Ketone phosphine oxide compound containing trifluoromethyl quaternary carbon center and preparation method and application thereof

Abstract

The present invention discloses a ketone phosphine oxide compound containing a trifluoromethyl quaternary carbon center and a preparation method and application thereof. The present invention adds a diaryl phosphine oxide compound, a trifluoromethyl ketene compound and a catalyst into water, stirs for 2 to 12 hours at 25 to 100° C. in a nitrogen atmosphere, and after the reaction is completed, quenches and extracts the reaction solution in sequence, washes, dries, concentrates and purifies the combined organic phase in sequence to obtain a ketone phosphine oxide compound containing a trifluoromethyl quaternary carbon center. The method of the present invention has the characteristics of mild conditions, simple operation, high yield, good functional group tolerance, wide substrate range, simple post-treatment, no pollution, high economic benefits, etc. The obtained ketone phosphine oxide compound has a wide range of uses, and some compounds can be used to prepare inhibitors of human colon cancer cell activity.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and in particular relates to a ketone phosphine oxide compound containing a trifluoromethyl quaternary carbon center, and a preparation method and application thereof. Background Art

[0002] Organic phosphine compounds play an important role in modern life and have been widely used in various fields such as drug manufacturing, pesticide chemistry and material science. Among them, γ-ketophosphine oxides and γ-ketophosphonates are important organic diarylphosphine oxides (J. Med. Chem. 1989, 32, 1886-1890; Chem. Bull. 2014, 63, 2114). Domestic and foreign researchers are working hard to develop effective methods to construct such organic phosphine compounds containing ketophosphine skeletons.

[0003] The classical synthesis strategy of γ-ketophosphine oxides is achieved by phospha-Michael reaction, that is, the addition of phosphine nucleophiles to α, β-unsaturated carbonyl compounds (Chem. Commun. 2022, 58, 8238). However, these reactions usually require the use of sensitive reagents (J. Org. Chem. 2010, 75, 6756-6763), composite catalysts (J. Org. Chem. 2014, 79, 2758-2764), stoichiometric bases and non-eco-friendly solvents (Synlett 2020, 31, 1295-1297), and occur at higher temperatures (J. Org. Chem. 2012, 77, 1378-1385). Although transition metal-catalyzed phosphination reactions have made great progress (J. Org. Chem. 2020, 85, 8185-8195), the green synthesis strategy of multifunctional γ-ketophosphine oxides is still in urgent need of establishment. However, there are no reports on the construction of highly spatially crowded γ-ketophosphine oxides containing trifluoromethyl and phosphineoxy groups fully substituted carbon centers by direct hydrophosphonation of trifluoromethyl enone (J. Fluorine Chem. 2000, 102, 73). Summary of the invention

[0004] The primary purpose of the present invention is to provide a method for preparing a ketophosphine oxide compound containing a trifluoromethyl quaternary carbon center, aiming to solve the various limitations existing in the existing preparation methods.

[0005] Another object of the present invention is to provide the above-mentioned ketophosphine oxide compound containing a trifluoromethyl quaternary carbon center.

[0006] Another object of the present invention is to provide the application of the above-mentioned ketophosphine oxide compound containing a trifluoromethyl quaternary carbon center.

[0007] The present invention is achieved by providing a ketophosphine oxide compound containing a trifluoromethyl quaternary carbon center, the chemical structure of the compound is shown in the following formula (I);

[0008]

[0009] wherein R is selected from any one of phenyl, methoxy substituted phenyl, methyl substituted phenyl, halogen substituted phenyl, nitro substituted phenyl, biphenyl, pyridyl, thienyl, naphthyl, cyclopropyl and cyclohexyl;

[0010] R' is selected from any one of methyl, ethyl, phenyl, benzyl and trifluoromethyl;

[0011] R 1 Any one selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, tert-butyl substituted phenyl, halogen substituted phenyl, biphenyl and naphthyl;

[0012] R 2 Any one selected from the group consisting of phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, tert-butyl-substituted phenyl, halogen-substituted phenyl, biphenyl and naphthyl.

[0013] The present invention further discloses a method for preparing the above-mentioned ketophosphine oxide compound, which comprises the following steps:

[0014] (1) adding a diarylphosphine oxide compound, a trifluoromethyl ketene compound and a catalyst into water, and stirring for 2 to 12 hours at 25 to 100° C. in a nitrogen atmosphere; wherein:

[0015] The chemical structural formula of the diarylphosphine oxide compound is shown in the following formula (II):

[0016]

[0017] In formula (II), R 1 Any one selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, tert-butyl substituted phenyl, halogen substituted phenyl, biphenyl and naphthyl;

[0018] R 2 Any one selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, tert-butyl substituted phenyl, halogen substituted phenyl, biphenyl and naphthyl;

[0019] The chemical structural formula of the trifluoromethyl ketene compound is shown in the following formula (III):

[0020]

[0021] In formula (III), R is selected from any one of phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, halogen-substituted phenyl, nitro-substituted phenyl, biphenyl, pyridyl, thienyl, naphthyl, cyclopropyl and cyclohexyl;

[0022] R' is selected from any one of methyl, ethyl, phenyl, benzyl and trifluoromethyl;

[0023] The catalyst is selected from any one of cesium carbonate, potassium carbonate, lithium hydroxide, sodium acetate, triethylenediamine and 1,8-diazabicyclo[5.4.0]undec-7-ene;

[0024] (2) After the reaction in step (1) is completed, the reaction solution is quenched and extracted in sequence, and the combined organic phase is washed, dried, concentrated and purified in sequence to obtain a ketophosphine oxide compound.

[0025] Preferably, in step (1), the catalyst is cesium carbonate.

[0026] Preferably, in step (1), the molar ratio of the diaryl phosphine oxide compound, the trifluoromethyl ketene compound, and the catalyst is 1-1.5:1.2-1:0-0.06.

[0027] Preferably, in step (1), the molar ratio of the diaryl phosphine oxide compound, the trifluoromethyl ketene compound and the catalyst is 1.2:1:0.06 mmol.

[0028] Preferably, in step (1), stirring is performed under nitrogen atmosphere at 70° C. for 12 h.

[0029] Preferably, in step (2), the quenching is quenching with a saturated NH4Cl solution; the extraction is extraction with ethyl acetate for 3 times; the washing is washing with saturated brine; the drying is drying with anhydrous sodium sulfate; and the concentration is vacuum concentration.

[0030] Preferably, in step (2), the purification is performed by silica gel column chromatography, and the column chromatography separation conditions are: the stationary phase is 300-400 mesh silica gel powder, the mobile phase is ethyl acetate A and petroleum ether B, and the mobile phase change program A:B is 1:5.

[0031] The invention further discloses the application of the ketophosphine oxide compound in preparing a human colon cancer cell activity inhibitor.

[0032] The present invention overcomes the deficiencies of the prior art and provides a ketophosphine oxide compound containing a trifluoromethyl quaternary carbon center and a preparation method and application thereof. The present invention is a method for constructing a γ-ketophosphine oxide compound with highly crowded space and a trifluoromethyl and phosphine oxide group fully substituted carbon center by an addition reaction of a diarylphosphine oxide compound to a trifluoromethyl enone compound in water without the participation of a transition metal. Specifically, the method comprises adding a diarylphosphine oxide compound, a trifluoromethyl enone compound and a catalyst to water, stirring for 2 to 12 hours at 25 to 100° C. in a nitrogen atmosphere, and finally obtaining a ketophosphine oxide compound containing a trifluoromethyl quaternary carbon center.

[0033] In the present invention, a diarylphosphine oxide compound and a trifluoromethylketene compound are subjected to an aqueous phase addition reaction, taking nitrogen atmosphere, stirring at 70° C. for 12 h, and cesium carbonate as a catalyst as an example, the reaction equation is as follows:

[0034]

[0035] In this reaction, the chemical structure of the diarylphosphine oxide compound is shown in the following formula (II):

[0036]

[0037] In formula (II), R 1 Any one selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, tert-butyl substituted phenyl, halogen substituted phenyl, biphenyl and naphthyl;

[0038] R 2 Any one selected from the group consisting of phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, tert-butyl-substituted phenyl, halogen-substituted phenyl, biphenyl and naphthyl.

[0039] Specifically, the diaryl phosphine oxide compound is selected from any one of diphenylphosphine oxide, bis(4-fluorophenyl)phosphine oxide, bis(4-chlorophenyl)phosphine oxide, di-m-tolylphosphine oxide, di-p-tolylphosphine oxide, di([1,1'-biphenyl]-4-yl)phosphine oxide, bis(4-(tert-butyl)phenyl)phosphine oxide, bis(4-methoxyphenyl)phosphine oxide, bis(naphthalene-2-yl)phosphine oxide, (4-chlorophenyl)(phenyl)phosphine oxide and phenyl(p-toluene)phosphine oxide.

[0040] The chemical structure of the trifluoromethyl ketene compound is shown in the following formula (III):

[0041]

[0042] In formula (III), R is selected from any one of phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, halogen-substituted phenyl, nitro-substituted phenyl, biphenyl, pyridyl, thienyl, naphthyl, cyclopropyl and cyclohexyl;

[0043] R' is selected from any one of methyl, ethyl, phenyl, benzyl and trifluoromethyl;

[0044] Specifically, the trifluoromethyl ketone compound is selected from (E)-4,4,4-trifluoro-3-methyl-1-phenylbut-2-ene-1-one, (E)-1-phenyl-3-(trifluoromethyl)pent-2-ene-1-one, (E)-3-benzyl-4,4,4-trifluoro-1-phenylbut-2-ene-1-one, (E)-4,4,4-trifluoro-1,3-diphenylbut-2-ene-1-one, 4,4,4-trifluoro-1-phenyl-3-(trifluoromethyl)pent-2-ene-1-one, methyl)but-2-en-1-one, (E)-1-(4-fluorophenyl)-3-(trifluoromethyl)pent-2-en-1-one, (E)-1-(4-chlorophenyl)-3-(trifluoromethyl)pent-2-en-1-one, (E)-1-(2-chlorophenyl)-3-(trifluoromethyl)pent-2-en-1-one, (E)-1-(4-bromophenyl)-3-(trifluoromethyl)pent-2-en-1-one, (E)-1-(3-bromophenyl)-3-(trifluoromethyl)pent-2-en-1-one (Trifluoromethyl)pent-2-en-1-one, (E)-1-(p-tolyl)-3-(trifluoromethyl)pent-2-en-1-one, (E)-1-([1,1'-biphenyl]-4-yl)-3-(trifluoromethyl)pent-2-en-1-one, (E)-1-(4-methoxyphenyl)-3-(trifluoromethyl)pent-2-en-1-one, (E)-1-(4-nitrophenyl)-3-(trifluoromethyl)pent-2-en-1-one, (E) -1-(naphthalen-2-yl)-3-(trifluoromethyl)pent-2-en-1-one, (E)-1-(thiophene-2-yl)-3-(trifluoromethyl)pent-2-en-1-one, (E)-1-(pyridin-3-yl)-3-(trifluoromethyl)pent-2-en-1-one, (E)-1-cyclopropyl-3-(trifluoromethyl)pent-2-en-1-one and (E)-1-cyclohexyl-3-(trifluoromethyl)pent-2-en-1-one.

[0045] In the reaction, the catalyst, in addition to cesium carbonate, can also be selected from any one of potassium carbonate, lithium hydroxide, sodium acetate, triethylenediamine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0046] Compared with the shortcomings and deficiencies of the prior art, the present invention has the following beneficial effects: the method of the present invention is a green transformation of the classic phospha-Michael reaction, the reaction is carried out in an aqueous system, and has the characteristics of mild conditions, simple operation, high yield, good functional group tolerance, wide substrate range, simple post-treatment, no pollution, high economic benefits, etc. The ketophosphine oxide compounds obtained by the present invention have a wide range of uses, and some compounds can be used to prepare inhibitors of human colon cancer cell activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 is the hydrogen spectrum of the target product a in Example 1 of the present invention;

[0048] Figure 2 is the fluorine spectrum of the target product a of Example 1 of the present invention;

[0049] Figure 3 is the phosphine spectrum of the target product a of Example 1 of the present invention;

[0050] Figure 4 is the carbon spectrum of the target product a of Example 1 of the present invention;

[0051] Figure 5 is the hydrogen spectrum of the target product b of Example 2 of the present invention;

[0052] Figure 6 is the fluorine spectrum of the target product b of Example 2 of the present invention;

[0053] Figure 7 is the phosphine spectrum of the target product b of Example 2 of the present invention;

[0054] Figure 8 The carbon spectrum of the target product b of Example 2 of the present invention;

[0055] Fig. 9 is the hydrogen spectrum of the target product c of Example 3 of the present invention;

[0056] Fig.10 is the fluorine spectrum of the target product c of Example 3 of the present invention;

[0057] Fig.11 is the phosphine spectrum of the target product c of Example 3 of the present invention;

[0058] Fig.12 The carbon spectrum of the target product c of Example 3 of the present invention;

[0059] Fig.13 These are the anti-HT-29 activity results of compounds a, d, f, s, and z. DETAILED DESCRIPTION

[0060] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0061] The raw materials used in the examples are trifluoromethyl ketene compounds, which are synthesized according to the literature (Org. Lett. 2018, 20, 1638). The diarylphosphine oxide compounds are prepared according to the literature (J. Org. Chem. 2022, 87, 7720-7733). Other raw materials are commercially available unless otherwise specified.

[0062] Example 1

[0063] (1) To a 10 mL Schlenk tube were added (E)-4,4,4-trifluoro-3-methyl-1-phenylbut-2-en-1-one (64.3 mg, 0.3 mmol, 1 equiv.), diphenylphosphine oxide (72.8 mg, 0.36 mmol, 1.2 equiv.), cesium carbonate (19.5 mg, 0.06 mmol, 0.2 equiv.) and water (2 mL) in sequence, and the reaction mixture was stirred at 70 °C for 12 h under nitrogen.

[0064] (2) After the reaction in step (1) was completed, the mixture was quenched with a saturated NH4Cl solution and extracted with ethyl acetate (20 mL×3); the combined organic phase was 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 300-400 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:5, and finally 108.6 mg of compound a (white solid) was obtained, and the yield of compound a was calculated to be 87%.

[0065] The above compound a is characterized, as Figures 1 to 3 As shown, specifically:

[0066] 1 H NMR (400MHz, CDCl3): δ=8.12-8.07(m,4H),7.90-7.83(m,2H),7.61-7.48(m,7H),7.42(t,J=7.7 Hz,2H),3.62(dd,J=15.2,9.0Hz,1H),3.35(dd,J=15.2,8.3Hz,1H),1.76(d,J=14.9Hz,3H)ppm.

[0067] 19F NMR (376MHz, CDCl3): δ = -63.46 (d, J = 4.0Hz, 3F) ppm.

[0068] 31 P NMR (162MHz, CDCl3): δ=31.06ppm.

[0069] 13 C NMR (100MHz, CDCl3): δ = 196.3 (d, J = 10.6Hz), 137.5, 133.2, 132.5-132.1 (m, 3C), 129.4 (dd, J = 95.3, 10.1Hz) ,128.6(d,J=5.3Hz), 128.4(d,J=16.9Hz), 127.0(q,J=283.4Hz), 49.7(dd,J=61.4,24.8Hz), 36.2,15.5ppm.

[0070] HRMS(m / z):calcd for C 23 H 21 F3O2P[M+H] + 417.1226, found:417.1224.

[0071] According to the characterization data, the prepared compound a is 3-(diphenylphosphinoyl)-4,4-4-trifluoro-3-methyl-1-phenylbutan-1-one (purity>98%), and the structural formula of the compound a is:

[0072]

[0073] Example 2

[0074] (1) To a 10 mL Schlenk tube were added (E)-1-(4-methoxyphenyl)-3-(trifluoromethyl)pent-2-en-1-one (77.4 mg, 0.3 mmol, 1 equiv.), diphenylphosphine oxide (72.8 mg, 0.36 mmol, 1.2 equiv.), cesium carbonate (19.5 mg, 0.06 mmol, 0.2 equiv.) and water (2 mL) in sequence, and the reaction mixture was stirred at 70 °C for 12 h under nitrogen.

[0075] (2) After the reaction in step (1) is completed, the reaction is quenched with a saturated NH4Cl solution and extracted with ethyl acetate (20 mL×3); the combined organic phase is washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product; the crude product is purified by silica gel column chromatography, and the column chromatography separation conditions are as follows: the stationary phase is 300-400 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1:4, and finally 117.2 mg of compound b (yellow oily liquid) is obtained, and the yield of compound b is calculated to be 85%.

[0076] The above compound b was characterized as follows Figures 4 to 6 As shown, specifically:

[0077] 1 H NMR (400MHz, CDCl3): δ=8.11-7.95(m,4H),7.90-7.82(m,2H),7.57-7.42(m,6H),6.94-6.84(m ,2H),3.82(s,4H),3.51(dd,J=16.2,12.9Hz,1H),2.57-2.23(m,2H),1.04(t,J=7.4Hz,3H)ppm.

[0078] 19 F NMR (376MHz, CDCl3): δ = -61.05 (s, 3F) ppm.

[0079] 31 P NMR (162MHz, CDCl3): δ=31.40ppm.

[0080] 13 C NMR (100MHz, CDCl3): δ = 194.4 (d, J = 8.7Hz), 163.4, 132.3 (dd, J = 30.0, 8.7Hz), 132.0 (dd, J = 7.2, 3.8Hz), 131.5, 130.5, 130.4 ,128.3(dd,J=12.0,8.1Hz),127.0(q,J=281.3Hz),113.6,55.3,54.0(dd,J=59.6,23.1Hz),32.7,22.2,9.0(d,J=5.4Hz)ppm.

[0081] HRMS(m / z):calcd for C 25 H 25 F3O3P[M+H] + 461.1488, found:461.1483.

[0082] According to the characterization data, the prepared compound b is 3-(diphenylphosphinoyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)pentane-1-one (purity>98%), and the structural formula of the compound b is:

[0083]

[0084] Example 3

[0085] (1) To a 10 mL Schlenk tube were added (E)-4,4,4-trifluoro-3-methyl-1-phenylbut-2-en-1-one (64.3 mg, 0.3 mmol, 1 equiv.), bis(naphthalen-2-yl)phosphine oxide (108.8 mg, 0.36 mmol, 1.2 equiv.), cesium carbonate (19.5 mg, 0.06 mmol, 0.2 equiv.) and water (2 mL) in sequence, and the reaction mixture was stirred at 70° C. for 12 h under nitrogen.

[0086] (2) After the reaction in step (1) was completed, the reaction was quenched with a saturated NH4Cl solution and extracted with ethyl acetate (20 mL×3); the combined organic phase was 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 300-400 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:4, and finally 153.1 mg of compound c (white solid) was obtained, and the yield of compound c was calculated to be 99%.

[0087] The above compound c was characterized as follows Figures 7 to 9 As shown, specifically:

[0088] 1 H NMR (400MHz, CDCl3): δ=8.01-7.91(m,4H),7.89-7.82(m,2H),7.56-7.48(m,1H),7.41(dd,J=8.4,7.1Hz,2H),7.04-6.96 (m,4H),3.84(s,3H),3.82(s,3H),3.58(dd,J=15.1,8.6Hz,1H),3.31(dd,J=15.1,8.2Hz,1H),1.70(d,J=14.9Hz,3H)ppm.

[0089] 19 F NMR (376MHz, CDCl3): δ = -63.51 (d, J = 3.7Hz, 3F) ppm.

[0090] 31 P NMR (162MHz, CDCl3): δ=31.54ppm.

[0091] 13 C NMR (100MHz, CDCl3): δ = 196.7 (d, J = 10.8Hz), 162.6 (t, J = 3.3Hz), 137.5, 134.2 (t, J = 10.8Hz), 133.2, 128.5, 128.3, 12 7.1 (q, J=282.2Hz), 120.4 (dd, J=104.5, 7.2Hz), 114.0 (d, J=12.7Hz), 55.3, 49.6 (dd, J=62.6, 24.6Hz), 36.1, 15.4ppm.

[0092] HRMS(m / z):calcd for C 25 H 25 F3O4P[M+H] + 477.1337, found:477.1336.

[0093] According to the characterization data, the prepared compound C is 3-(di(naphthalene-2-yl)phosphinoyl)-4,4-4-trifluoro-3-methyl-1-phenylbutan-1-one (purity>98%), and the structural formula of the compound C is:

[0094]

[0095] Example 4

[0096] Example 4 is substantially the same as Example 1, except that the cesium carbonate equivalent in step (1) is different, as shown in Table 1 below:

[0097] Table 1

[0098] Cesium carbonate (x mol%) Yield (%) Cesium carbonate (0 mol%) 36 Cesium carbonate (5 mol%) 58 Cesium carbonate (10 mol%) 77 Cesium carbonate (20 mol%) 87

[0099] It can be seen from Table 1 that under the same reaction conditions, different cesium carbonate equivalents are used, such as: cesium carbonate (0), the yield is 36%; cesium carbonate (5mol%), the yield is 58%; cesium carbonate (10mol%), the yield is 77%; when cesium carbonate (20mol%) is used, the reaction yield is the highest at 87%.

[0100] Example 5

[0101] Example 5 is substantially the same as Example 1, except that the type of catalyst (cesium carbonate) in step (1) is different, as shown in Table 2 below:

[0102] Table 2

[0103]

[0104]

[0105] It can be seen from Table 2 that under the same reaction conditions, different types of catalysts are replaced, such as: using triethylenediamine, the yield is 34%; using sodium acetate, the yield is 64%; using potassium carbonate, the yield is 73%; using lithium hydroxide, the yield is 74%; using 1,8-diazabicyclo[5.4.0]undec-7-ene, the yield is 64%; when cesium carbonate is used, the reaction yield is as high as 87%.

[0106] Example 6

[0107] Example 6 is basically the same as Example 1, except that the reaction temperature in step (1) is different, as shown in Table 3 below:

[0108] Table 3

[0109] Temperature(℃) Yield (%) 25 0 50 0 70 87 100 87

[0110] It can be seen from Table 3 that under the same reaction conditions, at room temperature, the reaction does not occur; when the temperature is 70°C, the reaction yield is the highest, which is 87%; when the temperature is further increased, the yield remains unchanged at 87%.

[0111] Example 7

[0112] Example 7 is basically the same as Example 1, except that in step (1), the molar ratio of the trans-trifluoromethyl ketene compound to the diarylphosphine oxide compound is different when the reaction is carried out for 6 hours, as shown in Table 4 below:

[0113] Table 4

[0114]

[0115]

[0116] It can be seen from Table 4 that under the same reaction conditions, when the reaction was carried out for 6 hours, when the molar ratio of the trifluoromethyl ketene compound to the diaryl phosphine oxide compound was 1:1, the reaction yield was 83%; when the molar ratio of the trifluoromethyl ketene compound to the diaryl phosphine oxide compound was 1.2:1, the reaction yield was 83%; when the molar ratio of the trifluoromethyl ketene compound to the diaryl phosphine oxide compound was 1:1.5, the reaction yield was the highest at 87%.

[0117] Example 8

[0118] Example 8 is basically the same as Example 1, except that in step (1), the reaction time is different, as shown in Table 5 below:

[0119] Table 5

[0120] Reaction time Yield (%) 2h 78 6h 85 12h 87

[0121] It can be seen from Table 5 that under the same reaction conditions, prolonging the reaction time is beneficial to increasing the reaction yield; when the reaction time is 12 h, the reaction yield is 87%.

[0122] Example 9

[0123] Example 9 is basically the same as Example 1, except that in step (1), the trifluoromethyl ketene compound is different. The target product obtained is specifically shown in Table 6 below:

[0124] Table 6

[0125]

[0126]

[0127] Example 10

[0128] Example 10 is basically the same as Example 1, except that in step (1), the diarylphosphine oxide compound is different. The target product obtained is specifically shown in Table 7 below:

[0129] Table 7

[0130]

[0131]

[0132] Application Examples

[0133] The compounds a, d, f, s and z obtained in the above examples were subjected to preliminary anti-human colon cancer cell (HT-29) activity tests, and the cell survival rate was determined by measuring the ATP level.

[0134] The test method is: exponentially growing cells (HT-29 cell line / 4×10 3 Cells / 100 μL / well) were incubated with test compounds for 72 hours. The test compound concentrations were 30 μM and 10 μM, respectively, and incubated in an incubator at 37°C with humidified CO2 and 95% air. Control wells containing dimethyl sulfoxide (DMSO) without compounds were also included in the experiment. The stock solution of the compound was initially dissolved in DMSO and then further diluted with PBS. After incubation, 20 μL of CTG reagent was added to each well. Then shake for 7 minutes and incubate at room temperature for 10 minutes. Readings were recorded on a microwell reader as absorbance at 570 nm.

[0135] The preliminary activity of compounds a, d, f, s, and z is as follows Fig.13As shown, it can be seen that compound s exhibits a certain function of inhibiting the activity of human colon cancer cells (HT-29), and the cell survival rate is less than 40%.

[0136] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. Use of a ketophosphine oxide compound in the preparation of a human colon cancer cell activity inhibitor, wherein the ketophosphine oxide compound is 1-cyclopropyl-3-(diphenylphosphinoyl)-3-(trifluoromethyl)pentan-1-one.

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