C3-trifluoropropionyloxylation reaction of N-substituted indole, 3-trifluoropropionyloxy-2-oxindole, and preparation method and application thereof

Abstract

The present invention relates to a kind of C3 trifluoropropionyloxylation reaction of N substituted indole, 3 trifluoropropionyloxy 2 oxindole and its preparation method and application, belong to the field of heterocyclic compound synthesis technology, solve the existing method using transition metal catalyst, unfriendly to the environment, limited substrate range, harsh reaction conditions, many by-products, low yield of target product, low purity and other problems. The inventive method adopts bis(trifluoropropionate) iodobenzene as oxidant and fluorine source, reacts in an organic solvent, and is applicable to various N substituted indoles, including N methyl, N ethyl, N propyl, N butyl and N benzyl indole. The inventive method does not need to use transition metal catalyst, has higher environmental protection and operational safety, mild reaction conditions, high yield, good selectivity, few by-products, can efficiently and environmentally friendly prepare 3 trifluoropropionyloxy 2 oxindole and its derivatives, for drug development and organic synthesis provide important technical means.

Description

Technical Field

[0001] The present invention relates to the technical field of heterocyclic compound synthesis, and in particular to a C3-trifluoropropionyloxylation reaction of an N-substituted indole, 3-trifluoropropionyloxy-2-oxindole, and a preparation method and application thereof. Background Art

[0002] 2-Indolinone, as an important chemical structure, is considered a privileged skeleton and is widely distributed in various drugs and natural products. Among them, 3-functionalized indolinones are key building blocks for the synthesis of various alkaloids and drug lead compounds. Therefore, the synthesis of these important structural units has received widespread attention. Currently, various methods have been developed to prepare 3-acyloxyindolinones. The traditional synthesis method of 3-acyloxyindolinones is through the nucleophilic addition reaction of 3-hydroxyindolinone with acid anhydride under alkaline conditions. For example, Lu reported a method for preparing 3-acyloxyindolinones through the hydroacylation reaction of isatin with aldehydes catalyzed by N-heterocyclic carbene. Maurya synthesized 3-acyloxyindolinones through the DBU-catalyzed coupling reaction of isatin with phenylacetyl azide.

[0003] Indole is a commercially available material, and its dearomatization functionalization is considered an effective strategy for constructing various 3-functionalized indolones. Significant progress has been made in the allylation, arylation, and cycloaddition reactions of indoles via dearomatization under the action of various transition metal catalysts. While some progress has been made in the synthesis of 3-functionalized indolones, the following deficiencies remain:

[0004] Catalyst Dependence: Many existing methods rely on transition metal catalysts, which are often expensive and potentially toxic, potentially harmful to the environment and operators.

[0005] Limited substrate scope: Existing methods have limitations in substrate applicability, especially for the selective functionalization of N-substituted indoles, as existing technologies are difficult to apply to a variety of different N substituents.

[0006] Harsh reaction conditions: Some methods require harsh reaction conditions such as high temperature, high pressure, or strong acid and strong base, which increases the complexity and cost of the operation.

[0007] By-product generation: In some synthetic routes, there are many by-products and the purification process is complicated, which affects the yield and purity of the target product.

[0008] Furthermore, there are currently few reports on the use of indole dearomatization under metal-free conditions to obtain 3-acyloxyindolones. In this context, it is very necessary to develop a more efficient and universal method for the preparation of 3-acyloxyindolones. Summary of the Invention

[0009] In view of the above analysis, the present invention aims to provide a C3-trifluoropropionyloxylation reaction of N-substituted indole, 3-trifluoropropionyloxy-2-oxindole and its preparation method and application, which can solve at least one of the following technical problems: (1) the existing method uses transition metal catalysts, which are not environmentally friendly and cause harm to operators; (2) the substrate range is limited; (3) the reaction conditions are harsh; (4) there are many by-products and the purification is complicated; (5) the yield and purity of the target product are low.

[0010] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0011] A C3-trifluoropropionyloxylation reaction of an N-substituted indole to obtain 3-trifluoropropionyloxy 2-oxindole, as shown in Structural Formula 3:

[0012]

[0013] wherein R1 is selected from an electron-donating functional group or an electron-withdrawing functional group, R2 is selected from any one of an alkyl group, an alkenyl group, an alkynyl group and a phenyl group; and R3 is selected from any one of a hydrogen group, a methyl group and an N-ethylacetamide group.

[0014] Optimized, structural formula 1 is used as a substrate, and in the presence of an organic solvent, it reacts with structural formula 2a to synthesize 3-trifluoropropionyloxy 2-oxindole and structural formula 3. The synthetic route is shown in the following reaction formula:

[0015]

[0016] In the reaction formula, R1 in structural formula 1 is selected from an electron-donating functional group or an electron-withdrawing functional group; R2 is selected from any one of an alkyl group, an alkenyl group, an alkynyl group, and a phenyl group; R3 is selected from any one of hydrogen, a methyl group, and an N-ethylacetamide group; and the molar ratio of structural formula 1 to structural formula 2a during the reaction is 1:1.2-2.5.

[0017] Further optimized, the electron-donating functional group is selected from any one of methyl and methoxy; the electron-withdrawing functional group is selected from any one of fluorine, chlorine, bromine, trifluoromethyl, and methoxycarbonylmethyl.

[0018] Further optimized, the substitution position of R1 in Structural Formula 1 can be any of C4, C5, C6 and C7 of indole, and the substitution position of R1 on the indole ring in Structural Formula 3 is the same as that in Structural Formula 1.

[0019] Further optimized, the organic solvent is selected from one or more of toluene, dichloromethane, N-methylformamide, N,N-dimethylformamide, tetrahydrofuran, acrylonitrile, acetonitrile, and methanol.

[0020] Further optimized, the organic solvent is selected from dichloromethane.

[0021] Further optimized, the reaction temperature is 20-150°C and the reaction time is 4-24 hours.

[0022] Further optimized, the reaction temperature is 20-100°C.

[0023] Further optimized, the reaction temperature was 70°C.

[0024] Further optimized, the molar ratio of the structural formula 1 to the structural formula 12a is 1:1.8-2.0.

[0025] Further optimized, the alkyl group refers to any one of methyl, ethyl, propyl, butyl and benzyl.

[0026] Further optimized, the R2 is selected from methyl.

[0027] Further optimized, the R1 is selected from bromine, and R1 is preferably 5-bromo-N-methylindole.

[0028] The present invention provides a 3-trifluoropropionyloxy-2-oxindole having a structure as shown in Structural Formula 3:

[0029]

[0030] wherein R1 is selected from an electron-donating functional group or an electron-withdrawing functional group, R2 is selected from any one of an alkyl group, an alkenyl group, an alkynyl group and a phenyl group; and R3 is selected from any one of a hydrogen group, a methyl group and an N-ethylacetamide group.

[0031] Optionally, the electron-donating functional group is selected from any one of methyl, hydrogen or methoxy; and the electron-withdrawing functional group is selected from any one of fluorine, chlorine, bromine, trifluoromethyl and methoxycarbonylmethyl.

[0032] Optionally, the alkyl group includes any one of a methyl group, an ethyl group, a propyl group, a butyl group and a benzyl group.

[0033] The present invention provides a method for preparing 3-trifluoropropionyloxy-2-oxindole, which is used to prepare the above-mentioned 3-trifluoropropionyloxy-2-oxindole, comprising: reacting a substrate having structural formula 1 with a reactant having structural formula 2a in an organic solvent to synthesize 3-trifluoropropionyloxy-2-oxindole shown in structural formula 3. The synthesis route is shown in the following reaction formula:

[0034]

[0035] In the reaction formula, R1 in structural formula 1 is selected from an electron-donating functional group or an electron-withdrawing functional group; R2 is selected from any one of an alkyl group, an alkenyl group, an alkynyl group and a phenyl group; and R3 is selected from any one of hydrogen, a methyl group and an N-ethylacetamide group.

[0036] Optionally, the molar ratio of the substrate having structural formula 1 to the reactant having structural formula 2a is 1:1.2-2.5.

[0037] Optionally, the substitution position of R1 in Structural Formula 1 is any one of C4, C5, C6 and C7 of indole, and the substitution position of R1 on the indole ring in Structural Formula 3 is the same as that in Structural Formula 1.

[0038] Optionally, the reaction temperature is 20-150°C.

[0039] The present invention also provides the use of the above-mentioned 3-trifluoropropionyloxy-2-oxindole and the above-mentioned preparation method in the preparation of anticancer drugs.

[0040] Compared with the prior art, the present invention can achieve at least one of the following beneficial effects:

[0041] The present invention provides a C3-trifluoropropionyloxylation reaction of N-substituted indoles, which uses a high-valent iodine compound as an oxidant and a fluorine source, and does not require a transition metal catalyst. Since no toxic metal catalysts or harsh reaction conditions are used, the method of the present invention is more environmentally friendly and reduces environmental pollution and operational risks.

[0042] The present invention introduces fluorine into the molecule to improve its physicochemical properties, metabolic stability, and bioavailability. Introducing fluorine or fluorine-containing functional groups into privileged backbones is one of the most important strategies for discovering and developing lead compounds, as fluorine or fluorine-containing groups can enhance their acidity, metabolic stability, and bioavailability. The present invention introduces a trifluoropropionyloxy group into the indolinone backbone to obtain 3-trifluoropropionyloxyindolin-2-one, which enhances its biological activity and provides a foundation for the subsequent development of active compounds.

[0043] The method of the present invention is applicable to a variety of N-substituted indoles, whether N-alkyl, N-acyl or other electron-attracting or electron-donating groups, and can effectively react to generate target products, showing a wide range of substrate compatibility.

[0044] This method is carried out under relatively mild conditions (room temperature, with an optimal temperature of 70°C), does not require harsh reaction conditions, is easy to operate, and is highly safe. It overcomes the harsh reaction conditions required by some existing synthesis methods, such as high temperature, high pressure, or strong acid and strong base.

[0045] By optimizing the reaction conditions, the method of the present invention can generate the target product 3-trifluoropropionyloxy-2-oxindole with high selectivity, few by-products, high yield and high purity, thereby simplifying the subsequent purification process.

[0046] In the present invention, the above-mentioned technical solutions can also be combined with each other to achieve more preferred combination solutions. Other features and advantages of the present invention will be described in the subsequent description, and some advantages may become obvious from the description or be understood through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The hydrogen spectrum of the product 5-bromo-1-methyl-2-oxindol-3-yl 3,3,3-trifluoropropanoate (3aa) in Example 1;

[0048] Figure 2 The carbon spectrum of the product 5-bromo-1-methyl-2-oxindol-3-yl 3,3,3-trifluoropropanoate (3aa) in Example 1;

[0049] Figure 3 The fluorine-NMR spectrum of the product 5-bromo-1-methyl-2-oxindol-3-yl 3,3,3-trifluoropropanoate (3aa) in Example 1;

[0050] Figure 4 The hydrogen spectrum of the product 1-methyl-2-oxindol-3-yl 3,3,3-trifluoropropanoate (3ab) in Example 1;

[0051] Figure 5 The carbon spectrum of the product 1-methyl-2-oxindol-3-yl 3,3,3-trifluoropropanoate (3ab) in Example 1;

[0052] Figure 6 The fluorine-NMR spectrum of the product 1-methyl-2-oxindol-3-yl 3,3,3-trifluoropropanoate (3ab) in Example 1;

[0053] Figure 7 The hydrogen spectrum of the product 1,4-dimethyl-2-oxoindole-3-yl 3,3,3-trifluoropropionate (3ac) in Example 1;

[0054] Figure 8 The carbon spectrum of the product 1,4-dimethyl-2-oxoindole-3-yl 3,3,3-trifluoropropionate (3ac) in Example 1;

[0055] Figure 9 The fluorine-NMR spectrum of the product 1,4-dimethyl-2-oxoindole-3-yl 3,3,3-trifluoropropionate (3ac) in Example 1;

[0056] Figure 10 The hydrogen spectrum of the product 4-fluoro-1-methyl-2-oxoindole-3-yl-3,3-trifluoropropionate (3ad) in Example 1;

[0057] Figure 11The carbon spectrum of the product 4-fluoro-1-methyl-2-oxoindole-3-yl-3,3-trifluoropropionate (3ad) in Example 1;

[0058] Figure 12 The nuclear magnetic resonance fluorine spectrum of the product 4-fluoro-1-methyl-2-oxoindole-3-yl-3,3-trifluoropropionate (3ad) in Example 1;

[0059] Figure 13 Hydrogen spectrum of product 3as;

[0060] Figure 14 Carbon spectrum of product 3as;

[0061] Figure 15 NMR fluorine spectrum of product 3as;

[0062] Figure 16 Hydrogen spectrum of product 3aj;

[0063] Figure 17 Carbon spectrum of product 3aj;

[0064] Figure 18 Fluorine NMR spectrum of product 3aj;

[0065] Figure 19 Hydrogen spectrum of product 3an;

[0066] Figure 20 Product 3an carbon spectrum;

[0067] Figure 21 NMR fluorine spectrum of product 3an;

[0068] Figure 22 Hydrogen spectrum of product 3bh;

[0069] Figure 23 Carbon spectrum of product 3bh;

[0070] Figure 24 Fluorine NMR spectrum of product 3bh;

[0071] Figure 25 Product 3at hydrogen spectrum;

[0072] Figure 26 Product 3at carbon spectrum;

[0073] Figure 27 3at NMR fluorine spectrum of the product;

[0074] Figure 28 Hydrogen spectrum of product 3ae;

[0075] Figure 29 Carbon spectrum of product 3ae;

[0076] Figure 30Fluorine NMR spectrum of product 3ae;

[0077] Figure 31 Hydrogen spectrum of product 3af;

[0078] Figure 32 Carbon spectrum of product 3af;

[0079] Figure 33 NMR fluorine spectrum of product 3af;

[0080] Figure 34 Hydrogen spectrum of product 3ag;

[0081] Figure 35 Carbon spectrum of product 3ag;

[0082] Figure 36 Fluorine NMR spectrum of product 3ag;

[0083] Figure 37 Hydrogen spectrum of product 3ah;

[0084] Figure 38 Carbon spectrum of product 3ah;

[0085] Figure 39 Fluorine NMR spectrum of product 3ah;

[0086] Figure 40 Hydrogen spectrum of product 3ai;

[0087] Figure 41 C-spectrometry of product 3ai;

[0088] Figure 42 NMR fluorine spectrum of product 3ai;

[0089] Figure 43 Hydrogen spectrum of product 3ak;

[0090] Figure 44 C-spectrometry of product 3ak;

[0091] Figure 45 Fluorine NMR spectrum of product 3ak;

[0092] Figure 46 Product 3al hydrogen spectrum;

[0093] Figure 47 Product 3al carbon spectrum;

[0094] Figure 48 3al NMR fluorine spectrum of the product;

[0095] Figure 49 Product 3am hydrogen spectrum;

[0096] Figure 50 Product 3am carbon spectrum;

[0097] Figure 51 Fluorine NMR spectrum of product 3am;

[0098] Figure 52 Hydrogen spectrum of product 3ao;

[0099] Figure 53 Product 3ao carbon spectrum;

[0100] Figure 54 NMR fluorine spectrum of product 3ao;

[0101] Figure 55 Product 3ap hydrogen spectrum;

[0102] Figure 56 Carbon spectrum of product 3ap;

[0103] Figure 57 NMR fluorine spectrum of product 3ap;

[0104] Figure 58 Hydrogen spectrum of product 3aq;

[0105] Figure 59 Carbon spectrum of product 3aq;

[0106] Figure 60 Fluorine NMR spectrum of product 3aq;

[0107] Figure 61 Product 3ar hydrogen spectrum;

[0108] Figure 62 Product 3ar carbon spectrum;

[0109] Figure 63 3ar NMR fluorine spectrum of the product;

[0110] Figure 64 Hydrogen spectrum of product 3ba;

[0111] Figure 65 Carbon spectrum of product 3ba;

[0112] Figure 66 NMR fluorine spectrum of product 3ba;

[0113] Figure 67 Hydrogen spectrum of product 3bb;

[0114] Figure 68 Product 3bb carbon spectrum;

[0115] Figure 69 NMR fluorine spectrum of product 3bb;

[0116] Figure 70 Proton spectrum of product 3bc;

[0117] Figure 71Product 3bc carbon spectrum;

[0118] Figure 72 Fluorine NMR spectrum of product 3bc;

[0119] Figure 73 Proton spectrum of product 3bg;

[0120] Figure 74 Carbon spectrum of product 3bg;

[0121] Figure 75 Fluorine NMR spectrum of product 3bg;

[0122] Figure 76 Hydrogen spectrum of product 3bi;

[0123] Figure 77 Carbon spectrum of product 3bi;

[0124] Figure 78 NMR fluorine spectrum of product 3bi;

[0125] Figure 79 Hydrogen spectrum of product 3bj;

[0126] Figure 80 Carbon spectrum of product 3bj;

[0127] Figure 81 Fluorine NMR spectrum of product 3bj;

[0128] Figure 82 Product 3bk hydrogen spectrum;

[0129] Figure 83 Carbon spectrum of product 3bk;

[0130] Figure 84 Fluorine NMR spectrum of product 3bk;

[0131] Figure 85 Hydrogen spectrum of product 3bl;

[0132] Figure 86 Carbon spectrum of product 3bl;

[0133] Figure 87 NMR fluorine spectrum of product 3bl. DETAILED DESCRIPTION

[0134] The preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings, wherein the accompanying drawings constitute a part of the present invention and are used together with the embodiments of the present invention to illustrate the principles of the present invention, but are not used to limit the scope of the present invention.

[0135] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this invention pertains. The terms used in the specification of this invention are intended only to describe specific embodiments and are not intended to limit this invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0136] The present invention, by adopting a high-valent iodine compound as a mediator, not only overcomes many deficiencies in the prior art, but also provides a highly efficient, environmentally friendly, widely applicable and easy-to-operate synthesis method, providing an important technical means for preparing 3-trifluoropropionyloxy-2-oxindole and its derivatives, and has broad application prospects.

[0137] In a first aspect, the present invention provides a 3-trifluoropropionyloxy-2-oxindole having a structure as shown in Structural Formula 3:

[0138]

[0139] wherein R1 is selected from an electron-donating functional group or an electron-withdrawing functional group, R2 is selected from any one of an alkyl group, an alkenyl group, an alkynyl group and a phenyl group; and R3 is selected from any one of a hydrogen group, a methyl group and an N-ethylacetamide group.

[0140] Specifically, the substitution position of R1 in structural formula 1 is any of C4, C5, C6, and C7 of indole. The electron-donating functional group is selected from any one of methyl, hydrogen, and methoxy; and the electron-withdrawing functional group is selected from any one of fluorine, chlorine, bromine, trifluoromethyl, and methoxycarbonylmethyl.

[0141] The alkyl group includes any one of a methyl group, an ethyl group, a propyl group, a butyl group and a benzyl group.

[0142] The organic solvent is selected from one or more of toluene, dichloromethane, N-methylformamide, N,N-dimethylformamide, tetrahydrofuran, acrylonitrile, acetonitrile and methanol.

[0143] In a second aspect, the present invention provides a method for preparing 3-trifluoropropionyloxy-2-oxindole, which is used to prepare the above-mentioned 3-trifluoropropionyloxy-2-oxindole, comprising: reacting a substrate having structural formula 1 with a reactant having structural formula 2a in an organic solvent to synthesize 3-trifluoropropionyloxy-2-oxindole shown in structural formula 3. The synthesis route is shown in the following reaction formula:

[0144]

[0145] In the reaction formula, R1 in structural formula 1 is selected from an electron-donating functional group or an electron-withdrawing functional group; R2 is selected from any one of an alkyl group, an alkenyl group, an alkynyl group and a phenyl group; and R3 is selected from any one of hydrogen, a methyl group and an N-ethylacetamide group.

[0146] The above preparation method comprises the following steps:

[0147] Step 1: mixing a substrate having structural formula 1 and an organic solvent to obtain a mixture;

[0148] Step 2: adding a reactant having structural formula 2a to the mixture of step 1 and reacting for a period of time to obtain a reaction mixture;

[0149] Step 3: Work-up to afford 3-trifluoropropionyloxy-2-oxindole.

[0150] Specifically, the molar ratio of the substrate having structural formula 1 to the reactant having structural formula 2a is 1:1.2-2.5, for example, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5.

[0151] In step 1, the molar (unit: mmol) volume (unit: mL) ratio of the substrate to the organic solvent is 0.2:(0.5-3), for example, 0.2:0.5, 0.2:1, 0.2:1.5, 0.2:2.5, 0.2:3.

[0152] In step 2, the reaction temperature is 20-150°C, for example, 20°C, 30°C, 50°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 120°C, 140°C, 150°C.

[0153] In step 2, the reaction time is 4-24 h, for example, 4 h, 4.5 h, 5 h, 5.5 h, 6 h, 6.5 h, 7 h, 7.5 h, 8 h, 10 h, 12 h, 14 h, 15 h, 18 h, 20 h, 22 h, 24 h.

[0154] The electron-donating functional group is selected from any one of methyl, hydrogen or methoxy; the electron-withdrawing functional group is selected from any one of fluorine, chlorine, bromine, trifluoromethyl and methoxycarbonylmethyl.

[0155] The alkyl group includes any one of a methyl group, an ethyl group, a propyl group, a butyl group and a benzyl group.

[0156] The organic solvent is selected from one or more of toluene, dichloromethane, N-methylformamide, N,N-dimethylformamide, tetrahydrofuran, acrylonitrile, acetonitrile and methanol.

[0157] The substitution position of R1 in Structural Formula 1 is any one of C4, C5, C6 and C7 of indole. The substitution position of R1 on the indole ring in Structural Formula 3 is the same as that in Structural Formula 1.

[0158] In step 3, post-processing includes concentration and purification. Specifically, it includes: concentrating the reaction mixture of step 2 under vacuum to obtain a residue, purifying the residue by flash chromatography on a silica gel column, and eluting to obtain 3-trifluoropropionyloxy-2-oxindole. The eluent is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the two is petroleum ether:ethyl acetate = 10:1 to 2:1, for example, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1.

[0159] In a third aspect, the present invention provides a use of the above-mentioned 3-trifluoropropionyloxy-2-oxindole and the above-mentioned preparation method in the preparation of anticancer drugs.

[0160] The preparation method of the present invention is described in detail below with reference to specific examples.

[0161] Example 1

[0162] 5-Bromo-1-methylindole (1) was selected as a model substrate, and the reactant had the structural formula 2a. 2a was added all at once to optimize the conditions for the oxidative dearomatization trifluoropropionyloxylation reaction. See reaction formula (1). The reaction conditions for reactions 1-11 were 40°C in the reaction solvent listed in Table 1 for 4 hours. The reaction conditions for reaction 12 were 4 hours at room temperature (the room temperature on the day of the experiment was approximately 20°C) in the reaction solvent listed in Table 1. The reaction conditions for reaction 13 were 70°C in the reaction solvent listed in Table 1 for 4 hours. The reaction conditions for reaction 14 were 100°C in the reaction solvent listed in Table 1 for 4 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum.

[0163] Specifically, in the reaction No. 13 in Table 1, the volume ratio of the eluent petroleum ether:ethyl acetate when determining the separation yield was 10:1.

[0164] In addition, unless otherwise specified, the processes of the present invention are all existing processes. For example, vacuum concentration, silica gel column flash chromatography, elution, etc. all adopt existing processes.

[0165] 1 reacts with 2a to produce the target product, 3-trifluoropropionyloxy-2-oxindole 3aa. In this example, the reaction was performed at a scale of 0.2 mmol for 1 and 1.0 mL for 1. The yield of 3aa was determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard. The reaction yields are shown in Table 1.

[0166] From the results in Table 1, it can be seen that when the equivalents of the reaction of 1 and 2a remain unchanged, that is, the molar ratio of 1 and 2a remains unchanged at 1:2, the effects of different solvents on the results were investigated in Nos. 1-7, 15-16. The results show that DCM is a better reaction medium than other solvents including DMF, THF, MeCN and MeOH, with a yield of 45% (No. 7).

[0167] Sequence numbers 7-11 investigated and evaluated the effect of the molar ratio between 2a and 1 on the results. Adjusting the 1:2a molar ratio from 1:2.0 to 1:1.8 resulted in comparable product yields (Sequence number 8). Further reducing the amount of 2a to 1.5 equivalents resulted in a lower yield (Sequence number 9). Furthermore, when the 1:2a molar ratio was 1:1.2, only a small amount of 3aa was detected, accompanied by the formation of the major product, 5-bromo-1-methylindolin-2-one 6a (Sequence number 10). When the 1:2a molar ratio was 1:3.0 equivalents, no product was formed, and the starting material 1 was converted to 5-bromo-1-methylindolin-2,3-dione 5a (Sequence number 11).

[0168] In addition, the reaction temperature was also investigated in this example, see No. 12-14, and it was found that 70° C. was the best choice for the reaction (No. 13).

[0169] (1)

[0170] Table 1. Optimization of reaction conditions

[0171]

[0172]

[0173] b The yield was determined by ^1H NMR using 1,3,5-trimethoxybenzene as the internal standard.

[0174] Example 2

[0175] In this embodiment, the molar ratio of 1 and 2a is 1:1.8, and the amount of 1 is 0.2 mmol, and the organic solvent used is dichloromethane in an amount of 1.0 mL; 2a, i.e., benzene-λ3-iodine diylbis(3,3,3-trifluoropropionate, 0.36 mmol), is added to the mixture of 1 and dichloromethane, and the mixture is stirred at 70 degrees Celsius (using a heating module) for 4 hours. After the reaction is completed, the reaction mixture is concentrated under vacuum. The residue is purified by flash chromatography on a silica gel column using a mixture of petroleum ether and ethyl acetate as an eluent to obtain the desired product 3.

[0176] Specifically, in the reactions of sequence numbers 1-5, 7, 8, 11, 12, 15, and 17-20 in Table 2, the volume ratio of petroleum ether: ethyl acetate during elution was 10:1; in the reaction of sequence number 6 in Table 2, the volume ratio of petroleum ether: ethyl acetate during elution was 9:1; in the reaction of sequence number 9 in Table 2, the volume ratio of petroleum ether: ethyl acetate during elution was 6:1; in the reactions of sequence numbers 10 and 16 in Table 2, the volume ratio of petroleum ether: ethyl acetate during elution was 8:1; in the reaction of sequence number 13 in Table 2, the volume ratio of petroleum ether: ethyl acetate during elution was 4:1; in the reaction of sequence number 14 in Table 2, the volume ratio of petroleum ether: ethyl acetate during elution was 2:1;.

[0177] This example is shown in reaction formula (2), which mainly investigates the effects of indoles with various functional groups on the benzene ring R1 on the reaction product 3aa. In the reaction formula, the reaction results of different substitution situations of R1 are shown in Table 2.

[0178] (2)

[0179] Table 2. Indole reactivity of R1 functional group

[0180]

[0181]

[0182] Note: Except for those specified in No. 2 and No. 14, R2 of reactant 1 in the remaining reactions is methyl and R3 is H. The yields in Table 2 are isolated yields.

[0183] Results showed that both electron-donating (-Me, -OMe) and electron-withdrawing (-F, -Cl, -Br, -CF3, -CO2Me) functional groups were tolerated, affording the target products 3aa-3at in yields of 29%-78%. The retained halogen groups in the products provide opportunities for further derivatization. Generally, electron-poor substituted indoles react more efficiently than electron-rich substituted indoles (e.g., 3ac with 3ad-3af; 3am, 3an with 3ao, 3ap), as the latter are easily oxidized to form unwanted byproducts. Furthermore, the reaction is insensitive to the position of the substituents on the phenyl ring. 3-Methylindole underwent this oxidative trifluoropropionyl oxidation smoothly, yielding the product in 63% (3as). Reaction No. 14 in Table 2, where the corresponding substrate 1 is melatonin (a drug that can improve sleep quality), was also amenable to this reaction, but with slightly lower yields (3at). However, free NH and 6-CN indoles failed to yield the target product, with the formation of an unknown mixture.

[0184] Example 3

[0185] In this embodiment, the molar ratio of 1 and 2a is 1: 1.8, and the amount of 1 is 0.2 mmol, and the organic solvent used is dichloromethane in an amount of 1.0 mL; 2a, i.e., benzene-λ3-iodine diylbis(3,3,3-trifluoropropionate, 0.36 mmol), is added to the mixture of 1 and dichloromethane, and the mixture is stirred at 70 degrees Celsius (using a heating module) for 4 hours. After the reaction is completed, the reaction mixture is concentrated under vacuum. The residue is purified by flash chromatography on a silica gel column using a mixture of petroleum ether and ethyl acetate as an eluent to obtain the desired product 3.

[0186] Specifically, in the reactions of sequence numbers 1 and 2 in Table 3, the volume ratio of petroleum ether: ethyl acetate during elution was 9:1; in the reactions of sequence numbers 3, 5, and 6 in Table 3, the volume ratio of petroleum ether: ethyl acetate during elution was 7:1; in the reactions of sequence numbers 4, 7, and 8 in Table 3, the volume ratio of petroleum ether: ethyl acetate during elution was 5:1; and in the reaction of sequence number 9 in Table 3, the volume ratio of petroleum ether: ethyl acetate during elution was 4:1.

[0187] In the structural formula 1 used in this example, R1 is bromine substituted at the C5 position, and R3 is hydrogen. Indoles with various functional groups at R2 were investigated, as shown in reaction formula (2). In reaction formula (2), the reaction results for different substitutions of R2 are shown in Table 3.

[0188] Table 3. Indole reactivity of R2 functional group

[0189]

[0190]

[0191] Note: 3ba, R3 is H; the yields in the table are isolated yields.

[0192] Indoles bearing various protecting groups R2 on the nitrogen atom were studied. Alkyl groups such as ethyl (3ba), propyl (3bb), butyl (3bc), and benzyl (3bj, 3bk) proved feasible, affording the corresponding 3-trifluoropropionyloxy-2-oxindole (3aa) in good yield. Notably, alkenyl (3bh) and alkynyl (3bi) groups were also successful. Furthermore, this oxidative trifluoropropionyl oxidation reaction is not limited to N-alkyl-substituted indoles; an N-phenyl-containing indole was also converted to the product (3bl) in 41% yield.

[0193] Example 4

[0194] In this embodiment, the molar ratio of 1 and 2a is 1: 1.8, and the amount of 1 is 0.2 mmol, and the organic solvent used is dichloromethane in an amount of 1.0 mL; 2a, i.e., benzene-λ3-iodine diylbis(3,3,3-trifluoropropionate, 0.36 mmol), is added to the mixture of 1 and dichloromethane, and the mixture is stirred at 70 degrees Celsius (using a heating module) for 4 hours. After the reaction is completed, the reaction mixture is concentrated under vacuum. The residue is purified by flash chromatography on a silica gel column using a mixture of petroleum ether and ethyl acetate as an eluent to obtain the desired product 3.

[0195] In this embodiment, the R2 substituent is a methyl group. This embodiment examines indoles with various functional groups at R3, as shown in reaction formula (2). In the reaction formula, the reaction results of different substitution situations of R3 are shown in Table 4.

[0196] Table 4. Indole reaction of R3 functional group

[0197]

[0198] Note: The yields in the table are isolated yields.

[0199] Example 5

[0200] To verify the applicability of the hypervalent iodine-induced indole trifluoropropionyl oxidation reaction, a gram-scale experiment was conducted using 5-bromo-N-methylindole (1a) as the substrate (see reaction equation (3)). 5-Bromo-N-methylindole was used in an amount of 1.04 g, 5 mmol, with a molar ratio of 2a to 1 of 1:1.8. The reaction was carried out in DCM as the organic solvent, at a temperature of 40°C, for 4 hours. The corresponding 3-trifluoropropionyloxy-2-oxindole product was obtained in a yield of 51%.

[0201] (3)

[0202] It can be seen from Example 5 that the preparation method of the present invention is still applicable after being scaled up, thereby verifying the feasibility of the reaction.

[0203] Example 6

[0204] This example summarizes a potential reaction mechanism of the present invention, as shown in reaction formula (4). First, intermediate A is generated through nucleophilic attack of 1 and 2a; iodine undergoes intramolecular nucleophilic attack on the imine to generate iodomethane salt B, which is converted to C through a ring-opening reaction promoted by the trifluoropropionate anion; when R is an acyl group, C undergoes deprotonation to generate 3-trifluoropropionyloxyindole product 4 (path a). On the other hand, intermediate C is converted to D through intramolecular nucleophilic attack (path b). Water acts as a nucleophile to attack D, subsequently losing a trifluoropropionate anion to generate F. F undergoes aromatization to generate enolate G, which reacts as a nucleophile with 2a to generate H. H undergoes a nucleophilic substitution reaction with the trifluoropropionate anion to generate 3-trifluoropropionyloxy-2-oxindole product 3.

[0205] (4)

[0206] Example 7

[0207] The reaction conditions of this embodiment are basically the same as those of embodiment No. 12 in Table 2, except that the reaction temperature is 20° C., the reaction time is 8 h, and the yield of the obtained product is 76%.

[0208] Example 8

[0209] The reaction conditions of this embodiment are basically the same as those of embodiment No. 12 in Table 2, except that the reaction temperature is 50° C., the reaction time is 6 h, and the yield of the obtained product is 77%.

[0210] Example 9

[0211] The reaction conditions of this embodiment are basically the same as those of embodiment No. 12 in Table 2, except that the reaction temperature is 80° C., the reaction time is 5 h, and the yield of the obtained product is 75%.

[0212] Example 10

[0213] The reaction conditions of this embodiment are basically the same as those of embodiment No. 12 in Table 2, except that the reaction temperature is 100° C., the reaction time is 4 h, and the yield of the obtained product is 73%.

[0214] Depend on Figure 1-3 It can be confirmed that the expected product 5-bromo-1-methyl-2-oxindol-3-yl 3,3,3-trifluoropropanoate (3aa) is obtained by the preparation method of the present invention.

[0215] Depend on Figure 4-6 It can be confirmed that the expected product 1-methyl-2-oxindol-3-yl 3,3,3-trifluoropropanoate (3ab) is obtained by the preparation method of the present invention.

[0216] Depend on Figure 7-9It can be confirmed that the expected product 1,4-dimethyl-2-oxoindole-3-yl 3,3,3-trifluoropropionate (3ac) is obtained by the preparation method of the present invention.

[0217] Depend on Figure 10-12 It can be confirmed that the expected product 4-fluoro-1-methyl-2-oxoindole-3-yl-3,3-trifluoropropionate (3ad) is obtained by the preparation method of the present invention.

[0218] Depend on Figure 16-18 It can be confirmed that the expected product 3aj is obtained by the preparation method of the present invention.

[0219] Specifically, 3aj was a pink solid (38.1 mg, 60% yield), R f =0.44(PE:EA=5:1).

[0220] Figure 16 middle, 1 H NMR (500MHz, CDCl3) δ7.36 (d, J = 8.3Hz 1H), 7.33 (s, 1H), 6.78 (d, J = 8.3Hz, 1H), 5.96 (s, 1H), 3.40-3.28 (m, 2H), 3.21 (s, 3H).

[0221] Figure 17 middle, 13 C NMR (126MHz, CDCl3) δ 170.8, 163.7 (q, J = 4.6Hz), 143.2, 130.8, 128.9, 126.2, 124.9, 123.1 (q, J = 276.6Hz), 109.8, 70.5, 39.4 (q, J = 31.4Hz), 26.7.

[0222] Figure 18 middle, 19 F NMR (471MHz, CDCl3) δ-63.31.

[0223] in addition, Figure 19-Figure 87 The hydrogen spectrum, carbon spectrum and nuclear magnetic resonance fluorine spectrum of other product 3 synthesized by the present invention can confirm that the expected product is obtained through the spectrum.

[0224] Application Example 1

[0225] This application example tests the in vitro anticancer activity of some 3-trifluoropropionyloxy-2-oxindoles synthesized in Examples 1-6.

[0226] The in vitro anticancer activities of the 11 target products synthesized in the present invention (see Table 5) against human leukemia cells (K562) and prostate cancer cells (PC-3) were evaluated using the MTT method (tetrazolium reduction method) with cisplatin as a positive control. The inhibitory activity against tumor cell growth was expressed as IC50 (half inhibitory concentration). The specific experimental results are shown in Table 6.

[0227] MTT method: dissolve the target product in a small amount of DMSO to prepare 10mmol·L -1 The stock solution was diluted to the required concentrations using RPMI1640 culture medium (GIBICO, Invitrogen) containing 10% fetal bovine serum, which were: 50 μmol·L -1 , 10 μmol·L -1 , 1 μmol·L -1 , 0.1 μmol·L -1 , 10 nmol·L -1 , 0.1 nmol·L -1 , maintaining the final DMSO concentration below 0.1%. Human leukemia cells (K562) and prostate cancer cells (PC-3) were cultured in RPMI1640 medium containing 10% fetal bovine serum in an incubator with a CO2 volume fraction of 5% at 37°C. Cell proliferation and growth inhibition were assessed using the MTT assay. The number of experimental cells was adjusted to obtain an absorbance of 1.3 to 2.2 at 570 nm. The cells were treated with the target product test solution at each of the six concentrations for 72 hours. The experiment was repeated at least three times in triplicate for each concentration. Statistical analysis was performed using GraphPad Prism 5.0 software to determine the IC50 value.

[0228] Table 5 Some target products of the present invention

[0229]

[0230]

[0231] Table 6 Anticancer activity of some target products of the present invention

[0232]

[0233]

[0234] Note: IC50 (half inhibitory concentration) refers to the drug concentration required to inhibit 50% cell growth. The lower the IC50 value, the stronger the drug activity.

[0235] As can be seen from Table 6, the IC50 of compounds 1-11 of the present application against human leukemia cells (K562) is 13.1-36.8 μmol·L -1The IC50 for prostate cancer cells (PC-3) is 13.9-37.2 μmol·L -1 , indicating that compounds 1-11 of the present application have inhibitory effects on the proliferation of both tumor cells. Compound 4 has significantly better inhibitory activity against K562 than cisplatin. Compounds 1, 3, 8, 9, 10, and 11 have inhibitory activities comparable to cisplatin. The inhibitory activities of the remaining compounds are slightly weaker than cisplatin. Compound 4 has the strongest inhibitory activity against K562 (IC50 = 13.1 μmol·L-1), which is 1.85 times that of cisplatin.

[0236] It can also be seen from Table 6 that the inhibitory activities of compounds 4 and 9 against PC-3 are significantly better than those of cisplatin. The inhibitory activities of compounds 1, 2, 3, 7, 8, and 10 are comparable to those of cisplatin. The inhibitory activities of the remaining compounds are slightly weaker than those of cisplatin. Compound 9 has the strongest inhibitory activity against PC-3 (IC50 = 13.9 μmol·L -1 ), which is 1.94 times that of cisplatin.

[0237] In addition to some of the target products listed in Table 5, the anticancer activities of other products are reasonably predicted:

[0238] The product with 3ab structure synthesized in the present invention has only one less methyl group at the C3 position compared with the product with 3as structure in Table 5 and Table 6, so it can be predicted that 3ab has anticancer activity.

[0239] The products of the structures 3ac, 3ae, and 3af synthesized in the present invention and the products of the structure 3ad in Tables 5 and 6 are all substituted at the R1C4 position, and only the substituent at the C4 position is different. It can be predicted that 3ac, 3ae, and 3af have anticancer activity.

[0240] The products of the structures 3aa, 3ag, 3ah, 3ai, 3aj, and 3al synthesized in the present invention and the products of the structure 3ak in Tables 5 and 6 all have R1C5 substitutions, and only the C5 substituent is different. It can be predicted that 3aa, 3ag, 3ah, 3ai, 3aj, and 3al have anticancer activity.

[0241] The products of the structures 3am, 3ao, and 3ap synthesized in the present invention and the products of the structure 3an in Tables 5 and 6 are all substituted at the R1C6 position, and only the substituent at the C6 position is different. It can be predicted that 3am, 3ao, and 3ap have anticancer activity.

[0242] The products of structure 3aq synthesized in the present invention and the products of structure 3ar in Tables 5 and 6 are both substituted at R1C7, with only the substituent at C7 being different. It can be predicted that 3aq has anticancer activity.

[0243] Compared with the product with structure 3bc in Tables 5 and 6, the products with structures 3ba and 3bb synthesized in the present invention have only R2 substituents changed from butyl to ethyl and propyl, respectively. It can be predicted that 3ba and 3bb have anticancer activity.

[0244] Compared with the product with structure 3bg in Tables 5 and 6, the products with structures 3bh and 3bi synthesized in the present invention have only the R2 substituent changed from acetoxyethyl to propenyl and alkynyl. It can be predicted that 3bh and 3bi have anticancer activity.

[0245] In summary, 3-trifluoropropionyloxy-2-oxindole is a class of compounds with anticancer activity.

[0246] This invention develops a highly efficient method for preparing 3-trifluoropropionyloxy-2-oxindole by oxidizing N-substituted indoles with (bistrifluoropropionate)iodobenzene. The reaction exhibits good tolerance to a variety of functional groups. Furthermore, when an acyl group is pre-installed on the nitrogen atom, 3-trifluoropropionyloxyindole can be obtained. The invention also discusses the reaction mechanism.

[0247] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by any technician familiar with this technical field within the technical scope disclosed by the present invention should be covered by the scope of protection of the present invention.

Claims

1. Use of 3-trifluoropropionyloxy-2-oxindole in the preparation of drugs for treating human leukemia cells K562 and prostate cancer cells PC-3, wherein the 3-trifluoropropionyloxy-2-oxindole has the structure shown in the following formula: 。

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