A fluoroalkyl-substituted pyrrole compound and its preparation method

Abstract

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

Description

Technical Field

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

[0002] Pyrrole is not only a key structural unit in many bioactive compounds, but also an important building block in materials chemistry (Chem. Rev. 2008, 108, 264-287). Therefore, its synthesis methods have attracted widespread attention. With the increasing importance of fluorinated compounds in the pharmaceutical and materials fields, developing efficient and precise synthetic strategies for fluorinated pyrrole has become a research hotspot (Eur. J. Org. Chem. 2019, 2339-2343). A common method is to introduce fluorinated units using substrates with various substituents. However, preparing a series of starting materials is usually quite cumbersome and time-consuming, which is not in line with green chemistry. Furthermore, controlling reaction selectivity is crucial for the synthesis (Org. Lett. 2024, 26, 6197-6202).

[0003] To address the aforementioned technical deficiencies, this invention innovatively develops a novel method for the synthesis of fluoroalkyl pyrroles. This method, through a base-promoted defluorination cyclization reaction of fluoroalkyl peroxides and p-cyanobenzylamine, 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 use of α-F bonds enables excellent chemoselectivity and regioselectivity; it also exhibits broad functional group compatibility and excellent atom economy. Therefore, this invention provides a novel synthetic route for fluoroalkylpyrrole compounds, solving a long-standing technical challenge in this field and providing crucial technical support for the development of fluorinated drugs and functional materials. 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 pyrrole compound.

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

[0008]

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

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

[0011] This invention further discloses a method for preparing a fluoroalkyl-substituted pyrrole compound, characterized in that:

[0012] Using p-cyanobenzylamine as the nitrogen source and the fluoroalkyl peroxide of Formula II as a catalyst, 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 method for preparing fluoroalkyl peroxides of the present invention, the fluoroalkyl peroxides include 1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexylbenzene, 1-tert-butyl-4-[1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]benzene, 1-[1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]benzene, etc. [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-[ ... -(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, ethyl 4-[1.(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]benzoate, 1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]benzoate One of the following: 6,7,7,8,8,8-tridecylfluorooctylbenzene, 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 pyrrole compound of the present invention, the molar ratio of the fluoroalkyl peroxide and the p-cyanobenzylamine is 1:3.0 to 7.0; preferably, the molar ratio is 1:5.0.

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

[0018] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted pyrrole compound of the present invention, the defluorination cyclization reaction is carried out at a temperature of 30–110°C; preferably, the reaction temperature is 40°C.

[0019] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted pyrrole compound of the present invention, the molar ratio of the fluoroalkyl peroxide to the triethylenediamine and potassium phosphate is 1:1.5–3.5:1.5–3.5; preferably, the molar ratio is 1:3.5:3.5.

[0020] In a preferred embodiment of the method for preparing the fluoroalkyl-substituted pyrrole compound of the present invention, the base comprises triethylenediamine and any combination of cesium fluoride, cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium tert-butoxide, and potassium phosphate; preferably, the base is a combination of triethylenediamine and potassium phosphate.

[0021] This invention further discloses the application of the above-mentioned fluoroalkyl-substituted pyrrole compounds in the preparation of activity inhibitors of human breast cancer cells (MDA).

[0022] In summary, the optimal reaction equation for this invention is as follows:

[0023]

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] This invention provides a method for the defluorination cyclization reaction of fluoroalkyl peroxides and p-cyanobenzylamine under the promoting conditions of triethylenediamine and potassium phosphate, synthesizing a series of fluoroalkyl pyrrole 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 pyrrole compounds was achieved. This method features mild conditions, good functional group tolerance, simple post-processing, green procedures, low pollution, and high economic benefits. Furthermore, the obtained compounds exhibit certain anti-human breast cancer cell (MDA) activity and can be used to prepare active inhibitors against MDA cells. Attached Figure Description

[0026] 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:

[0027] Figure 1 The proton spectrum of target product a in Example 1 of this invention;

[0028] Figure 2 The fluorine spectrum of target product a in Example 1 of this invention;

[0029] Figure 3 The carbon spectrum of target product a in Example 1 of this invention;

[0030] Figure 4 The proton spectrum of target product b in Example 2 of this invention;

[0031] Figure 5 The fluorine spectrum of target product b in Example 2 of the present invention;

[0032] Figure 6 The carbon spectrum of target product b in Example 2 of this invention;

[0033] Figure 7 The proton spectrum of target product c in Example 3 of this invention;

[0034] Figure 8 The fluorine spectrum of target product c in Example 3 of this invention;

[0035] Figure 9 The carbon spectrum of target product c in Example 3 of this invention;

[0036] Figure 10 The proton spectrum of the target product d in Example 4 of this invention;

[0037] Figure 11 The fluorine spectrum of the target product d in Example 4 of this invention;

[0038] Figure 12 The carbon spectrum of the target product d in Example 4 of this invention;

[0039] Figure 13 The proton spectrum of target product e in Example 5 of this invention;

[0040] Figure 14 The fluorine spectrum of target product e in Example 5 of this invention;

[0041] Figure 15 The carbon spectrum of target product e in Example 5 of this invention; Detailed Implementation

[0042] 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.

[0043] 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.

[0044] 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.

[0045] The fluoroalkyl peroxide used in the examples was prepared by the method reported in the reference (J.Org.Chem.2016, 81, 5878-5885.).

[0046] Example 1

[0047] (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.), p-cyanobenzylamine (0.18 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 40 °C for 12 hours.

[0048] (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 / 10 to 1 / 6. Finally, 83.9 mg of target product a is obtained.

[0049] The target product a was characterized as follows: Figure 1 As shown in Figures 2 and 3, the result is: a yellow solid;

[0050] 1 H NMR (400MHz, DMSO-d6): δ10.16 (d, J=5.4Hz, 1H), 8.11 (d, J=4.8Hz, 2H, NH2), 8.03-8.00 (m, 2H), 7.93-7. 90(m, 2H), 7.85-7.82(m, 2H), 7.80-7.77(m, 4H), 7.49-7.45(m, 1H), 7.44-7.39(m, 2H), 5.85(s, 1H)ppm.

[0051] 19F NMR (376MHz, DMSO-d6): δ-50.42 (s, 3F)ppm.

[0052] 13 C NMR (100MHz, DMSO-d6): δ187.6, 158.0, 139.7, 134.9, 134.8, 132.6, 132.5 , 132.4 (d, J=3.7Hz), 131.2, 130.1, 129.9, 128.5, 127.7, 126.9, 123.6 (q, J C-F =268.7Hz), 119.5, 118.8, 118.7, 111.5, 110.1, 110.6 (q, J C-F =35.0Hz), 93.3ppm.

[0053] HRMS(m / z): calcd for C 28 H 18 F3N4O + [M+H] + 483.1427, found: 483.1422.

[0054] Characterization data revealed that the obtained reaction product was (Z)4,4′-[3-(1-amino-3-oxo-3-phenylprop-1-en-1-yl)-4-(trifluoromethyl)-1H-pyrrole-2,5-diyl]dibenzonitrile (purity > 98%), and the structural formula of this compound is:

[0055]

[0056] The product yield was calculated to be 58%.

[0057] Example 2

[0058] (1) A solution of 1-tert-butyl-4-[1-(tert-butylperoxy)-3,3,4,4,5,5,6,6,6-nonafluorohexyl]benzene (0.141 g, 0.3 mmol, 1 equiv.), p-cyanobenzylamine (0.18 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 40 °C for 12 hours.

[0059] (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 / 10 to 1 / 6. Finally, 74.7 mg of the target product b is obtained.

[0060] The target product b was characterized as follows: Figure 4 As shown in Figures 5 and 6, the result is: a yellow solid;

[0061] 1 H NMR (400MHz, DMSO-d6): δ10.16 (d, J=5.6Hz, 1H), 8.08 (brs, 2H, NH2), 8.03 (d, J=8.5Hz, 2H), 7.92 (d, J=8.6Hz, 2H), 7.85 (d , J=8.6Hz, 2H), 7.80 (d, J=8.3Hz, 2H), 7.74 (d, J=8.6Hz, 2H), 7.43 (d, J=8.6Hz, 2H), 5.84 (d, J=1.6Hz, 1H), 1.26 (s, 9H)ppm.

[0062] 19 F NMR (376MHz, DMSO-d6): δ-50.46 (s, 3F)ppm.

[0063] 13 C NMR (100MHz, DMSO-d6): δ187.3, 157.5, 153.9, 137.0, 134.84, 134.76, 132.6, 132.5, 132.3 (q, J C-F =3.4Hz), 130.0, 129.7, 127.6, 126.8, 125.2, 123.5 (q, J C-F =268.5Hz), 119.6, 118.8, 118.6, 111.4, 110.7 (q, J C-F =34.6Hz), 110.1, 93.2, 34.6, 31.0ppm.

[0064] HRMS(m / z): calcd for C 32 H 26 F3N4O + [M+H] + 539.2053, found: 539.2052.

[0065] Characterization data revealed that the obtained reaction product was (Z)-4,4′-[3-(1-amino-3-(4-(tert-butyl)phenyl)-3-oxoprop-1-en-1-yl)-4-(trifluoromethyl)-1H-pyrrole-2,5-diyl]dibenzonitrile (purity > 98%), and the structural formula of this compound is:

[0066]

[0067] The product yield was calculated to be 46%.

[0068] Example 3

[0069] (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.), p-cyanobenzylamine (0.18 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 40 °C for 12 hours.

[0070] (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 / 10 to 1 / 6. Finally, 64.5 mg of the target product c is obtained.

[0071] The target product c was characterized as follows: Figure 7 As shown in Figures 8 and 9, the result is: a white solid;

[0072] 1 H NMR (400MHz, DMSO-d6): δ10.12 (d, J=5.8Hz, 1H), 8.03 (brs, 2H, NH2), 8.01 (s, 2H), 7.92 (d, J=8.0Hz, 2H), 7.84 (d , J=8.6Hz, 2H), 7.79 (d, J=7.6Hz, 2H), 7.69 (d, J=6.5Hz, 2H), 7.22 (d, J=7.9Hz, 2H), 5.81 (s, 1H), 2.32 (s, 3H)ppm.

[0073] 19 F NMR (376MHz, DMSO-d6): δ-50.45 (s, 3F)ppm.

[0074] 13 C NMR (100MHz, DMSO-d6): δ187.4, 157.5, 141.0, 137.1, 134.8, 134.7, 132.5, 132.21 (t, J C-F =3.5Hz), 132.18, 130.0, 129.7, 129.0, 127.6, 126.9, 123.5 (q, J C-F =268.6Hz), 119.5, 118.8, 118.6, 111.4, 111.0 (q, J C-F =32.5Hz), 110.0, 93.1, 21.0ppm.

[0075] HRMS(m / z): calcd for C 29 H 20 F3N4O + [M+H] + 497.1584, found: 497.1586.

[0076] Characterization data revealed that the obtained reaction product was (Z)4,4′-[3-(1-amino-3-oxo-3-(p-tolyl)prop-1-en-1-yl)-4-(trifluoromethyl)-1H-pyrrole-2,5-diyl]dibenzonitrile (purity > 98%), and the structural formula of this compound is:

[0077]

[0078] The product yield was calculated to be 43%.

[0079] Example 4

[0080] (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.), p-cyanobenzylamine (0.18 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 40 °C for 12 hours.

[0081] (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 / 10 to 1 / 8. Finally, 92.8 mg of the target product d is obtained.

[0082] The target product d was characterized as follows: Figure 10 As shown in Figures 11 and 12, the result is: a yellow solid;

[0083] 1 H NMR (400MHz, DMSO-d6): δ10.14 (d, J=5.5Hz, 1H), 8.17 (d, J=5.6Hz, 2H, NH2), 8.04-8.00 (m, 2H), 7.92 (d, J=8.5Hz, 2H), 7.89-7.85 (m, 2H), 7.84-7.81 (m, 2H), 7.78 (d, J=8.2Hz, 2H), 7.23 (t, J=8.8Hz, 2H), 5.83 (d, J=1.5Hz, 1H)ppm.

[0084] 19 F NMR (376MHz, DMSO-d6): δ-50.45(s, 3F), -109,55(s, 1F)ppm.

[0085] 13 C NMR (100MHz, DMSO-d6): δ186.1, 164.0 (d, J=248.6Hz), 158.2, 136.2 (d, J=2.4Hz), 134.8 (d, J=7.0Hz), 132.6, 132.5, 132.3 (q, J=3.3Hz), 130.0, 129 .8, 129.5 (d, J = 9.0Hz), 127.7, 123.6 (d, J = 267.9Hz), 119.4 (d, J = 2.1Hz), 118.8, 118.7, 115.5, 115.3, 111.5, 110.7 (q, J=34.1Hz), 110.1, 93.0ppm.

[0086] HRMS(m / z): calcd for C 28 H 17 F4N4O + [M+H] +501.1333, found: 501.1337.

[0087] Characterization data revealed that the obtained reaction product was (Z)-4,4′-[3-(1-amino-3-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)-4-(trifluoromethyl)-1H-pyrrole-2,5-diyl]dibenzanilonitrile (purity > 98%), and the structural formula of this compound is:

[0088]

[0089] The product yield was calculated to be 62%.

[0090] Example 5

[0091] (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.), p-cyanobenzylamine (0.18 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 40 °C for 12 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 / 10 to 1 / 4. Finally, 57.9 mg of the target product e is obtained.

[0093] The target product e is characterized as follows: Figure 13 As shown in Figures 14 and 15, the result is: a yellow solid;

[0094] 1H NMR (400MHz, DMSO-d6): δ10.28 (s, 1H), 8.35 (brs, 2H, NH2), 8.03 (dd, J=8.4, 1.8Hz, 2H), 7.99 (d, J=6.8Hz, 2H), 7.95- 7.90 (m, 4H), 7.85 (dd, J=8.9, 2.6Hz, 2H), 7.79 (d, J=8.5Hz, 2H), 5.90 (d, J=8.9Hz, 1H), 4.32 (m, 2H), 1.32 (m, 3H)ppm.

[0095] 19 F NMR (376MHz, DMSO-d6): δ-50.42 (s, 3F)ppm.

[0096] 13 C NMR (100MHz, DMSO-d6): δ186.2, 165.4, 158.8, 143.5, 134.73, 134.68, 132.6, 132.4, 132.3, 131.7, 130.0, 129.8, 129.3, 127.7, 127.1, 123.5 (q, J C-F =268.2Hz), 119.2, 118.7, 118.6, 111.5, 110.7 (q, J C-F =31.5Hz), 110.2, 93.6, 61.0, 14.1ppm.

[0097] HRMS(m / z): calcd for C 31 H 22 F3N4O3 + [M+H] + 555.1639, found: 555.1638.

[0098] Characterization data revealed that the obtained reaction product was (Z)-4-[3-amino-3-(2,5-bis(4-cyanophenyl)-4-(trifluoromethyl)-1H-pyrrolo-3-yl)acryloyl]ethyl benzoate (purity > 98%), and the structural formula of this compound is:

[0099]

[0100] The product yield was calculated to be 35%.

[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)]]> 18 DABCO(3.5)+CsF(3.5) 55 DABCO(3.5) + NaOAc(3.5) 53 <![CDATA[DABCO(3.5)+K2CO3(3.5)]]> 48 DABCO(3.5) + KOH(3.5) 50 DABCO(3.5) + NaOH(3.5) 51 <![CDATA[DABCO(3.5)+ t BuOLi(3.5)]]> 30

[0105] As can be seen from Table 1, under the same reaction conditions, the combination of triethylenediamine (DABCO) and various bases does not yield as high as that of triethylenediamine (DABCO) and potassium phosphate.

[0106] Example 7

[0107] Example 7 is basically the same as Example 1, except that in step (1), the reaction solvent is different at 60°C, as shown in Table 2 below:

[0108] Table 2

[0109]

[0110]

[0111] As can be seen from Table 2, under the same reaction conditions, using a solvent such as tert-butanol ( t The yields of BuOH, ethyl acetate (EtOAc), water (H2O), tetrahydrofuran (THF), and toluene were low; the yield was 42% with dimethyl sulfoxide (DMSO); 46% with N,N-dimethylformamide (DMF); 43% with N,N-dimethylacetamide (DMA); and 36% with acetonitrile (MeCN).

[0112] Example 8

[0113] Example 8 is basically the same as Example 1, except that the temperature is different in step (1), as shown in Table 3 below:

[0114] Table 3

[0115] Temperature (°C) Yield (%) 30 46 60 53 80 46 100 15

[0116] As can be seen from Table 3, under the same reaction conditions, the yield is not as high as at 40℃ at different temperatures.

[0117] Example 9

[0118] Example 9 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 4 below:

[0119] Table 4

[0120]

[0121]

[0122] Application Examples

[0123] Compounds b, c, d, e, and i obtained in the above implementation examples were subjected to preliminary anti-human breast cancer cell (MDA) activity tests, 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 spots 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.

[0124] The test results for compounds b, c, d, e, and i are shown in Table 5. It can be seen that the EC50 values ​​are 51 μm, 54 μm, 9 μm, 55 μm, and 10 μm, respectively, indicating that compounds b, c, d, e, and i all exhibit inhibitory activity against human breast cancer cells (MDA). Among them, compound d has the lowest EC50 value and exhibits the best inhibitory activity against MDA.

[0125] Table 5

[0126] Test compounds EC50 value (μm) b 51 c 54 d 9 e 55 i 10

[0127] This invention provides a method for the defluorination cyclization reaction of fluoroalkyl peroxides and p-cyanobenzylamine under the promoting conditions of triethylenediamine and potassium phosphate, synthesizing a series of fluoroalkyl pyrrole 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 pyrrole compounds was achieved. This method features mild conditions, good functional group tolerance, simple post-processing, green procedures, low pollution, and high economic benefits. Furthermore, the obtained compounds exhibit certain anti-human breast cancer cell (MDA) activity and can be used to prepare active inhibitors against MDA cells.

[0128] 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 pyrrole compound, characterized in that: Its structural formula is shown in Formula I; R is selected from one of tert-butyl, methyl, halogen, and ester groups; C n F 2n+1 Selected from one of trifluoromethyl, heptafluoropropyl, undecylfluoropentyl, and pentadecylfluoroheptyl; n = 1-7.

2. The method for preparing the fluoroalkyl-substituted pyrrole compound as described in claim 1, characterized in that, The method includes the following steps: (1) Fluoroalkyl peroxide, p-cyanobenzylamine, and a base are added to a solvent, and the mixture is stirred and reacted in air at 30–100°C for 6–12 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 tert-butyl, methyl, halogen, and ester groups; C n F 2n+1 Selected from one of trifluoromethyl, heptafluoropropyl, 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 pyrrole compounds.

3. The method as described in claim 2, characterized in that, In step (1), the molar ratio of the fluoroalkyl peroxide and the p-cyanobenzylamine is 1:5.0 to 9.

0.

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

5. The method as described in claim 2, characterized in that, In step (1), the reaction temperature is 30 to 100°C.

6. The method 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.

7. The method as described in claim 2, characterized in that, In step (1), the base includes triethylenediamine and any combination of cesium fluoride, cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium tert-butoxide, and potassium phosphate.

8. The use of the fluoroalkyl-substituted pyrrole compound of claim 1 in the preparation of an activity inhibitor of human breast cancer cells (MDA).

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