3-hydroxy-2-aroylindolines containing a trifluoromethyl quaternary carbon center, and methods of making and using the same

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a 3-hydroxy-2-aroyl indoline compound containing a trifluoromethyl quaternary carbon center, a preparation method and application thereof. The application further provides a preparation method of the indoline compound: taking an o-N-substituted amino trifluorobenzene ethanone compound and an arylacyl dimethyl sulfide ylide compound as raw materials, the target product is obtained by one-step construction through heating reaction in an organic solvent. The method does not need any metal catalyst, has mild reaction conditions, simple operation, wide substrate application range, and the yield can reach 72% to 89%. The compound has a significant proliferation inhibition effect on HeLa tumor cells, and the IC 50 value can reach 0.52 to 6.86 μM, and can be used for preparing an antitumor drug.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a 3-hydroxy-2-aramidoline compound containing a trifluoromethyl quaternary carbon center, its preparation method, and its application. Background Technology

[0002] The indoline (2,3-dihydroindole) skeleton is a crucial nitrogen-containing heterocyclic structural unit in medicinal chemistry. Many pharmacologically active natural products and drug candidates contain an indoline core, such as rhynchophylline, isorhynchophylline, evodiamine derivatives, and strychnine alkaloids. Due to the unique properties of the trifluoromethyl group, its introduction into molecules typically enhances lipophilicity, bioavailability, and metabolic stability. The trifluoromethyl quaternary carbon center (TFQC), formed by the combination of a trifluoromethyl group and a quaternary carbon center, is a special structure characterized by the trifluoromethyl group directly attached to a tetrasubstituted carbon atom, giving the molecule strong rigidity and unique electronic properties. Therefore, heterocyclic skeletons containing trifluoromethyl quaternary carbon centers are a class of active structural units with broad application value and promising prospects in current medicine and pesticide science. Against this backdrop, the efficient construction of indoline compounds containing trifluoromethyl quaternary carbon centers is of great significance.

[0003] Currently, reported methods for synthesizing indoline skeletons mainly include transition metal catalysis, small organic molecule catalysis, and radical cyclization. For example, some literature reports the use of rhodium-catalyzed asymmetric intermolecular dearomatization cyclopropanation reaction of indole with N-trifluoromethanesulfonylhydrazone to construct cyclopropane-fused indoline containing a trifluoromethyl quaternary carbon center; others report the use of copper-catalyzed Friedel-Crafts alkylation reaction of trifluoropyruvate with indole to synthesize indole compounds containing a chiral trifluoromethyl quaternary carbon. While these methods provide diverse strategies for the construction of indoline, they all have some limitations: transition metal catalysts are not only expensive but also prone to causing product and environmental pollution; small organic molecule catalysts, such as some commonly used phosphine catalysts, often exhibit high toxicity and air instability (e.g., Bu3P). Although transition metal catalysis is a highly challenging and popular research area in organic chemistry, the pharmaceutical industry still urgently needs to develop efficient synthetic routes that can avoid metal residues in drug products.

[0004] Thiol ylide reagents are an important class of synthetic molecules in organic synthesis. Due to their ease of preparation and controllable reactions, they have become essential reagents for the synthesis of various carbon / heterocyclic compounds. For example, Zhang Yanping et al. reported the catalyst-free [4+1] cycloaddition reaction of thioyl ylide with 2-hydroxy-β-nitrostyrene to construct dihydrobenzofuran compounds; Anshul Jain et al. reported a method for constructing 2,3-disubstituted dihydroindole with thioyl ylide and o-aminochalcone under the action of Cs2CO3. However, there are no reports in the prior art of constructing 2-aromatic indoline compounds containing both a free hydroxyl group and a trifluoromethyl quaternary carbon center at the C3 position through a one-step cyclization reaction using N-substituted o-aminotrifluoroacetophenone and aromatic dimethyl thioyl ylide as substrates. Summary of the Invention

[0005] In order to overcome the shortcomings of the prior art, the present invention aims to provide a 3-hydroxy-2-aramidoline compound containing a trifluoromethyl quaternary carbon center, its preparation method and application.

[0006] The objective of this invention is achieved through the following technical solution:

[0007] The first aspect of this invention provides a 3-hydroxy-2-aramidoline compound containing a trifluoromethyl quaternary carbon center, the structural formula of which is shown in Formula I:

[0008]

[0009] In the formula, R1 and R2 represent substituents at any position on the benzene ring; R1 is selected from H, halogen atom, C1-C6 alkoxy, C1-C6 alkyl, phenyl, trifluoromethyl, nitro, and cyano; R2 is selected from H or halogen atom; and R3 is sulfonyl group.

[0010] This invention provides for the first time a 3-hydroxy-2-aramidoline compound of Formula I containing a trifluoromethyl quaternary carbon center. This type of compound contains both a free hydroxyl group and a trifluoromethyl quaternary carbon center at the C3 position, possessing both a rigid framework and unique electronic effects. The sulfonamide structure in the molecule has the potential to exert various therapeutic effects through specific binding to biological targets, and the introduction of a halogen atom can further enhance drug-likeness, making it a highly valuable structural segment in drug molecules.

[0011] Furthermore, R1 is selected from H, a halogen atom, C1-C6 alkoxy, and C1-C6 alkyl; R2 is a halogen atom; and R3 is p-toluenesulfonyl.

[0012] Furthermore, the 3-hydroxy-2-aramidoindoline compound containing a trifluoromethyl quaternary carbon center is selected from any of the following:

[0013]

[0014] ;

[0015] When R1 is an electron-donating group (such as methoxy or methyl) or a fluorine atom, the reaction yield is higher (up to 89%); when R2 is a halogen atom such as bromine, iodine, or fluorine, the product has a higher IC50 response to HeLa cells. 50 The value can be as low as 0.5 μM, indicating that specific combinations of substituents can significantly enhance the antitumor activity of the compound, providing a preferred structural template for subsequent drug screening.

[0016] The second aspect of the present invention provides a method for preparing the above-mentioned 3-hydroxy-2-aramidoindoline compounds containing a trifluoromethyl quaternary carbon center, wherein the o-N-substituted aminotrifluoroacetophenone compound of formula II and the aramidodimethylthioylide compound of formula III are reacted by heating in an organic solvent to obtain the compound of formula I.

[0017] ;

[0018] In the formula, R1 and R2 represent substituents at any position on the benzene ring; R1 is selected from H, halogen atom, C1-C6 alkoxy, C1-C6 alkyl, phenyl, trifluoromethyl, nitro, and cyano; R2 is selected from H or halogen atom; and R3 is sulfonyl group.

[0019] This invention utilizes the ortho-N-substituted aminotrifluoroacetophenone compound of Formula II and the aromatic acyldimethylthio ylide compound of Formula III as starting materials to efficiently construct an indoline skeleton containing a trifluoromethyl quaternary carbon center and a free hydroxyl group through a one-step cyclization reaction, avoiding the cumbersome operations of traditional multi-step synthesis. This reaction requires no metal catalyst, fundamentally solving the problem of metal residues in pharmaceutical products and aligning with the development direction of green chemistry.

[0020] Furthermore, the heating reaction is carried out at a temperature of 50–70°C for 10–14 hours. Most preferably, the heating reaction is carried out under mild conditions of 60°C for 12 hours. Under these conditions, energy consumption is low and side reactions are few, which is beneficial for improving product yield.

[0021] Furthermore, the molar ratio of the ortho-N-substituted aminotrifluoroacetophenone compound to the aryl dimethyl thioylide compound is 1:(1.2-1.8); an appropriate excess of the compound of formula III (thioylide) can ensure the complete conversion of the substrate of formula II, while avoiding excessive amounts that would lead to waste of raw materials and difficulties in separation, thus ensuring both yield and economy and ease of post-processing.

[0022] Furthermore, the organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, toluene, dichloromethane, and ethyl acetate, and is more preferably acetonitrile.

[0023] Furthermore, in the o-N-substituted aminotrifluoroacetophenone compound represented by Formula II, R1 is one of H, a halogen atom, C1-C6 alkoxy, or C1-C6 alkyl, and R3 is p-toluenesulfonyl; in the aryl dimethyl thioyl ylide compound represented by Formula III, R2 is H or a halogen atom.

[0024] Furthermore, the o-N-substituted aminotrifluoroacetophenone compound represented by Formula II is selected from any of the following:

[0025] N-(4-methoxy-2-(2,2,2-trifluoroacetyl)phenyl)-4-methylbenzenesulfonamide, N-(4-fluoro-2-(2,2,2-trifluoroacetyl)phenyl)-4-methylbenzenesulfonamide, N-(4-methyl-2-(2,2,2-trifluoroacetyl)phenyl)-4-methylbenzenesulfonamide, 4-methyl-N-(2-(2,2,2-trifluoroacetyl)phenyl)benzenesulfonamide;

[0026] The aryl dimethyl thio ylide compound represented by Formula III is selected from any one of the following:

[0027] p-Bromophenyldimethylthioyl ylethyl ketone, p-iodophenyldimethylthioyl ylethyl ketone, p-fluorophenyldimethylthioyl ylethyl ketone.

[0028] The preferred substrate combinations described above all underwent successful cyclization reactions, yielding the target product in yields of 72%–89%, demonstrating the broad substrate versatility of this method. The p-toluenesulfonyl (Ts) group, as a protecting group, not only stabilizes the NH bond and prevents side reactions but also allows for further derivatization via deprotection in the later stages, facilitating the expansion of the compound library.

[0029] Furthermore, the reaction requires no metal catalyst. One of the greatest innovations of this invention is that it achieves cyclization transformation without any metal catalyst. Compared with existing indoline synthesis methods that rely on transition metals (such as Rh, Cu, Pd, etc.), this invention fundamentally avoids the problem of metal residues, reduces costs, and improves the biosafety of the product, making it particularly suitable for the field of drug synthesis.

[0030] Furthermore, the preparation method also includes a post-processing step after the reaction: after the reaction, the solvent is removed by rotary evaporation, dichloromethane is added and heated to reflux to completely dissolve the crude product, and after natural cooling to room temperature, n-hexane is added. The product is then filtered, washed, and dried to obtain the pure product shown in Formula I. The post-processing of this invention uses recrystallization purification, and high-purity products can be obtained through a dichloromethane / n-hexane system without the need for column chromatography separation. This method is simple to operate, low in cost, and easy for industrial-scale production.

[0031] A third aspect of this invention provides the application of the above-mentioned 3-hydroxy-2-aramidoindoline compound containing a trifluoromethyl quaternary carbon center in the preparation of an antitumor drug. MTT assay results show that the compound of this invention has a significant inhibitory effect on the proliferation of HeLa tumor cells, with an IC50 concentration of [missing information]. 50 Values ​​can range from 0.52 to 6.86 μM, with the IC50 of compound 1e (R2=I) being particularly high. 50 With a value as low as 0.52 μM, it has the potential to be developed into an anti-tumor drug.

[0032] Furthermore, the antitumor drug is a drug that inhibits the proliferation of HeLa cells. HeLa cells are a standard in vitro model of cervical cancer, and the compounds of this invention have a potent inhibitory effect (IC50) on this cell line. 50 The low concentration (as low as 0.52 μM) indicates its potential application value in the treatment of cervical cancer. Furthermore, the novel skeleton of this class of compounds, distinct from existing topoisomerase inhibitors or tubulin inhibitors, holds promise for exerting antitumor effects through novel mechanisms, providing new candidate molecules for overcoming drug resistance.

[0033] A fourth aspect of the present invention also provides a pharmaceutical composition for inhibiting tumor proliferation, the pharmaceutical composition comprising the compound described in the first aspect as an active ingredient, and pharmaceutically acceptable excipients.

[0034] The present invention has the following advantages over the prior art:

[0035] 1. This invention provides for the first time a class of 3-hydroxy-2-aramidoindoline compounds (Formula I) containing a trifluoromethyl quaternary carbon center. These compounds possess both a free hydroxyl group and a trifluoromethyl quaternary carbon center at the C3 position, exhibiting both a rigid skeleton and unique electronic effects, making them highly valuable structural fragments for drug molecules. MTT assay results show that the compounds of this invention have a significant inhibitory effect on the proliferation of HeLa tumor cells, with an IC50 value of [missing information]. 50 The concentration can reach 0.52–6.86 μM, showing promising potential for the development of antitumor drugs.

[0036] 2. This invention uses o-N-substituted aminotrifluoroacetophenone (Formula II) and aromatic dimethyl thioylide compound (Formula III) as raw materials to efficiently construct the target product through a one-step cyclization reaction without the addition of any metal catalyst. This avoids the use of transition metal catalysts, fundamentally solving the problem of metal residues in pharmaceutical products, reducing synthesis costs, and aligning with the development direction of green chemistry. The reaction conditions are mild, the operation is simple, the substrate range is wide, and the yield can reach 72%–89%. Attached Figure Description

[0037] Figure 1 Compound 1a of the present invention 1 H NMR spectrum;

[0038] Figure 2 Compound 1a of the present invention 19 F NMR spectrum;

[0039] Figure 3 Compound 1a of the present invention 13 C NMR spectrum;

[0040] Figure 4 Compound 1b of the present invention 1 H NMR spectrum;

[0041] Figure 5 Compound 1b of the present invention 19 F NMR spectrum;

[0042] Figure 6 Compound 1b of the present invention 13 C NMR spectrum;

[0043] Figure 7 Compound 1c of the present invention 1 H NMR spectrum;

[0044] Figure 8 Compound 1c of the present invention 19 F NMR spectrum;

[0045] Figure 9 Compound 1c of the present invention 13 C NMR spectrum;

[0046] Figure 10 Compound 1d of the present invention 1 H NMR spectrum;

[0047] Figure 11 Compound 1d of the present invention 19 F NMR spectrum;

[0048] Figure 12 Compound 1d of the present invention13 C NMR spectrum;

[0049] Figure 13 Compound 1e of the present invention 1 H NMR spectrum;

[0050] Figure 14 Compound 1e of the present invention 19 F NMR spectrum;

[0051] Figure 15 Compound 1e of the present invention 13 C NMR spectrum;

[0052] Figure 16 Compound 1f of the present invention 1 H NMR spectrum;

[0053] Figure 17 Compound 1f of the present invention 19 F NMR spectrum;

[0054] Figure 18 Compound 1f of the present invention 13 C NMR spectrum;

[0055] Figure 19 This is a dose-response curve of the inhibitory effect of compound 1a of the present invention on the proliferation of HeLa cells. Detailed Implementation

[0056] The technical solution of the present invention will be further described below with reference to specific embodiments. However, those skilled in the art should understand that the following embodiments are only for illustrating the present invention and should not be regarded as limiting the present invention. Specific conditions not specified in the embodiments are performed according to conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the reagents or instruments used are all conventional products obtained through commercial channels.

[0057] The raw materials N-(4-methoxy-2-(2,2,2-trifluoroacetyl)phenyl)-4-methylbenzenesulfonamide (CAS: 2131817-65-5), N-(4-fluoro-2-(2,2,2-trifluoroacetyl)phenyl)-4-methylbenzenesulfonamide (CAS: 2416330-30-6), N-(4-methyl-2-(2,2,2-trifluoroacetyl)phenyl)-4-methylbenzenesulfonamide (CAS: 2480125-94-6), and 4-methyl-N-(2-(2,2,2-trifluoroacetyl)phenyl)benzenesulfonamide (CAS: 2416330-29-3) used in the following embodiments of the present invention can all be obtained through commercial channels. Alternatively, reference can be made to existing patent literature CN113651707A - Preparation method of ortho-aminotrifluoroacetophenone and its derivatives, and non-patent literature Zhu, Y.-N.; Huang, Y. Org. Preparation. Lett. 2020, 22, 6750–6755.

[0058] Preparation Example

[0059] The preparation process of the raw materials p-bromophenyldimethylthioyl ylidene ketone, p-iodophenyldimethylthioyl ylidene ketone, and p-fluorophenyldimethylthioyl ylidene ketone in this invention is based on non-patent literature Steele, RT; Fujiu, M.; Sarpong, R. Science 2025, 388, 631-638, and the specific process is as follows:

[0060]

[0061]

[0062] Compound 1 (100 mmol) and dimethyl sulfide (150 mmol) were added to a 1 L round-bottom flask, followed by 200 mL of acetone solution. The mixture was stirred overnight at room temperature. The resulting precipitate was filtered and washed with acetone. The precipitate was then added to a dichloromethane / water mixture (300 mL, 2:1, v / v), and 500 mL of 1 M sodium hydroxide aqueous solution was added. The mixture was stirred for 30 min. The reaction solution was extracted three times with dichloromethane (200 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain the substituted phenyl dimethyl sulfide ethyl ketone derivatives.

[0063] Example 1

[0064] A 3-hydroxy-2-aramidoline compound containing a trifluoromethyl quaternary carbon center, named 1a, is prepared as follows:

[0065]

[0066] N-(4-methoxy-2-(2,2,2-trifluoroacetyl)phenyl)-4-methylbenzenesulfonamide (CAS: 2131817-65-5, 100 mmol), p-bromophenyl dimethyl thioyl ethyl ketone (150 mmol), and acetonitrile solution (CH3CN, 200 mL) were added sequentially to a dry reaction flask. The mixture was stirred at 60 °C for 12 h, and the reaction was monitored by liquid chromatography. The reaction was stopped when the substrate N-(4-methoxy-2-(2,2,2-trifluoroacetyl)phenyl)-4-methylbenzenesulfonamide was completely consumed. The solvent was removed by rotary evaporation, and 15 mL of dichloromethane was added. The mixture was heated to reflux to dissolve the crude product completely. The mixture was then allowed to return to room temperature with stirring, and 10 mL of n-hexane was added. The mixture was filtered and washed again with 10 mL of n-hexane to give a white solid compound 1a, with a yield of 81%.

[0067] Compound 1a 1 H NMR, 19 F NMR and 13 C NMR such as Figure 1-3 As shown; 1 H NMR (400 MHz,Chloroform-d) δ 2.38 (s, 3H), 3.74 (d, 3H), 3.91 (s, 1H), 5.57 (s, 1H), 6.85(d,1H), 6.97 (dt, 1H), 7.25 (d, 2H), 7.55 – 7.63 (m, 3H), 7.63 – 7.70 (m, 2H), 7.71 – 7.76 (m, 2H); 19 F NMR (376 MHz, CDCl3) δ -81.06; 13 C NMR (101 MHz, Chloroform-d) δ 21.7, 29.8, 55.9, 67.8, 81.2 (q, J = 31.4 Hz), 110.4, 115.8,118.9, 122.4, 125.2, 127.2 (q, J = 282.8 Hz), 129.4, 130.0, 130.3, 132.2,133.8, 134.9, 136.3, 145.1, 157.1, 194.0. HRMS (ESI) calcd for C 24 H 19 BrF3NO5S[M+Na + ] 592.0017, found 592.0012.

[0068] Example 2

[0069] A 3-hydroxy-2-aramidoline compound containing a trifluoromethyl quaternary carbon center, named 1b, has the following structural formula:

[0070] ;

[0071] The preparation method of compound 1b is basically the same as that of Example 1, except that the raw material N-(4-methoxy-2-(2,2,2-trifluoroacetyl)phenyl)-4-methylbenzenesulfonamide in Example 1 is replaced with compound N-(4-fluoro-2-(2,2,2-trifluoroacetyl)phenyl)-4-methylbenzenesulfonamide (CAS: 2416330-30-6).

[0072] Compound 1b in this embodiment is a white solid with a yield of 83%; compound 1b... 1 H NMR, 19 F NMR and 13 C NMR such as Figure 4-6 As shown; 1 H NMR (400 MHz, Chloroform-d) δ 2.40 (s, 3H), 3.31 (s, 1H), 5.67(s, 1H), 7.07 (d, 1H), 7.17 (td, 1H), 7.28 (d, 2H), 7.62 – 7.65 (m, 2H), 7.65– 7.659 (m, 3H), 7.76 – 7.82 (m, 2H); 19 F NMR (376 MHz, CDCl3) δ -81.20 ppm; 13 C NMR (101 MHz, Chloroform-d) δ 21.7, 67.5, 80.7 (q, J = 31.6 Hz), 112.8,113.1, 115.7, 115.8, 119.6, 119.8, 122.2, 125.0, 127.3(q, J = 285.5 Hz), 127.4, 127.5, 129.7, 130.1, 130.3, 132.3, 133.9, 134.7, 139.1 (d, J = 2.4Hz), 145.3, 158.5, 160.9, 193.7.

[0073] Example 3

[0074] A 3-hydroxy-2-aramidoline compound containing a trifluoromethyl quaternary carbon center, named 1c, has the following structural formula:

[0075] ;

[0076] The preparation method of compound 1c is basically the same as that of Example 1, except that the raw material N-(4-methoxy-2-(2,2,2-trifluoroacetyl)phenyl)-4-methylbenzenesulfonamide in Example 1 is replaced with compound N-(4-methyl-2-(2,2,2-trifluoroacetyl)phenyl)-4-methylbenzenesulfonamide (CAS: 2480125-94-6).

[0077] Compound 1c in this embodiment is a white solid with a yield of 89%; the compound 1c... 1 H NMR, 19 F NMR and 13 C NMR such as Figure 7-9 As shown; 1 H NMR (400 MHz, Chloroform-d) δ 2.29 (s, 3H), 2.37 (s, 3H), 3.64 (s, 1H), 5.60 (s, 1H), 7.14 (s, 1H), 7.18 – 7.29 (m, 3H), 7.53 (d, 1H), 7.59(d, 2H), 7.67 (d, 2H), 7.74 (d, 2H); 19 F NMR (376 MHz, CDCl3) δ -81.16; 13 C NMR(101 MHz, Chloroform-d) δ 21.0, 21.7, 67.7, 81.2 (q, J = 31.8 Hz), 114.5,122.5, 125.3, 126.0, 127.3 (q, J = 285.8 Hz), 128.1, 128.7, 129.4, 130.0,130.3, 130.9, 132.3, 134.3, 140.7, 145.4, 187.5, 193.8.

[0078] Example 4

[0079] A 3-hydroxy-2-aramidoline compound containing a trifluoromethyl quaternary carbon center, named 1d, has the following structural formula:

[0080] ;

[0081] The preparation method of compound 1d is basically the same as that of Example 1, except that the raw material N-(4-methoxy-2-(2,2,2-trifluoroacetyl)phenyl)-4-methylbenzenesulfonamide in Example 1 is replaced with compound 4-methyl-N-(2-(2,2,2-trifluoroacetyl)phenyl)benzenesulfonamide (CAS: 2416330-29-3).

[0082] In this embodiment, compound 1d is a white solid with a yield of 85%; compound 1d... 1 H NMR, 19 F NMR and 13 C NMR such as Figure 10-12 As shown; 1 H NMR (400 MHz, Chloroform-d) δ 2.40 (s, 3H) ppm, 3.42 (s,1H), 5.70 (s, 1H), 7.12 (td, 1H), 7.31 – 7.23 (m, 2H), 7.37 (d, 1H), 7.46(ddd, 1H), 7.68 – 7.62 (m, 3H), 7.73 – 7.69 (m, 2H), 7.83 – 7.78 (m, 2H); 19 FNMR (376 MHz, CDCl3) δ -81.27; 13 C NMR (101 MHz, Chloroform-d) δ 21.8, 67.3,81.0(q, J = 30.3 Hz), 114.5, 124.6, 125.8(q, J = 271.7), 127.3, 129.5, 130.1(d, J = 10.1 Hz), 130.3, 132.3, 132.8, 134.3, 134.9, 143.1, 145.2, 193.7.

[0083] Example 5

[0084] A 3-hydroxy-2-aramidoline compound containing a trifluoromethyl quaternary carbon center, named 1e, has the following structural formula:

[0085] ;

[0086] The preparation method of compound 1e is basically the same as that of Example 1, except that the raw material p-bromophenyldimethylthioyl ylidene ketone in Example 1 is replaced with compound p-iodophenyldimethylthioyl ylidene ketone.

[0087] Compound 1e in this embodiment is a white solid with a yield of 82%; compound 1e's... 1 H NMR, 19 F NMR and 13 C NMR such as Figure 13-15 As shown; 1 H NMR (400 MHz, Chloroform-d) δ 2.38 (s, 3H), 3.38 (s, 1H), 5.66 (s, 1H), 7.09 (td, 1H), 7.24 (d, 2H), 7.35 (d, 1H), 7.43 (ddd, 1H), 7.61(t, 3H), 7.65 – 7.70 (m, 2H), 7.79 – 7.89 (m, 2H); 19 F NMR (376 MHz, CDCl3) δ-81.22 ppm; 13 C NMR (101 MHz, Chloroform-d) δ 21.7, 67.3, 81.1 (q, J = 31.7Hz), 102.5, 114.3, 119.6, 122.5, 124.5, 125.3, 125.8, 127.2(d, J = 285.8 Hz),128.1, 128.5, 128.6, 130.0, 130.0, 130.6, 132.1 (d, J = 10.1 Hz), 132.6,134.2, 135.3, 138.2, 142.9, 145.1, 194.1.

[0088] Example 6

[0089] A 3-hydroxy-2-aramidoline compound containing a trifluoromethyl quaternary carbon center, named 1f, has the following structural formula:

[0090] ;

[0091] The preparation method of compound 1f is basically the same as that of Example 1, except that the raw material p-bromophenyldimethylthioyl ylidene ketone in Example 1 is replaced with compound p-fluorophenyldimethylthioyl ylidene ketone.

[0092] Compound 1f in this embodiment is a white solid with a yield of 83%; compound 1f... 1 H NMR, 19 F NMR and 13 C NMR such as Figure 16-18 As shown; 1H NMR (400 MHz, Chloroform-d) δ 2.39 (s, 3H), 3.81 (s, 1H), 5.75 (s, 1H), 7.11 (tt, 1H), 7.17 (ddt, 2H), 7.27 (dd, 2H), 7.37 (d, 1H), 7.44 (tt, 1H), 7.64 (d, 1H), 7.66 (s, 1H), 7.70 (d, 1H), 7.72 (t, 1H), 7.98(ddd, 2H); 19 F NMR (376 MHz, CDCl3) δ -81.22, -103.06; 13 C NMR (101 MHz, Chloroform-d) δ 21.7, 67.1, 81.2 (q, J = 31.6 Hz), 114.4, 116.1, 116.3,122.5, 124.5, 125.3, 125.7, 126.0, 127.2, 127.3 (q, J = 282.8 Hz), 128.2,128.7, 129.9, 130.0, 131.6, 131.7, 132.6, 132.6, 132.6, 134.4, 143.0, 167.6,193.0.

[0093] Examples 7-12

[0094] The contents of Examples 7-12 are basically the same as those of Example 1. The differences and the yield of compound 1a are shown in Table 1.

[0095]

[0096] Test case

[0097] The classic MTT assay was used to analyze the cytotoxicity of compounds 1a-1f. The specific testing method was as follows: HeLa tumor cells were seeded in 96-well plates, with three replicates for each concentration. After cell adhesion and growth, cells were treated with different concentrations of compounds 1a-1f (0, 4, 8, 12, 24, 50 μM) for 24 h. After drug treatment, MTT solution (5 mg / mL MTT stock solution, 10 μL per well) was added, and the cells were incubated for another 4 h. After terminating the culture, the culture medium was carefully aspirated, and DMSO (100 μL per well) was added using a pipette. The plates were shaken in the dark for 10 min to ensure complete dissolution of any purple formazan crystals. The absorbance (OD) value at 490 nm was read using a microplate reader. Cell viability was calculated using the formula and the fluorescence intensity of the blank control group, and the IC50 of compounds 1a-1f was then calculated. 50 For values, see the results for compound 1a. Figure 19 The results for compounds 1b to 1f are shown in Table 2, as per Table 1.

[0098]

[0099] Depend on Figure 19 As shown in Table 2, the 3-hydroxy-2-aramidoline compounds (1a-1f) containing a trifluoromethyl quaternary carbon center provided by this invention all exhibited varying degrees of inhibitory effects on the proliferation of HeLa tumor cells, with IC50 values ​​of 100%. 50 The values ​​ranged from 0.52 to 6.86 μM, indicating that these compounds have significant potential for antitumor activity.

[0100] Finally, 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. The basic principles and main features of the present invention have been described above with specific implementation schemes. Based on the present invention, some modifications or substitutions can be made, but these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of protection claimed by the present invention.

Claims

1. A 3-hydroxy-2-aramidoline compound containing a trifluoromethyl quaternary carbon center, characterized in that, The structural formula of the indoline compound is shown in Formula I: In the formula, R1 and R2 represent substituents at any position on the benzene ring; R1 is selected from H, halogen atom, C1-C6 alkoxy, C1-C6 alkyl, phenyl, trifluoromethyl, nitro, and cyano; R2 is selected from H or halogen atom; and R3 is sulfonyl group.

2. The 3-hydroxy-2-aramidoline compound containing a trifluoromethyl quaternary carbon center according to claim 1, characterized in that, R1 is selected from H, halogen atom, C1-C6 alkoxy group, and C1-C6 alkyl group; R2 is halogen atom; R3 is p-toluenesulfonyl group.

3. A method for preparing a 3-hydroxy-2-aramidoline compound containing a trifluoromethyl quaternary carbon center as described in claim 1, characterized in that, The o-N-substituted aminotrifluoroacetophenone compound of Formula II was reacted with the aryl dimethyl thio ylide compound of Formula III in an organic solvent by heating to obtain the compound of Formula I. ； In the formula, R1 and R2 represent substituents at any position on the benzene ring; R1 is selected from H, halogen atom, C1-C6 alkoxy, C1-C6 alkyl, phenyl, trifluoromethyl, nitro, and cyano; R2 is selected from H or halogen atom; and R3 is sulfonyl group.

4. The preparation method according to claim 3, characterized in that, The heating reaction is carried out at a temperature of 50–70°C for 10–14 hours.

5. The preparation method according to claim 3, characterized in that, The molar ratio of the ortho-N-substituted aminotrifluoroacetophenone compound to the aryl dimethyl thioylide compound is 1:(1.2 to 1.8).

6. The preparation method according to claim 3, characterized in that, The organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, toluene, dichloromethane, and ethyl acetate.

7. The preparation method according to claim 3, characterized in that, In the o-N-substituted aminotrifluoroacetophenone compound of Formula II, R1 is one of H, a halogen atom, C1-C6 alkoxy, or C1-C6 alkyl, and R3 is p-toluenesulfonyl; in the aryl dimethyl thioyl ylide compound of Formula III, R2 is H or a halogen atom.

8. The use of the 3-hydroxy-2-aramidoline compound containing a trifluoromethyl quaternary carbon center as described in claim 1 or 2 in the preparation of antitumor drugs.

9. The application according to claim 8, characterized in that, The antitumor drug is a drug that inhibits the proliferation of HeLa cells.

10. A pharmaceutical composition for inhibiting tumor proliferation, characterized in that, It comprises the compound according to any one of claims 1 to 2 as the active ingredient, and pharmaceutically acceptable excipients.

Images