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

Abstract

The invention relates to a-C3-trifluoropropionyloxylation reaction of N-substituted indole, 3-trifluoropropionyloxy-2-oxindole as well as a preparation method and application of the 3-trifluoropropionyloxy-2-oxindole, belongs to the technical field of synthesis of heterocyclic compounds, and solves the problems that a transition metal catalyst used in the existing method is unfriendly to the environment, limited in substrate range, harsh in reaction condition, more in by-products, low in cost and the like. The target product is low in yield, low in purity and the like. According to the method, bis (trifluoropropionate) iodobenzene is adopted as an oxidizing agent and a fluorine source, reaction is carried out in an organic solvent, and the method is suitable for various N-substituted indoles including N-methyl, N-ethyl, N-propyl, N-butyl and N-benzyl indoles. The method does not need to use a transition metal catalyst, has higher environmental protection property and operation safety, mild reaction conditions, high yield, good selectivity and few byproducts, can be used for efficiently and environmentally preparing the 3-trifluoropropionyloxy-2-oxindole and the derivative thereof, and provides an important technical means for drug development and organic synthesis.

Description

Technical Field

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

[0002] As an important chemical structure, 2-oxindole is considered a privileged scaffold and is widely distributed in various drugs and natural products. Among them, 3-functionalized oxindole is a key building block for the synthesis of various alkaloids and drug lead compounds. Therefore, the synthesis of these important structural units has received extensive attention. Currently, a variety of methods have been developed to prepare 3-acyl-oxindoles. The traditional method for synthesizing 3-acyl-oxindoles is through the nucleophilic addition reaction of 3-hydroxyoxindole with acid anhydride under basic conditions. For example, Lu reported a method for preparing 3-acyl-oxindoles by the hydroacylation reaction of isatin with aldehydes catalyzed by N-heterocyclic carbenes. Maurya synthesized 3-acyl-oxindoles through the coupling reaction of isatin with phenylacetyl azide catalyzed by DBU.

[0003] Indole is a commercially available material, and its dearomatization functionalization is considered an effective strategy for constructing various 3-functionalized oxindoles. Under the action of different transition metal catalysts, significant progress has been made in the allylation, arylation, and cycloaddition reactions of indole through the dearomatization process. In the prior art, although some progress has been made in the synthesis methods of 3-functionalized oxindoles, there are still the following deficiencies:

[0004] Catalyst dependence: Many existing methods rely on transition metal catalysts, which are usually expensive and potentially toxic, and may pose hazards 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, it is difficult for the prior art to be applicable to various different N-substituents.

[0006] Harsh reaction conditions: Some methods require harsh reaction conditions such as high temperature, high pressure, or strong acids and bases, increasing the complexity and cost of operation.

[0007] By-product formation: In some synthetic routes, there are many by-products and the purification process is complex, resulting in the yield and purity of the target product being affected.

[0008] Moreover, there are few reports on obtaining 3-acyl-oxindoles by the dearomatization of indole under metal-free conditions. In this context, it is very necessary to develop a more efficient and general preparation method for 3-acyl-oxindoles. 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 at least solve one of the following technical problems: (1) The existing methods use transition metal catalysts, which are not environmentally friendly and harmful to operators; (2) The substrate scope is limited; (3) The reaction conditions are harsh; (4) There are many by-products and the purification is complex; (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 N-substituted indole, reacting to obtain 3-trifluoropropionyloxy-2-oxindole, as shown in Structural Formula 3:

[0012]

[0013] In the formula, 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; R3 is selected from any one of hydrogen, a methyl group and an N-ethylacetamido group.

[0014] Optimally, using Structural Formula 1 as the substrate, in the presence of an organic solvent, reacting with Structural Formula 2a, to synthesize 3-trifluoropropionyloxy-2-oxindole and Structural Formula 3, and the synthesis route is shown in the following reaction formula:

[0015]

[0016] In the reaction formula, in Structural Formula 1, 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; R3 is selected from any one of hydrogen, a methyl group and an N-ethylacetamido group; when reacting, the molar ratio of Structural Formula 1 to Structural Formula 2a is 1:1.2 - 2.5.

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

[0018] Further optimally, the substitution position of R1 in Structural Formula 1 can be 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.

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

[0020] Further optimally, 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 is 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, which has the structure shown in structural formula 3:

[0029]

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

[0031] Optionally, the electron - donating functional group is selected from any one of methyl, hydrogen, and methoxy; 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 methyl, ethyl, propyl, butyl, and benzyl.

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

[0034]

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

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

[0037] Optionally, the substitution position of R1 in the 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 the structural formula 3 is the same as that in the 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 indole, using a hypervalent iodine compound as an oxidant and a fluorine source, without using a transition metal catalyst. Since no toxic metal catalyst and harsh reaction conditions are used, the method of the present invention is more environmentally friendly, reduces environmental pollution and operation risks.

[0042] Introducing fluorine into the molecule in the present invention can improve its physicochemical properties, metabolic stability, bioavailability, etc. Introducing fluorine or fluorine-containing functional groups into privileged skeletons is one of the most important strategies for discovering and developing lead compounds, because fluorine or fluorine-containing groups can improve their acidity, metabolic stability and bioavailability. The present invention introduces trifluoropropionyloxy into the indolinone skeleton to obtain 3-trifluoropropionyloxyindol-2-one, which can improve its biological activity and provide a basis for the subsequent development of active compounds.

[0043] The method of the present invention is applicable to various N-substituted indoles. Whether it is N-alkyl, N-acyl or other electron-withdrawing or electron-donating groups, they can all effectively react to generate the target product, showing wide substrate compatibility.

[0044] This method is carried out under relatively mild conditions (it can be carried out at room temperature, and the optimal temperature is 70 °C), does not require harsh reaction conditions, is easy to operate and has high safety. It overcomes the harsh reaction conditions such as high temperature, high pressure or strong acid and strong base required by some synthesis methods in the prior art.

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

[0046] In the present invention, the above technical solutions can also be combined with each other to achieve more preferred combined solutions. Other features and advantages of the present invention will be described in the subsequent description, and some advantages can be made obvious from the description, or can be understood by implementing the present invention. Description of the Drawings

[0047] Figure 1 1H NMR spectrum of a product 5-bromo-1-methyl-2-oxoindol-3-yl 3,3,3-trifluoropropionate (3aa) in the example;

[0048] Figure 2 13C NMR spectrum of a product 5-bromo-1-methyl-2-oxoindol-3-yl 3,3,3-trifluoropropionate (3aa) in the example;

[0049] Figure 3 19F NMR spectrum of a product 5-bromo-1-methyl-2-oxoindol-3-yl 3,3,3-trifluoropropionate (3aa) in the example;

[0050] Figure 4 1H NMR spectrum of a product 1-methyl-2-oxoindol-3-yl 3,3,3-trifluoropropionate (3ab) in the example;

[0051] Figure 5 13C NMR spectrum of a product 1-methyl-2-oxoindol-3-yl 3,3,3-trifluoropropionate (3ab) in the example;

[0052] Figure 6 19F NMR spectrum of a product 1-methyl-2-oxoindol-3-yl 3,3,3-trifluoropropionate (3ab) in the example;

[0053] Figure 7 1H NMR spectrum of a product 1,4-dimethyl-2-oxoindol-3-yl 3,3,3-trifluoropropionate (3ac) in the example;

[0054] Figure 8 13C NMR spectrum of a product 1,4-dimethyl-2-oxoindol-3-yl 3,3,3-trifluoropropionate (3ac) in the example;

[0055] Figure 9 19F NMR spectrum of a product 1,4-dimethyl-2-oxoindol-3-yl 3,3,3-trifluoropropionate (3ac) in the example;

[0056] Figure 10 1H NMR spectrum of a product 4-fluoro-1-methyl-2-oxoindol-3-yl 3,3,3-trifluoropropionate (3ad) in the example;

[0057] Figure 11Carbon spectrum of a product 4-fluoro-1-methyl-2-oxoindol-3-yl 3,3,3-trifluoropropionate (3ad) in the example;

[0058] Figure 12 19F NMR spectrum of a product 4-fluoro-1-methyl-2-oxoindol-3-yl 3,3,3-trifluoropropionate (3ad) in the example;

[0059] Figure 13 1H NMR spectrum of product 3as;

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

[0061] Figure 15 19F NMR spectrum of product 3as;

[0062] Figure 16 1H NMR spectrum of product 3aj;

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

[0064] Figure 18 19F NMR spectrum of product 3aj;

[0065] Figure 19 1H NMR spectrum of product 3an;

[0066] Figure 20 Carbon spectrum of product 3an;

[0067] Figure 21 19F NMR spectrum of product 3an;

[0068] Figure 22 1H NMR spectrum of product 3bh;

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

[0070] Figure 24 19F NMR spectrum of product 3bh;

[0071] Figure 25 1H NMR spectrum of product 3at;

[0072] Figure 26 Carbon spectrum of product 3at;

[0073] Figure 27 19F NMR spectrum of product 3at;

[0074] Figure 28 1H NMR spectrum of product 3ae;

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

[0076] Figure 3019F NMR spectrum of product 3ae;

[0077] Figure 31 1H NMR spectrum of product 3af;

[0078] Figure 32 13C NMR spectrum of product 3af;

[0079] Figure 33 19F NMR spectrum of product 3af;

[0080] Figure 34 1H NMR spectrum of product 3ag;

[0081] Figure 35 13C NMR spectrum of product 3ag;

[0082] Figure 36 19F NMR spectrum of product 3ag;

[0083] Figure 37 1H NMR spectrum of product 3ah;

[0084] Figure 38 13C NMR spectrum of product 3ah;

[0085] Figure 39 19F NMR spectrum of product 3ah;

[0086] Figure 40 1H NMR spectrum of product 3ai;

[0087] Figure 41 13C NMR spectrum of product 3ai;

[0088] Figure 42 19F NMR spectrum of product 3ai;

[0089] Figure 43 1H NMR spectrum of product 3ak;

[0090] Figure 44 13C NMR spectrum of product 3ak;

[0091] Figure 45 19F NMR spectrum of product 3ak;

[0092] Figure 46 1H NMR spectrum of product 3al;

[0093] Figure 47 13C NMR spectrum of product 3al;

[0094] Figure 48 19F NMR spectrum of product 3al;

[0095] Figure 49 1H NMR spectrum of product 3am;

[0096] Figure 50 13C NMR spectrum of product 3am;

[0097] Figure 51 19F NMR spectrum of product 3am;

[0098] Figure 52 1H NMR of product 3ao;

[0099] Figure 53 13C NMR of product 3ao;

[0100] Figure 54 19F NMR spectrum of product 3ao;

[0101] Figure 55 1H NMR of product 3ap;

[0102] Figure 56 13C NMR of product 3ap;

[0103] Figure 57 19F NMR spectrum of product 3ap;

[0104] Figure 58 1H NMR of product 3aq;

[0105] Figure 59 13C NMR of product 3aq;

[0106] Figure 60 19F NMR spectrum of product 3aq;

[0107] Figure 61 1H NMR of product 3ar;

[0108] Figure 62 13C NMR of product 3ar;

[0109] Figure 63 19F NMR spectrum of product 3ar;

[0110] Figure 64 1H NMR of product 3ba;

[0111] Figure 65 13C NMR of product 3ba;

[0112] Figure 66 19F NMR spectrum of product 3ba;

[0113] Figure 67 1H NMR of product 3bb;

[0114] Figure 68 13C NMR of product 3bb;

[0115] Figure 69 19F NMR spectrum of product 3bb;

[0116] Figure 70 1H NMR of product 3bc;

[0117] Figure 71Carbon spectrum of product 3bc;

[0118] Figure 72 19F NMR spectrum of product 3bc;

[0119] Figure 73 1H NMR spectrum of product 3bg;

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

[0121] Figure 75 19F NMR spectrum of product 3bg;

[0122] Figure 76 1H NMR spectrum of product 3bi;

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

[0124] Figure 78 19F NMR spectrum of product 3bi;

[0125] Figure 79 1H NMR spectrum of product 3bj;

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

[0127] Figure 81 19F NMR spectrum of product 3bj;

[0128] Figure 82 1H NMR spectrum of product 3bk;

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

[0130] Figure 84 19F NMR spectrum of product 3bk;

[0131] Figure 85 1H NMR spectrum of product 3bl;

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

[0133] Figure 87 19F NMR spectrum of product 3bl. Detailed implementation mode

[0134] The preferred embodiments of the present invention will be specifically described below in conjunction with the accompanying drawings, where the accompanying drawings form a part of the present invention and are used together with the embodiments of the present invention to explain the principle of the present invention, rather than to limit the scope of the present invention.

[0135] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this invention pertains. The terms used in the description of this invention herein are for the purpose of describing specific embodiments only and are not intended to limit this invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0136] Mediated by the use of hypervalent iodine compounds, the present invention 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, which provides an important technical means for the preparation of 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 the structure shown in Structural Formula 3:

[0138]

[0139] In the formula, 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; R3 is selected from any one of hydrogen, a methyl group, and an N-ethylacetamido group.

[0140] Specifically, the substitution position of R1 in Structural Formula 1 is any one of C4, C5, C6, and C7 of indole. The electron-donating functional group is selected from any one of a methyl group, hydrogen, and a methoxy group; 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 for preparing the above-mentioned 3-trifluoropropionyloxy-2-oxindole, which includes: 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, and 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 alkyl, alkenyl, alkynyl, and phenyl; R3 is selected from any one of hydrogen, methyl, and N-ethylacetamido.

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

[0147] Step 1: Mix the substrate with Structural Formula 1 and an organic solvent to obtain a mixture;

[0148] Step 2: Add the reactant with Structural Formula 2a to the mixture obtained in Step 1, and react for a period of time to obtain a reaction mixture;

[0149] Step 3: Perform post-treatment to obtain 3-trifluoropropionyloxy-2-oxindole.

[0150] Specifically, the molar ratio of the substrate with Structural Formula 1 to the reactant with 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) to 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, and methoxy; the electron-withdrawing functional group is selected from any one of fluorine, chlorine, bromine, trifluoromethyl, and methoxycarbonylmethyl.

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

[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-treatment includes concentration and purification. Specifically, the reaction mixture of step 2 is concentrated under vacuum to obtain a residue, and the residue is purified by silica gel column flash chromatography and eluted 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 an application 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 embodiments.

[0161] Example 1

[0162] 5-Bromo-1-methylindole (1) was selected as a model substrate, the structural formula of the reactant was 2a, and 2a was added at one time to optimize the conditions of the oxidative dearomatization trifluoropropionyloxylation reaction. See reaction formula (1), the reaction conditions of No. 1-11 were 40°C in the reaction solvent listed in the corresponding sequence number in Table 1 for 4 hours, the reaction conditions of No. 12 were 4 hours at room temperature (the room temperature on the day of the experiment was about 20°C) in the reaction solvent listed in the corresponding sequence number in Table 1, the reaction conditions of No. 13 were 70°C in the reaction solvent listed in the corresponding sequence number in Table 1 for 4 hours, and the reaction conditions of No. 14 were 100°C in the reaction solvent listed in the corresponding sequence number in Table 1 for 4 hours. After the reaction was completed, the reaction mixture was concentrated under vacuum.

[0163] Specifically, in the reaction of sequence number 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 obtain the target product 3-trifluoropropionyloxy 2-oxindole 3aa. In this example, the reaction was carried out at a scale of 0.2 mmol for 1 and 1.0 mL for solvent; b used 1,3,5-trimethoxybenzene as an internal standard, and the yield of 3aa was measured by ^1HNMR. The reaction yields are shown in Table 1.

[0166] As can be seen from the results in Table 1, while keeping the equivalents of the reaction between 1 and 2a unchanged, that is, the molar ratio of 1 to 2a being 1:2, the effects of different solvents on the results were investigated for Entries 1-7 and 15-16. The results showed that DCM was a better reaction medium than other solvents including DMF, THF, MeCN, and MeOH, with a yield of 45% (Entry 7).

[0167] Entries 7-11 evaluated the effect of the molar ratio between 2a and 1 on the results. When the molar ratio of 1:2a was adjusted from 1:2.0 to 1:1.8, the yields of the products were comparable (Entry 8); further reducing the amount of 2a to 1.5 equivalents led to a decrease in yield (Entry 9). In addition, when the molar ratio of 1:2a 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 (Entry 10); when the molar ratio of 1:2a was 1:3.0 equivalents, no product was formed, and the starting material 1 was converted to 5-bromo-1-methylindoline-2,3-dione 5a (Entry 11).

[0168] In addition, the reaction temperature was investigated in this example, as shown in Entries 12-14, and it was found that 70 °C was a better choice for the reaction (Entry 13).

[0169] (1)

[0170] Table 1. Optimization of reaction conditions

[0171]

[0172]

[0173] b Yield determined by ^1H NMR using 1,3,5-trimethoxybenzene as the internal standard. Yield after separation.

[0174] Example 2

[0175] In this example, the molar ratio of 1 to 2a was 1:1.8, and the amount of 1 used was 0.2 mmol. The organic solvent used was dichloromethane with a volume of 1.0 mL; 2a, that is, benzenesulfonyldi(3,3,3-trifluoropropionate), 0.36 mmol, was added to the mixture of 1 and dichloromethane, and then the mixture was stirred and reacted at 70 °C (using a heating module) for 4 hours. After the reaction was completed, the reaction mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, using a mixture of petroleum ether and ethyl acetate as the eluent, to obtain the desired product 3.

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

[0177] In this example, see Reaction Formula (2). The influence of indoles with various functional groups on R1 in the benzene ring on the reaction product 3aa was mainly investigated. In the reaction formula, the reaction results for different substitution cases of R1 are shown in Table 2.

[0178] (2)

[0179] Table 2. Reaction conditions of indoles with R1 functional groups

[0180]

[0181]

[0182] Note: Except as specifically stated for No. 2 and No. 14, for the rest of the reactions, R2 of Reactant 1 is methyl and R3 is H. The yields in Table 2 are isolation yields.

[0183] The results show that both electron-donating groups (-Me, -OMe) and electron-withdrawing (-F, -Cl, -Br, -CF3, -CO2Me) functional groups can be tolerated, and the target products 3aa - 3at are obtained with yields ranging from 29% to 78%. The halogen groups retained in the products provide opportunities for further derivatization. Generally, indoles with electron-deficient substitutions react more efficiently than those with electron-rich substitutions (such as 3ac vs. 3ad - 3af; 3am, 3an vs. 3ao, 3ap), because the latter are easily oxidized to form unwanted by-products. In addition, the reaction is not sensitive to the position of the substituents on the benzene ring. 3-Methylindole smoothly undergoes this oxidative trifluoropropionylation reaction with a product yield of 63% (3as). In the reaction numbered 14 in Table 2, the corresponding Substrate 1 is melatonin (a drug that can improve sleep quality) and it is also applicable to this reaction, but the yield is slightly lower (3at). However, free NH and 6-CN indoles failed to form the target products, accompanied by the formation of unknown mixtures.

[0184] Example 3

[0185] In this example, the molar ratio of 1 to 2a is 1:1.8, and the amount of 1 used is 0.2 mmol. The organic solvent used is dichloromethane, with an amount of 1.0 mL. 2a, namely benzenesulfonyl-λ3-iododiylbis(3,3,3-trifluoropropionate, 0.36 mmol), is added to the mixture of 1 and dichloromethane, and then the mixture is stirred and reacted at 70 °C (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 column chromatography on silica gel, using a mixture of petroleum ether and ethyl acetate as the eluent to obtain the desired product 3.

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

[0187] In this example, R1 in Structural Formula 1 is bromine-substituted at the C5 position, and R3 is hydrogen; indoles with various functional groups on R2 were investigated, as shown in Reaction Formula (2). In Reaction Formula (2), the reaction results for different substitution cases of R2 are shown in Table 3.

[0188] Table 3. Reaction conditions of indoles with R2 functional groups

[0189]

[0190]

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

[0192] Indoles with different protecting groups R2 on the nitrogen atom were studied. R2 being other alkyl groups, such as ethyl (3ba), propyl (3bb), butyl (3bc), and benzyl (3bj, 3bk), was proven to be feasible, and the corresponding 3-trifluoropropionyloxy-2-oxindole (3aa) was obtained in good yields. It is worth noting that alkenyl (3bh) and alkynyl (3bi) are also feasible. In addition, this trifluoropropionylation oxidation reaction is not limited to N-alkyl-substituted indoles, and indoles with N-phenyl can also be converted to the product (3bl) with a yield of 41%.

[0193] Example 4

[0194] In this example, the molar ratio of 1 to 2a is 1:1.8, and the amount of 1 is 0.2 mmol. The organic solvent used is dichloromethane with an amount of 1.0 mL. 2a, namely benzenesulfonyldi(3,3,3-trifluoropropionate), 0.36 mmol, is added to the mixture of 1 and dichloromethane. Then the mixture is stirred and reacted at 70 °C (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 column chromatography on silica gel using a mixture of petroleum ether and ethyl acetate as the eluent to obtain the desired product 3.

[0195] In this example, the R2 substituent is methyl. Indoles with various functional groups on R3 are investigated in this example, as shown in Reaction Scheme (2); in the reaction scheme, the reaction results for different substitution cases of R3 are shown in Table 4.

[0196] Table 4. Reaction of indoles with R3 functional groups

[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 trifluoropropionylation reaction, a gram-scale experiment using 5-bromo-N-methylindole (1a) as the substrate was carried out in this example, as shown in Reaction Scheme (3); the amount of 5-bromo-N-methylindole is 1.04 g, 5 mmol, the molar ratio of 2a to 1 is 1:1.8, the organic solvent for the reaction is DCM, the reaction temperature is 40 °C, and the reaction time is 4 hours. The corresponding 3-trifluoropropionyloxy-2-oxindole product was obtained with 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, thus verifying the feasibility of the reaction.

[0203] Example 6

[0204] A potential reaction mechanism of the reaction of the present invention is outlined in this example, as shown in Reaction Scheme (4). First, intermediate A is generated through the nucleophilic attack of 1 on 2a; iodine undergoes an intramolecular nucleophilic attack on the imine to form iodonium 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 form the 3-trifluoropropionyloxyindole product 4 (path a). On the other hand, intermediate C is converted to D through an intramolecular nucleophilic attack (path b). Water acts as a nucleophile to attack D, followed by the loss of a trifluoropropionate anion to form F. The aromatization of F generates enolate G, which reacts with 2a as a nucleophile to form H. H undergoes a nucleophilic substitution reaction with the trifluoropropionate anion to form the 3-trifluoropropionyloxy-2-oxindole product 3.

[0205] (4)

[0206] Example 7

[0207] This example has basically the same reaction conditions as the example numbered 12 in Table 2, except that: the reaction temperature is 20 °C, the reaction time is 8 h, and the product yield obtained is 76%.

[0208] Example 8

[0209] This example has basically the same reaction conditions as the example numbered 12 in Table 2, except that: the reaction temperature is 50 °C, the reaction time is 6 h, and the product yield obtained is 77%.

[0210] Example 9

[0211] This example has basically the same reaction conditions as the example numbered 12 in Table 2, except that: the reaction temperature is 80 °C, the reaction time is 5 h, and the product yield obtained is 75%.

[0212] Example 10

[0213] This example has basically the same reaction conditions as the example numbered 12 in Table 2, except that: the reaction temperature is 100 °C, the reaction time is 4 h, and the product yield obtained is 73%.

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

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

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

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

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

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

[0220] Figure 16 In 1 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 8.3 Hz 1H), 7.33 (s, 1H), 6.78 (d, J = 8.3 Hz, 1H), 5.96 (s, 1H), 3.40 - 3.28 (m, 2H), 3.21 (s, 3H).

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

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

[0223] In addition, Figure 19 - Figure 87 The 1H NMR, 13C NMR and 19F NMR spectra of other products 3 synthesized in the present invention are shown. It can be confirmed from the spectra that the obtained products are the expected products.

[0224] Application Example 1

[0225] This application example tested the in vitro anti-cancer activity of some 3-trifluoropropionyloxy-2-oxoindoles synthesized in Examples 1 - 6.

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

[0227] The specific procedure of the MTT method: Dissolve the target product to be tested in a small amount of DMSO to prepare a stock solution of 10 mmol·L -1 . Dilute the stock solution to the required concentrations with RPMI1640 culture medium (GIBICO, Invitrogen) containing 10% fetal bovine serum, which are: 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 , keeping the final DMSO concentration less than 0.1%. Culture human leukemia cells (K562) and prostate cancer cells (PC-3) with RPMI1640 culture medium containing 10% fetal bovine serum in an incubator at 37 °C with a CO2 volume fraction of 5%. Use the MTT method to detect cell proliferation and growth inhibition. Adjust the number of experimental cells to obtain an absorbance of 1.3 - 2.2 at 570 nm. Treat the cells with the test solutions of the above 6 concentrations of the target product for 72 h, with at least 3 parallels and 3 repeated experiments for each concentration. Use GraphPad Prism 5.0 software for statistical analysis to determine the IC50 value.

[0228] Table 5 Some target products in this invention

[0229]

[0230]

[0231] Table 6 Anticancer activities of some target products in this invention

[0232]

[0233]

[0234] Note: IC50 (half inhibitory concentration) refers to the drug concentration required to inhibit 50% of 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 in this application against human leukemia cells (K562) is 13.1 - 36.8 μmol·L -1, the IC50 for prostate cancer cells (PC-3) was 13.9 - 37.2 μmol·L -1 , indicating that Compounds 1 - 11 of this application have inhibitory effects on the proliferation of both types of tumor cells. The inhibitory activity of Compound 4 against K562 is significantly better than that of cisplatin. The inhibitory activities of Compounds 1, 3, 8, 9, 10, and 11 are comparable to that of cisplatin. The inhibitory activities of the remaining compounds are slightly weaker than that of 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 that of cisplatin. The inhibitory activities of Compounds 1, 2, 3, 7, 8, and 10 are comparable to that of cisplatin. The inhibitory activities of the remaining compounds are slightly weaker than that 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] Except for some of the target products in Table 5, the anticancer activities of other products are reasonably predicted:

[0238] The product with the 3ab structure synthesized in this invention has one less methyl group at the C3 position compared to the product with the 3as structure in Tables 5 and 6. It can be predicted that 3ab has anticancer activity.

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

[0240] The products with the 3aa, 3ag, 3ah, 3ai, 3aj, and 3al structures synthesized in this invention and the product with the 3ak structure in Tables 5 and 6 are all substituted at the R1C5 position, and only the substituents at the C5 position are different. It can be predicted that 3aa, 3ag, 3ah, 3ai, 3aj, and 3al have anticancer activity.

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

[0242] The product with the 3aq structure synthesized in this invention and the product with the 3ar structure in Tables 5 and 6 are all substituted at the R1C7 position, and only the substituents at the C7 position are different. It can be predicted that 3aq has anticancer activity.

[0243] Compared with the product of structure 3bc in Table 5 and Table 6, the products of structure 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 of structure 3bg in Table 5 and Table 6, the R2 substituent of the products of structure 3bh and 3bi synthesized in the present invention is changed from acetoxyethyl to propenyl and alkynyl, which can predict that 3bh and 3bi have anticancer activity.

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

[0246] The present invention develops an efficient method for preparing 3-trifluoropropionyloxy-2-oxoindole by oxidation of N-substituted indole with (bistrifluoropropionate) iodobenzene. The reaction has good tolerance to various functional groups. In addition, when an acyl group is pre-installed on the nitrogen atom, 3-trifluoropropionyloxy indole can be obtained. The present invention also discusses the reaction mechanism.

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

Claims

1. The C3-trifluoropropionyloxylation reaction of N-substituted indole, characterized in that, The reaction gives 3-trifluoropropionyloxy-2-oxindole, as shown in Structural Formula 3: In the formula, R1 is selected from an electron-donating functional group or an electron-withdrawing functional group, and 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-ethylacetamido group.

2. The C3-trifluoropropionyloxylation reaction of an N-substituted indole according to claim 1, characterized in that, Using Structural Formula 1 as a substrate, in the presence of an organic solvent, it reacts with Structural Formula 2a to synthesize 3-trifluoropropionyloxy-2-oxindole and Structural Formula 3. The synthesis route is as shown in the following reaction formula: In the reaction formula, in Structural Formula 1, 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; R3 is selected from any one of hydrogen, a methyl group, and an N-ethylacetamido group; the molar ratio of Structural Formula 1 to Structural Formula 2a during the reaction is 1:1.2 - 2.5; and / or, The electron-donating functional group is selected from any one of a methyl group or a methoxy group; the electron-withdrawing functional group is selected from any one of fluorine, chlorine, bromine, a trifluoromethyl group, and a methoxycarbonylmethyl group; and / or, 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; and / or, The organic solvent is selected from one or more of toluene, dichloromethane, N-methylformamide, N,N-dimethylformamide, tetrahydrofuran, acrylonitrile, acetonitrile, and methanol; and / or, The reaction temperature is 20 - 150 °C; and / or, The alkyl group refers to any one of a methyl group, an ethyl group, a propyl group, a butyl group, and a benzyl group.

3. A 3-trifluoropropionyloxy-2-oxindole, characterized in that, It has the structure as shown in Structural Formula 3: In the formula, R1 is selected from an electron-donating functional group or an electron-withdrawing functional group, and 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-ethylacetamido group.

4. The 3-trifluoropropionyloxy-2-oxindole according to claim 3, wherein The electron-donating functional group is selected from any one of a methyl group, hydrogen, and a methoxy group; the electron-withdrawing functional group is selected from any one of fluorine, chlorine, bromine, a trifluoromethyl group, and a methoxycarbonylmethyl group.

5. The 3-trifluoropropionyloxy-2-oxindole according to claim 3 or 4, characterized in that, The alkyl group includes any one of a methyl group, an ethyl group, a propyl group, a butyl group, and a benzyl group.

6. A method for preparing 3-trifluoropropionyloxy-2-oxindole, characterized in that, For preparing the 3-trifluoropropionyloxy-2-oxindole according to any one of Claims 3 - 5, it includes: reacting a substrate having Structural Formula 1 with a reactant having Structural Formula 2a in an organic solvent to synthesize the 3-trifluoropropionyloxy-2-oxindole shown in Structural Formula 3. The synthesis route is as shown in the following reaction formula: In the reaction formula, in Structural Formula 1, 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; R3 is selected from any one of hydrogen, a methyl group, and an N-ethylacetamido group.

7. The preparation method according to claim 6, characterized in that, The molar ratio of the substrate having Structural Formula 1 to the reactant having Structural Formula 2a is 1:1.2 - 2.

5.

8. The preparation method according to claim 6, characterized in that, 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.

9. The preparation method according to any one of claims 6-8, characterized in that, The reaction temperature is 20 - 150 °C.

10. Use of the 3-trifluoropropionyloxy-2-oxindole according to any one of Claims 3 - 5 and the preparation method according to any one of Claims 6 - 9 in the preparation of an anticancer drug.

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