exponentially growing cells (PANC-1 cell line / 4 × 10³ cells / 100 μL / well) were incubated with the test compounds for 48 hours. The test compounds were started at a concentration of 0.1 μM and increased to 1000 wells by 3-fold dilution in intact culture medium, and incubated at 37°C in a humidified CO2 and 95% air incubator. Control wells without the compounds were also included in the experiment. The stock solution of the compounds was initially dissolved in DMSO and then further diluted with PBS. After incubation, 20 μL of CTG reagent was added to each well. The wells were then shaken for 7 minutes and incubated at room temperature for 10 minutes. Readings were recorded as absorbance at 570 nm on a microwell reader. Cytotoxic effects are expressed as a 50% lethal dose, which is the concentration of a compound that induces a 50% reduction in cell viability compared to cells in culture medium alone. EC50 values ​​are estimated as described.

[0134] The test results for compounds a, d, e, f, g, h, k, l, m, and n are shown in Table 6. It can be seen that the EC50 values ​​are >100 μm, >100 μm, 59 μm, >100 μm, 55 μm, 58 μm, >100 μm, >100 μm, >100 μm, and >100 μm, respectively. Compounds a, d, e, f, g, h, k, l, m, and n all exhibit the function of inhibiting the activity of human multiple myeloma cells (U266). Among them, compound g has the lowest EC50 value and the best inhibitory effect on human multiple myeloma cells (U266).

[0135] Table 5

[0136] Test compounds EC50 value (μm) a ＞100 d ＞100 e 59 f ＞100 g 55 h 58 k ＞100 l ＞100 m ＞100 n ＞100

[0137] This invention provides a method for the defluorination cyclization reaction of fluoroalkyl peroxides and benzylamine under the promoting conditions of triethylenediamine and potassium phosphate, synthesizing a series of fluoroalkylpyridine compounds. This reaction selectively activates the six C(sp) atoms at three carbon sites on the fluoroalkyl chain. 3 By exploiting the -F bond, the precise synthesis of fluoroalkyl-substituted pyridine compounds was achieved. This method features mild conditions, good functional group tolerance, simple post-processing, green steps, low pollution, and high economic benefits. Furthermore, the obtained compounds exhibit certain anti-human multiple myeloma cells (U266) activity and can be used to prepare active inhibitors against human multiple myeloma cells.

[0138] 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 pyridine compound, characterized in that: Its structural formula is shown in Formula I; R is selected from one of methoxy, methyl, halogen, and ester groups; C n F 2n+1 Selected from one of trifluoromethyl, heptafluoropropyl, nonafluorobutyl, undecylfluoropentyl, and pentadecylfluoroheptyl; n = 1-7.

2. The method for preparing a fluoroalkyl-substituted pyridine compound as described in claim 1, characterized in that, The method includes the following steps: (1) Fluoroalkyl peroxide, benzylamine, and a base are added to a solvent, and the mixture is stirred at room temperature to 60°C for 6 to 12 hours; wherein, The chemical structural formula of the fluoroalkyl peroxide is shown in formula (II) below: In formula (II), R is selected from one of methoxy, methyl, halogen, and ester groups; C n F 2n+1 Selected from one of trifluoromethyl, heptafluoropropyl, nonafluorobutyl, undecylfluoropentyl, and pentadecylfluoroheptyl; n = 1-7. (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 products. The crude products are purified to obtain fluoroalkyl-substituted pyridine compounds.

3. The method for preparing the fluoroalkyl-substituted pyridine compound as described in claim 2, characterized in that, In step (1), the molar ratio of the fluoroalkyl peroxide to the benzylamine is 1:3.0 to 5.

0.

4. The method for preparing the fluoroalkyl-substituted pyridine compound as described in claim 2, characterized in that, In step (1), the solvent includes one of acetonitrile, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N-methylpyrrolidone, tert-butanol, and water.

5. The method for preparing the fluoroalkyl-substituted pyridine compound as described in claim 2, characterized in that, In step (1), the reaction temperature is room temperature to 60°C.

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

7. The method for preparing the fluoroalkyl-substituted pyridine compound according to claim 2, characterized in that, In step (1), the reaction environment is a nitrogen, oxygen, or air atmosphere.

8. The method for preparing the fluoroalkyl-substituted pyridine compound as described in claim 2, characterized in that, In step (1), the molar ratio of the fluoroalkyl peroxide, triethylenediamine and potassium phosphate is 1:1.5 to 3.5:1.5 to 3.

5.

9. The method for preparing the fluoroalkyl-substituted pyridine compound according to claim 2, characterized in that, In step (1), the base comprises triethylenediamine and any combination of cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium tert-butoxide, or potassium phosphate.

10. The use of the fluoroalkyl-substituted pyridine compound of claim 1 in the preparation of an activity inhibitor of human multiple myeloma cells (U266).

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