A β-fluoroalkyl-β-amino vinyl ketone compound, a preparation method thereof and an application thereof

Abstract

The present invention discloses a β-fluoroalkyl-β-amino vinyl ketone compound, a preparation method thereof and an application thereof. The amidine hydrochloride and the allyl fluoride compound containing a hydroxyl group are subjected to a defluorination reaction in a solvent under the action of ammonium carbonate and water to obtain the β-fluoroalkyl-β-amino vinyl ketone compound. The reaction conditions of the present invention are mild, the functional group tolerance is good, and it has the characteristics of simple post-treatment, green steps, low pollution, high economic benefits, etc.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound synthesis, and particularly relates to a β-fluoroalkyl-β-amino vinyl ketone compound, a preparation method thereof, and an application thereof. Background Art

[0002] Amino vinyl ketone compounds, as an important structural fragment, exist in many drugs and bioactive molecules (Nat. Rev. Drug Discov. 2006, 5, 821 - 834). They have been proven to be general building blocks for the synthesis of different heterocyclic systems through cyclization reactions (Adv. Synth. Catal. 2022, 364, 1508 - 1521). Although many practical strategies have been developed to construct this skeleton, the direct synthesis of fluoroalkylated β-amino vinyl ketone compounds from readily available and diverse precursors remains challenging. Importantly, due to the unique properties of fluorine atoms, the introduction of fluoroalkyl groups into amino vinyl ketones can significantly improve biological activity (J. Agric. Food Chem. 2009, 57, 8303 - 8307) and reactivity (Chem. Commun. 2010, 46, 2145 - 2147). Active methylene compounds can react with gaseous trifluoroacetonitrile (CF3CN) to form β-trifluoromethylated amino vinyl ketones. This method highly depends on the use of toxic CF3CN and usually requires harsh conditions to achieve the desired transformation. Additionally, the intermolecular condensation of pre-fluorinated diketone compounds or alkynone compounds with ammonium salts is an effective method to obtain simple enaminones. However, there are also some inevitable problems, such as the formation of regioisomers and stereoisomers. Recently, a research group found that the reductive ring cleavage reaction of isoxazoles can produce fluoroalkylated enamines, where a copper catalyst and stoichiometric diamine are necessary conditions for the success of the reaction (J. Org. Chem. 2021, 86, 4557 - 4566). However, metal residues are not conducive to the development of green and sustainable chemistry, especially in drug research and development and late-stage derivatization. Therefore, there is great concern about discovering new green reactions to obtain such β-fluoroalkyl-β-amino vinyl ketone compounds, hoping to exclude the influence of toxic reagents and transition metals.

[0003] Therefore, developing a catalyst-free and additive-free reaction system with a wide substrate scope and simple operation is a topic worthy of further exploration. Summary of the Invention

[0004] The purpose of this part is to outline some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Simplifications or omissions may be made in this part, as well as in the abstract and title of the present application, to avoid obscuring the purpose of this part, the abstract, and the title. However, such simplifications or omissions shall not be used to limit the scope of the present invention.

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

[0006] One object of the present invention is to provide a method for preparing a β-fluoroalkyl-β-amino vinyl ketone compound. The reaction conditions of the present invention are mild, the functional group tolerance is good, and it has the characteristics of simple post-treatment, green steps, low pollution, high economic benefits, etc.

[0007] To solve the above technical problems, the present invention provides the following technical solution: A β-fluoroalkyl-β-amino vinyl ketone compound, whose structural formula is shown in Formula I:

[0008]

[0009] Wherein, R is selected from one of phenyl, methoxy-substituted phenyl, ethoxy-substituted phenyl, methyl-substituted phenyl, halogen-substituted phenyl, nitro-substituted phenyl, cyano-substituted phenyl, trifluoromethyl-substituted phenyl, thiophenyl, pyridyl, cyclopropyl;

[0010] R 1 、R 2 are each independently selected from one of methyl, isobutyl, methoxy-substituted benzyl, halogen-substituted benzyl, cyclobutyl, cyclohexyl, indenyl;

[0011] R f is selected from perfluoropropyl, perfluoropentyl, perfluoroheptyl, perfluorononyl.

[0012] Another object of the present invention is to provide a method for preparing a β-fluoroalkyl-β-amino vinyl ketone compound, including

[0013] Performing a defluorination reaction on the amidine hydrochloride shown in Formula II and the hydroxy-containing allyl fluoride compound shown in Formula III in a solvent under the action of a base to obtain the compound shown in Formula I;

[0014]

[0015] Wherein, R, R 1 、R 2 、R f in Formula (II) and Formula (III) correspond to R, R 1 、R 2 、R f in Formula (I) respectively and are consistent.

[0016] As a preferred embodiment of the preparation method of the β-fluoroalkyl-β-amino vinyl ketone compound of the present invention, wherein: the amidine hydrochloride includes one of benzamidine hydrochloride, 4-methoxybenzamidine hydrochloride, 2-ethoxybenzamidine hydrochloride, 4-methylbenzamidine hydrochloride, 3-methylbenzamidine hydrochloride, 4-fluorobenzamidine hydrochloride, 4-chlorobenzamidine hydrochloride, 4-bromobenzamidine hydrochloride, 4-iodobenzamidine hydrochloride, 4-nitrobenzamidine hydrochloride, 3-cyanobenzamidine hydrochloride, 4-trifluoromethylbenzene-1-carboxamidine hydrochloride, thiophene-2-carboxamidine hydrochloride, 3-pyridinecarboxamidine hydrochloride, cyclopropylcarboxamidine hydrochloride.

[0017] As a preferred embodiment of the preparation method of the β-fluoroalkyl-β-amino vinyl ketone compound of the present invention, wherein: the allyl fluoride compound containing a hydroxyl group includes one of 5,5,6,6,7,7,8,8,8-nonafluoro-3-iodo-2-methyl-3-octen-2-ol, 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3-iodo-2-methyl-3-decen-2-ol, 5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-heptadecafluoro-3-iodo-2-methyl-3-dodecen-2-ol, 5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,14,14,14-henicosafluoro-3-iodo-2-methyl-3-tetradecen-2-ol, 7,7,8,8,9,9,10,10,10-nonafluoro-5-iodo-2,4-dimethyl-5-decen-4-ol, 5,5,6,6,7,7,8,8,8-nonafluoro-3-iodo-1-(4-methoxyphenyl)-2-methyl-3-octen-2-ol, 1-(4-chlorophenyl)-5,5,6,6,7,7,8,8,8-nonafluoro-3-iodo-2-methyl-3-octen-2-ol, 1-(3,3,4,4,5,5,6,6,6-nonafluoro-1-iodo-1-hexen-1-yl)cyclobutan-1-ol, 1-(3,3,4,4,5,5,6,6,6-nonafluoro-1-iodo-1-hexen-1-yl)cyclohexan-1-ol, 2-(3,3,4,4,5,5,6,6,6-nonafluoro-1-iodo-1-hexen-1-yl)inden-2-ol.

[0018] As a preferred embodiment of the preparation method of the β-fluoroalkyl-β-amino vinyl ketone compound of the present invention, wherein: the molar ratio of the amidine hydrochloride to the allyl fluoride compound containing a hydroxyl group is 1:1 to 2.

[0019] As a preferred embodiment of the preparation method of the β-fluoroalkyl-β-amino vinyl ketone compound of the present invention, wherein: the base is one or more of ammonium carbonate, ammonium chloride, ammonium acetate, cesium carbonate; the preferred base is ammonium carbonate.

[0020] As a preferred embodiment of the preparation method of the β-fluoroalkyl-β-amino vinyl ketone compound of the present invention, wherein: the molar ratio of the amidine hydrochloride to the base is 1:2.7 to 8.2; the preferred molar ratio is 1:6.4.

[0021] As a preferred embodiment of the preparation method of the β-fluoroalkyl-β-amino vinyl ketone compound of the present invention, wherein: the solvent includes one of acetonitrile, dimethyl sulfoxide, and N,N-dimethylacetamide; the preferred solvent is N,N-dimethylacetamide.

[0022] As a preferred embodiment of the preparation method of the β-fluoroalkyl-β-amino vinyl ketone compound of the present invention, wherein: for the defluorination reaction, the reaction temperature is 50 to 90 °C; the preferred reaction temperature is 50 °C.

[0023] As a preferred embodiment of the preparation method of the β-fluoroalkyl-β-amino vinyl ketone compound of the present invention, wherein: for the defluorination reaction, the reaction time is 6 to 24 h; the preferred reaction time is 24 h.

[0024] As a preferred embodiment of the preparation method of the β-fluoroalkyl-β-amino vinyl ketone compound of the present invention, wherein: it further includes adding water to the reaction system.

[0025] As a preferred embodiment of the preparation method of the β-fluoroalkyl-β-amino vinyl ketone compound of the present invention, wherein: the molar ratio of the amidine hydrochloride to the water is 1:0 to 10; the preferred molar ratio is 1:5.

[0026] In summary, the reaction equation under the optimal conditions of the present invention is as follows:

[0027]

[0028] Another object of the present invention is to provide an application of a β-fluoroalkyl-β-amino vinyl ketone compound in the preparation of an anti-tumor drug.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The present invention provides a method for realizing the generation of a series of β-fluoroalkyl-β-amino vinyl ketone compounds by the defluorination reaction of amidine hydrochloride and allyl fluoride compounds containing hydroxyl groups under the action of a base in a solvent under metal-free conditions; the reaction conditions are mild, the functional group tolerance is good, and it has the characteristics of simple post-treatment, green steps, low pollution, and high economic benefits. Description of the Drawings

[0031] To more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings. Among them:

[0032] Figure 1 1H NMR spectrum of the target product (Z)-5-amino-6,6,7,7,8,8,8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z)-amino(phenyl)methylene)carbamate of Example 1 of the present invention;

[0033] Figure 2 19F NMR spectrum of the target product (Z)-5-amino-6,6,7,7,8,8,8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z)-amino(phenyl)methylene)carbamate of Example 1 of the present invention;

[0034] Figure 3 13C NMR spectrum of the target product (Z)-5-amino-6,6,7,7,8,8,8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z)-amino(phenyl)methylene)carbamate of Example 1 of the present invention;

[0035] Figure 4 1H NMR spectrum of the target product (Z)-5-amino-6,6,7,7,8,8,8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z)-amino(4-methoxyphenyl)methylene)carbamate of Example 2 of the present invention;

[0036] Figure 5 19F NMR spectrum of the target product (Z)-5-amino-6,6,7,7,8,8,8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z)-amino(4-methoxyphenyl)methylene)carbamate of Example 2 of the present invention;

[0037] Figure 6 13C NMR spectrum of the target product (Z)-5-amino-6,6,7,7,8,8,8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z)-amino(4-methoxyphenyl)methylene)carbamate of Example 2 of the present invention;

[0038] Figure 7 1H NMR spectrum of the target product (Z)-7-amino-8,8,9,9,10,10,10-heptafluoro-2,4-dimethyl-5-oxodec-6-en-4-yl ((Z)-amino(phenyl)methylene)carbamate of Example 3 of the present invention;

[0039] Figure 8 19F NMR spectrum of the target product (Z)-7-amino-8,8,9,9,10,10,10-heptafluoro-2,4-dimethyl-5-oxodec-6-en-4-yl ((Z)-amino(phenyl)methylene)carbamate in Example 3 of the present invention;

[0040] Figure 9 13C NMR spectrum of the target product (Z)-7-amino-8,8,9,9,10,10,10-heptafluoro-2,4-dimethyl-5-oxodec-6-en-4-yl ((Z)-amino(phenyl)methylene)carbamate in Example 3 of the present invention;

[0041] Figure 10 1H NMR spectrum of the target product (Z)-5-amino-6,6,7,7,8,8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z)-amino(4-methoxyphenyl)methylene)carbamate in Example 4 of the present invention;

[0042] Figure 11 19F NMR spectrum of the target product (Z)-5-amino-6,6,7,7,8,8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z)-amino(4-methoxyphenyl)methylene)carbamate in Example 4 of the present invention;

[0043] Figure 12 13C NMR spectrum of the target product (Z)-5-amino-6,6,7,7,8,8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z)-amino(4-methoxyphenyl)methylene)carbamate in Example 4 of the present invention;

[0044] Figure 13 4T1 activity and Hela cell activity values of the compound measured in Example 12 of the present invention. Detailed Description of the Invention

[0045] In order to make the above objects, features and advantages of the present invention more obvious and understandable, the following detailed description of the specific embodiments of the present invention will be given in conjunction with the embodiments of the specification.

[0046] In the following description, many specific details are set forth in order to fully understand the present invention. However, the present invention can also be implemented in other ways different from those described herein. Those skilled in the art can make similar extensions without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0047] Secondly, the "one embodiment" or "embodiment" referred to herein means a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The appearances of "in one embodiment" in different places in this specification do not all refer to the same embodiment, nor are they separate or alternative embodiments that are mutually exclusive of other embodiments.

[0048] The allyl fluoride compound containing hydroxyl groups in the raw materials used in the embodiments was prepared by the method reported in the reference (Angew. Chem. Int. Ed. 2014, 53, 4910 - 4914). Without special instructions, other raw materials were commercially purchased.

[0049] Example 1

[0050] (1) 5,5,6,6,7,7,8,8,8 - nonafluoro - 3 - iodo - 2 - methyl - 3 - octen - 2 - ol (193.5 mg, 0.45 mmol, 1.5 equiv.), benzamidine hydrochloride (47 mg, 0.3 mmol, 1 equiv.), ammonium carbonate (184.4 mg, 1.92 mmol, 6.4 equiv.), N,N - dimethylacetamide (2 mL), and water (27 mg, 1.5 mmol, 5 equiv.) were successively added to a 10 mL Schlenk tube, and the reaction mixture was stirred at 50 °C for 24 h in air.

[0051] (2) After the reaction in step (1) was completed, it was quenched with saturated NH4Cl solution and extracted with ethyl acetate (20 mL × 3); the combined organic phases were successively washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product; the crude product was purified by silica gel column chromatography. The column chromatography separation conditions were as follows: the stationary phase was silica gel powder of 300 - 400 mesh, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:7. Finally, 98.9 mg of the target product a was obtained.

[0052] The above - mentioned target product a was characterized, as shown in Figure 1 , Figures 2 and 3, and the results were as follows: yellow solid;

[0053] 1 H NMR (400 MHz, DMSO - d6): δ = 9.22 (brs, 2H), 9.14 (brs, 2H), 7.95 (d, J = 7.2 Hz, 2H), 7.60–7.54 (m, 1H), 7.50–7.44 (m, 2H), 5.47 (s, 1H), 1.45 (s, 6H) ppm.

[0054] 1919F NMR (376 MHz, DMSO-d6): δ = -80.24 (t, J = 9.5 Hz, 3F), -120.12 (q, J = 9.6 Hz, 2F), -127.11 (s, 2F) ppm.

[0055] 13 13C NMR (100 MHz, DMSO-d6): δ = 199.7, 167.3, 162.8, 147.0 (t, J C-F = 24.0 Hz), 134.2, 132.1, 128.4, 127.8, 88.4, 81.5, 24.3 ppm.

[0056] HRMS (m / z): calcd for C 17 H 17 F7N3O3 [M+H] + 444.1153, found: 444.1154.

[0057] According to the characterization data, the prepared reaction product is (Z)-5-amino-6,6,7,7,8,8,8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z)-amino(phenyl)methylene)carbamate (purity > 98%), and the structural formula of this compound is:

[0058]

[0059] The product yield was calculated, and the result was 74%.

[0060] Example 2

[0061] (1) 5,5,6,6,7,7,8,8,8-Nonafluoro-3-iodo-2-methyl-3-octen-2-ol (193.5 mg, 0.45 mmol, 1.5 equiv.), 4-methoxybenzimidine hydrochloride (56 mg, 0.3 mmol, 1 equiv.), ammonium carbonate (184.4 mg, 1.92 mmol, 6.4 equiv.), N,N-dimethylacetamide (2 mL), and water (27 mg, 1.5 mmol, 5 equiv.) were successively added to a 10 mL Schlenk tube, and the reaction mixture was stirred at 50 °C for 24 h in air.

[0062] (2) After the reaction in step (1) was completed, it was quenched with saturated NH4Cl solution and extracted with ethyl acetate (20 mL × 3); the combined organic phases were successively washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product; the crude product was purified by silica gel column chromatography. The column chromatography separation conditions were as follows: the stationary phase was silica gel powder of 300 - 400 mesh, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:7. Finally, 85.4 mg of the target product b was obtained.

[0063] The above target product b was characterized as follows Figure 4 , as shown in Figures 5 and 6, the results were: yellow solid;

[0064] 1 1H NMR (400 MHz, CDCl3): δ = 9.50 (brs, 2H), 7.85–7.79 (m, 2H), 6.90–6.84 (m, 2H), 6.79 (brs, 2H), 5.76 (s, 1H), 3.81 (s, 3H), 1.54 (s, 6H) ppm.

[0065] 19 19F NMR (376 MHz, CDCl3): δ = -80.31 (s, 3F), -120.10 (s, 2F), -127.13 (s, 2F) ppm.

[0066] 13 13C NMR (100 MHz, CDCl3): δ = 201.6, 168.1, 163.7, 163.1, 147.3 (t, J C-F = 24.5 Hz), 129.3, 126.4, 114.0, 91.2, 82.6, 55.5, 24.1 ppm.

[0067] HRMS (m / z): calcd for C 18 H 19 F7N3O4 [M + H] + 474.1258, found: 474.1252.

[0068] Based on the characterization data, the prepared reaction product was (Z)-5-amino-6,6,7,7,8,8,8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z)-amino(4-methoxyphenyl)methylene)carbamate (purity > 98%), and the structural formula of this compound was:

[0069]

[0070] The product yield was calculated, and the result was 60%.

[0071] Example 3

[0072] (1) 7,7,8,8,9,9,10,10,10-Nonafluoro-5-iodo-2,4-dimethyl-5-decen-4-ol (212.5 mg, 0.45 mmol, 1.5 equiv.), benzamidine hydrochloride (47 mg, 0.3 mmol, 1 equiv.), ammonium carbonate (184.4 mg, 1.92 mmol, 6.4 equiv.), N,N-dimethylacetamide (2 mL), and water (27 mg, 1.5 mmol, 5 equiv.) were successively added to a 10 mL Schlenk tube, and the reaction mixture was stirred at 50 °C for 24 h in air.

[0073] (2) After the reaction in step (1) was completed, it was quenched with saturated NH4Cl solution and extracted with ethyl acetate (20 mL × 3); the combined organic phases were successively washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product; the crude product was purified by silica gel column chromatography, and the column chromatography separation conditions were as follows: the stationary phase was silica gel powder of 300 - 400 mesh, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:4, and finally 93.6 mg of the target product c was obtained.

[0074] The above target product c was characterized, as shown in Figure 7 , Figures 8 and 9, and the results were as follows: yellow solid;

[0075] 1 1H NMR (400 MHz, CDCl3): δ = 9.50 (brs, 2H), 7.86–7.80 (m, 2H), 7.54–7.48 (m, 1H), 7.45–7.38 (m, 2H), 6.70 (brs, 2H), 5.80 (s, 1H), 1.94–1.87 (m, 1H), 1.82–1.71 (m, 2H), 1.61 (s, 3H), 0.95 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.4 Hz, 3H) ppm.

[0076] 19 19F NMR (376 MHz, CDCl3): δ = -80.26 (t, J = 9.1 Hz, 3F), -120.07 (q, J = 9.5 Hz, 2F), -127.09 (s, 2F) ppm.

[0077] 13 13C NMR (100 MHz, CDCl3): δ = 201.6, 168.6, 163.7, 147.1 (t, J C-F= 24.4 Hz), 134.7, 132.4, 128.8, 127.4, 91.9, 85.5, 46.0, 24.5, 24.3, 23.8, 20.8 ppm.

[0078] HRMS (m / z): calcd for C 20 H 23 F7N3O3 [M+H] + 486.1622, found: 486.1622.

[0079] According to the characterization data, the prepared reaction product is (Z)-7-amino-8,8,9,9,10,10,10-heptafluoro-2,4-dimethyl-5-oxodec-6-en-4-yl ((Z)-amino(phenyl)methylene)carbamate (purity > 98%), and the structural formula of this compound is:

[0080]

[0081] The product yield was calculated, and the result was 64%.

[0082] Example 4

[0083] (1) 5,5,6,6,7,7,8,8,8-Nonafluoro-3-iodo-1-(4-methoxyphenyl)-2-methyl-3-octen-2-ol (241.3 mg, 0.45 mmol, 1.5 equiv.), benzamidine hydrochloride (47 mg, 0.3 mmol, 1 equiv.), ammonium carbonate (184.4 mg, 1.92 mmol, 6.4 equiv.), N,N-dimethylacetamide (2 mL), and water (27 mg, 1.5 mmol, 5 equiv.) were successively added to a 10 mL Schlenk tube, and the reaction mixture was stirred at 50 °C for 24 h in air.

[0084] (2) After the reaction in step (1) was completed, it was quenched with saturated NH4Cl solution and extracted with ethyl acetate (20 mL × 3); the combined organic phases were successively washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product; the crude product was purified by silica gel column chromatography, and the column chromatography separation conditions were: the stationary phase was silica gel powder of 300 - 400 mesh, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:10, and finally 109.3 mg of the target product d was obtained.

[0085] The above target product d was characterized as shown in Figure 10 , 11 and 12, and the results were: yellow solid; 11H NMR (400 MHz, CDCl3): Z-isomer δ = 9.54 (brs, 2H), 7.89–7.82 (m, 2H), 7.56–7.50 (m, 1H), 7.47–7.40 (m, 2H), 7.10–7.03 (m, 2H), 6.83–6.77 (m, 2H), 6.70 (brs, 2H), 5.80 (s, 1H), 3.76 (s, 3H), 3.28 (d, J = 14.0 Hz, 1H), 3.09 (d, J = 14.0 Hz, 1H), 1.50 (s, 3H) ppm.

[0086] 19 19F NMR (376 MHz, CDCl3): Z-isomer δ = -80.21 (t, J = 9.0 Hz, 3F), -119.95– -120.01 (m, 2F), -127.01 (s, 2F) ppm.

[0087] 13 13C NMR (100 MHz, CDCl3): Z-isomer δ = 200.8, 168.7, 163.7, 158.6, 147.1 (t, J C-F = 24.0 Hz), 134.5, 132.5, 131.7, 128.9, 127.5, 127.4, 113.7, 91.9, 85.3, 55.3, 42.5, 20.6 ppm, carbons corresponding to the C3F7 group cannot be identified due to C-F coupling.

[0088] HRMS (m / z): calcd for C 24 H 23 F7N3O4 [M + H] + 550.1571, found: 550.1569.

[0089] According to the characterization data, the prepared reaction product is (Z)-5-amino-6,6,7,7,8,8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z)-amino(4-methoxyphenyl)methylene)carbamate (purity > 98%), and the structural formula of this compound is:

[0090]

[0091] The product yield was calculated, and the result was 66%.

[0092] Example 5

[0093] Example 5 is basically the same as Example 1, except that in step (1), the base is different, as shown in Table 1 below:

[0094] Table 1

[0095] Base Yield (%) Ammonium chloride / Cesium carbonate = 2:1 66 Ammonium acetate / Cesium carbonate = 2:1 12 Ammonia water / Cesium carbonate = 2:1 trace Ammonium carbonate 74

[0096] As can be seen from Table 1, under the same reaction conditions, when using bases such as ammonium acetate / cesium carbonate = 2:1 and ammonia / cesium carbonate = 2:1, the yield is relatively low; when using ammonium chloride / cesium carbonate = 2:1 as the base, the yield is 66%, and when using ammonium carbonate as the base, the highest reaction yield is 74%.

[0097] Example 6

[0098] Example 6 is basically the same as Example 1, except that in step (1), the molar ratio of amidine hydrochloride to ammonium carbonate is different, as shown in Table 2 below:

[0099] Table 2

[0100] Amidine hydrochloride (mmol) Ammonium carbonate (mmol) Yield (%) 0.3 0.81 37 0.3 1.38 35 0.3 1.92 74 0.3 2.46 38

[0101] As can be seen from Table 2, under the same reaction conditions, when the molar amount of amidine hydrochloride is fixed, increasing the molar amount of ammonium carbonate is beneficial to the improvement of the reaction yield. Especially when the molar amount of amidine hydrochloride is 0.3 mmol and the molar amount of ammonium carbonate is 1.92 mmol, the highest reaction yield is 74%. When further increasing the molar amount of ammonium carbonate, it will instead lead to a decrease in the reaction yield.

[0102] Example 7

[0103] Example 7 is basically the same as Example 1, except that in step (1), the molar ratio of amidine hydrochloride to water is different, as shown in Table 3 below:

[0104] Table 3

[0105] Amidine hydrochloride (mmol) Water (mmol) Yield (%) 0.3 0 65 0.3 1.5 74 0.3 3 72

[0106] As can be seen from Table 3, under the same reaction conditions, when the molar amount of amidine hydrochloride is fixed, adding water is beneficial to the improvement of the reaction yield. Especially when the molar amount of amidine hydrochloride is 0.3 mmol and the molar amount of water is 1.5 mmol, the reaction yield is the highest. When further increasing the molar amount of water, it will instead lead to a decrease in the reaction yield.

[0107] Example 8

[0108] Example 8 is basically the same as Example 1, except that in step (1), the reaction solvent is different, as shown in Table 4 below:

[0109] Table 4

[0110] Reaction solvent Yield (%) DMA 74 DMSO 52 MeCN 4 DCE trace <![CDATA t BuOH]]> trace

[0111] As can be seen from Table 4, under the same reaction conditions, when using solvents such as acetonitrile (MeCN), 1,2-dichloroethane (DCE), and tert-butanol ( t BuOH), the yield is relatively low; when using dimethyl sulfoxide (DMSO) as the solvent, the reaction yield is 52%; when using N,N-dimethylacetamide (DMA) as the solvent, the reaction yield is the highest.

[0112] Example 9

[0113] Example 9 is basically the same as Example 1, except that in step (1), the temperature is different, as shown in Table 5 below:

[0114] Table 5

[0115] Temperature (°C) Yield (%) 50 74 70 44 90 tarce

[0116] As can be seen from Table 5, under the same reaction conditions, at a reaction temperature of 50 °C, the reaction yield is the highest; increasing the reaction temperature will lead to a decrease in the reaction yield.

[0117] Example 10

[0118] Example 10 is basically the same as Example 1, except that in step (1), the reaction time is different, as shown in Table 6 below:

[0119] Table 6

[0120] Reaction time Yield (%) 6h 53 12h 62 24h 74

[0121] As can be seen from Table 6, under the same reaction conditions, extending the reaction time is beneficial to the increase of the reaction yield; when the reaction time is 24 h, the reaction yield is 74%.

[0122] Example 11

[0123] Example 11 is basically the same as Example 1, except that in step (1), the amidine hydrochloride compound is different, and the obtained target products are shown in Table 7 below:

[0124] Table 7

[0125]

[0126]

[0127] Example 11

[0128] Example 11 is basically the same as Example 3, except that in step (1), the allyl fluoride compound containing a hydroxyl group is different, and the obtained target products are shown in Table 8 below:

[0129] Table 8

[0130]

[0131]

[0132] Example 12

[0133] Test the activity of the obtained compounds using 4T1 (breast tumor) and hela (cervical cancer) cell lines

[0134] (I) Test compounds selected:

[0135] Compound 1: (Z)-5-Amino-6,6,7,7,8,8,8-heptafluoro-2-methyl-3-oxooct-4-ene-2-yl ((Z)-amino(phenyl)methylene)carbamate (Example 1)

[0136] Compound 2: (Z)-5-Amino-6,6,7,7,8,8,8-heptafluoro-2-methyl-3-oxooct-4-ene-2-yl ((Z)-amino(4-methoxyphenyl)methylene)carbamate (Example 2)

[0137] Compound 3: (Z)-7-Amino-8,8,9,9,10,10,10-heptafluoro-2,4-dimethyl-5-oxodec-6-ene-4-yl ((Z)-amino(phenyl)methylene)carbamate (Example 3)

[0138] Compound 4: (Z)-5-Amino-6,6,7,7,8,8,8-heptafluoro-2-methyl-3-oxooct-4-ene-2-yl ((Z)-amino(thiophen-2-yl)methylene)carbamate

[0139] Compound 5: (Z)-5-Amino-6,6,7,7,8,8,9,9,10,10,10-undecafluoro-2-methyl-3-oxodec-4-ene-2-yl ((Z)-amino(phenyl)methylene)carbamate

[0140] Compound 6: (Z)-5-Amino-6,6,7,7,8,8,8-heptafluoro-1-(4-methoxyphenyl)-2-methyl-3-oxooct-4-ene-2-yl ((Z)-amino(phenyl)methylene)carbamate (Example 4)

[0141] (II) DMSO stock solution

[0142] For Compound 1, accurately weigh 8.86 mg and dissolve it in 1 mL of DMSO to obtain 20 mM.

[0143] Compound 2 was accurately weighed at 9.46 mg and dissolved in 1 mL of DMSO to obtain 20 mM.

[0144] Compound 3 was accurately weighed at 9.70 mg and dissolved in 1 mL of DMSO to obtain 20 mM.

[0145] Compound 4 was accurately weighed at 8.98 mg and dissolved in 1 mL of DMSO to obtain 20 mM.

[0146] Compound 5 was accurately weighed at 10.86 mg and dissolved in 1 mL of DMSO to obtain 20 mM.

[0147] Compound 6 was accurately weighed at 10.98 mg and dissolved in 1 mL of DMSO to obtain 20 mM.

[0148] (III) Investigation of concentration

[0149] The inhibitory effects of concentrations of 500, 250, 100, 50, 25, 10, 5, 2.5, and 1 μM on cells were investigated. The CCK-8 method was used to measure the sensitivity of different concentrations of various chemical substances to cell viability and toxicity, and thus the IC50 was calculated.

[0150] (IV) Co-culture time

[0151] After co-culturing the drug-containing solution with cells for 24 h to 36 h, CCK8 was used for testing, with 6 replicate wells for each sample.

[0152] (V) The activities of the measured compound 4T1 and Hela cells are shown in Table 9 and Figure 13 as follows.

[0153] Table 9

[0154]

[0155] The present invention provides a method for generating a series of β-fluoroalkyl-β-amino vinyl ketone compounds through a defluorination reaction of amidine hydrochloride and allylic fluorine compounds containing hydroxyl groups under the action of ammonium carbonate and water in N,N-dimethylacetamide under metal-free conditions; the reaction conditions are mild, the functional group tolerance is good, and it has the characteristics of simple post-treatment, green steps, low pollution, and high economic efficiency.

[0156] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and they should all be covered within the scope of the claims of the present invention.

Claims

1. Use of a β-fluoroalkyl-β-amino vinyl ketone compound in the preparation of an anti-tumor drug, characterized in that: Its structural formula is shown in Formula I: Among them, R is selected from one of phenyl, methoxy-substituted phenyl, ethoxy-substituted phenyl, methyl-substituted phenyl, halogen-substituted phenyl, nitro-substituted phenyl, cyano-substituted phenyl, trifluoromethyl-substituted phenyl, thiophenyl, pyridyl, cyclopropyl; R 1 、R 2 is selected from one of methyl, isobutyl, methoxy-substituted benzyl, halogen-substituted benzyl, cyclobutyl, cyclohexyl, indenyl; R f Selected from perfluoropropyl, perfluoropentyl, perfluoroheptyl, perfluorononyl.

2. The application according to claim 1, characterized in that: The preparation method of the β-fluoroalkyl-β-amino vinyl ketone compound includes Performing a defluorination reaction on the amidine hydrochloride shown in Formula II and the allyl fluoride compound containing a hydroxyl group shown in Formula III in a solvent under the action of a base to obtain the compound shown in Formula I; Among them, R, R 1 , R 2 , R f in Formula (II) and (III) are correspondingly consistent with R, R 1 , R 2 , R f in Formula (I).

3. The application according to claim 2, characterized in that: The molar ratio of the amidine hydrochloride to the allyl fluoride compound containing a hydroxyl group is 1:1 to 2.

4. The application according to claim 2 or 3, characterized in that: The molar ratio of the amidine hydrochloride to the base is 1:2.7 to 8.

2.

5. The application according to claim 4, wherein: The base is one or more of ammonium carbonate, ammonium chloride, ammonium acetate, cesium carbonate.

6. The application according to claim 5, characterized in that: The base is ammonium carbonate.

7. The application according to any one of claims 2, 3, 5, and 6, characterized in that: The solvent includes one of acetonitrile, dimethyl sulfoxide, N,N-dimethylacetamide.

8. The application according to claim 7, characterized in that: When performing the defluorination reaction, the reaction temperature is 50 to 90 °C, and the reaction time is 6 to 24 h.

9. The application according to any one of claims 2, 3, 5, 6, and 8, characterized in that: It also includes adding water to the reaction system, and the molar ratio of the amidine hydrochloride to the water is 1:0 to 10.

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