2-acyl indoline derivative as well as synthesis method and application thereof

Abstract

The invention relates to a 2-acyl indoline derivative as well as a synthesis method and application thereof. The synthesis method comprises the following steps: under the irradiation of visible light, carrying out a reaction on an indole derivative as shown in a formula 1 and an aryl formic acid compound as shown in a formula 2 under the action of a photocatalyst, Ph3P and alkali to obtain the 2-acyl indoline derivative as shown in a formula (I), the reaction formula is as follows. The synthesis method disclosed by the invention has the advantages of simplicity, high efficiency, high chemical selectivity, high yield, mild reaction conditions, environment friendliness, low synthesis cost and the like. The 2-acyl indoline derivative prepared by the invention has certain anti-tumor activity, and part of compounds have excellent anti-tumor activity. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and medicine, and specifically relates to a 2-acylindole derivative and a synthesis method and application thereof. Background Art

[0002] As one of the most valuable core heterocycles, indoline often appears in a large number of alkaloid natural products, agrochemicals, drugs and bioactive molecules. Therefore, people have been committed to developing efficient methods for the synthesis of indoline.

[0003] Dearomatization of electron-deficient indoles is one of the methods for synthesizing indoline. However, due to the difficulty in overcoming the reverse reactivity of indole, this method has been less studied. - The method is considered to be a feasible strategy. However, the existing reaction substrates and reaction types are very limited.

[0004] In the past decade, visible light has been used as a sustainable green energy source to power a variety of chemical transformations through single electron or energy transfer methods. However, due to the significant interference of aromaticity, the application of this unique reaction mode of single electron transfer (SET) in dearomatization reactions is very limited, and the following are only a few examples.

[0005] Masson's group reported the photocatalytic hydroacylation of indole with aldehydes by decatungstate, the reaction formula is:

[0006]

[0007] In this method, tetrabutylammonium paratungstate (TBADT) is used as a hydrogen atom transfer (HAT) photocatalyst to initiate the formation of acyl radicals by abstracting hydrogen from aldehydes, which can provide acyl radicals for olefin addition. However, when aldehydes have multiple weak CH bonds and highly reactive hydrogen atom transfer reagents are used, competitive extraction occurs, resulting in a complex reaction mixture; in addition, deacylation transformation inevitably occurs in this reaction; and aldehydes are not stable enough and are easily oxidized.

[0008] Mita and Yeung's research group successfully reported the dearomatization reaction of electron-poor indole with formate. They used HAT catalyst to induce the generation of strongly nucleophilic formate radical anion, which then reacted with electron-deficient indole to dearomatize. However, the reaction process required the use of high temperature and unstable HAT reagent. The reaction formula is:

[0009]

[0010] In summary, the dearomatization of electron-deficient indoles to synthesize indolines remains a huge challenge for this type of reaction substrate, as it is still a huge challenge to destroy the stable aromaticity. Given the importance of 2-acylindoline derivatives in drugs and bioactive molecules, it is still highly desirable to find an economical, environmentally friendly, mild and efficient method to synthesize 2-acylindoline derivatives using stable and readily available indoles as raw materials. Summary of the invention

[0011] Based on this, the purpose of the present invention is to provide a new synthesis method of 2-acylindole derivatives, which is efficient, high in yield, economical and environmentally friendly, and has mild reaction conditions.

[0012] The specific technical solution is as follows.

[0013] A method for synthesizing a 2-acylindole derivative comprises the following steps:

[0014] Under the irradiation of visible light, the indole derivative shown in Formula 1 reacts with the aryl formic acid compound shown in Formula 2 under the action of a photocatalyst, Ph3P and a base to obtain a 2-acylindole derivative shown in Formula (I);

[0015] The photocatalyst is:

[0016]

[0017] The reaction formula is:

[0018]

[0019] Among them, R 1 and R 2 are each independently selected from: electron-withdrawing substituents;

[0020] R 3 is selected from: hydrogen, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, cyano, C1-C6 alkylamino, C1-C6 alkylthio, halogen-substituted C1-C6 alkylthio, or two adjacent R 3 Together with the carbon atoms on the benzene ring, it forms a 5-8 membered heterocyclic group;

[0021] R 4 Selected from: substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0022] In some embodiments, R 1 Selected from: tert-butyloxycarbonyl, p-toluenesulfonyl, acetyl, benzyloxycarbonyl, benzoyl.

[0023] In some embodiments, R 2Selected from: ester group, amide group; preferably selected from: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, or the following groups:

[0024]

[0025] In some embodiments, R 3 Selected from: hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkoxy, cyano, C1-C3 alkylamino, C1-C3 alkylthio, halogen-substituted C1-C3 alkylthio.

[0026] In some embodiments, R 4 Select from: 1 or more R 5 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 5 Substituted or unsubstituted 5-14 membered heteroaryl;

[0027] Each R 5 are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, cyano, C1-C6 alkylamino, C1-C6 alkylthio, halogen-substituted C1-C6 alkylthio, C3-C 12 Cycloalkyl, halogen-substituted C3-C 12 Cycloalkyl, 1 or more R 6 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 6 Substituted or unsubstituted 5-10 membered heteroaryl, or two adjacent R 5 Together they form a 5-8 membered heterocyclic group;

[0028] Each R 6 are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, cyano, C1-C6 alkylamino, C1-C6 alkylthio, halogen-substituted C1-C6 alkylthio, C3-C 12 Cycloalkyl, halogen-substituted C3-C 12 Cycloalkyl, 1 or more R 7 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 7 Substituted or unsubstituted 5-10 membered heteroaryl, or two adjacent R 5 Together they form a 5-8 membered heterocyclic group;

[0029] Each R 7are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, cyano, C1-C6 alkylamino, C1-C6 alkylthio, halogen-substituted C1-C6 alkylthio, C3-C 12 Cycloalkyl.

[0030] In some embodiments, R 4 Select from: 1 or more R 5 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 5 a substituted or unsubstituted 5-12 membered heteroaryl group;

[0031] Each R 5 R is independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkoxy, cyano, C1-C3 alkylamino, C1-C3 alkylthio, halogen-substituted C1-C3 alkylthio, adamantyl, one or more R 6 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 6 Substituted or unsubstituted 5-10 membered heteroaryl, or two adjacent R 5 Together they form a 5-8 membered oxygen-containing heterocyclic group;

[0032] Each R 6 R is independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkoxy, cyano, C1-C3 alkylamino, C1-C3 alkylthio, halogen-substituted C1-C3 alkylthio, adamantyl, one or more R 7 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 7 Substituted or unsubstituted 5-10 membered heteroaryl, or two adjacent R 5 Together they form a 5-8 membered oxygen-containing heterocyclic group;

[0033] Each R 7 They are independently selected from the group consisting of: hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkoxy, cyano, C1-C3 alkylamino, C1-C3 alkylthio, halogen-substituted C1-C3 alkylthio, and adamantyl.

[0034] In some embodiments, R 4 Selected from:

[0035]

[0036] In some embodiments, the indole derivative represented by Formula 1 is selected from:

[0037]

[0038] The aryl formic acid compound shown in Formula 2 is selected from:

[0039]

[0040] The 2-acylindole derivative represented by formula (I) is selected from:

[0041]

[0042] In some of the embodiments, the base is selected from at least one of K2HPO4, Cs2CO3, Na2CO3 and 2,6-lutidine, preferably K2HPO4 and / or Na2CO3.

[0043] In some embodiments, the organic solvent is selected from at least one of MeCN, dichloromethane (DCM), and N,N-dimethylacetamide (DMA), preferably MeCN.

[0044] In some embodiments, the visible light is blue light, and the wavelength of the blue light is preferably 430nm to 460nm.

[0045] In some of the embodiments, the wavelength of the blue light is 450nm-456nm.

[0046] In some embodiments, the reaction temperature is 15° C. to 40° C., and the reaction time is 8 hours to 36 hours.

[0047] In some embodiments, the reaction temperature is 20° C. to 30° C., and the reaction time is 20 hours to 28 hours.

[0048] In some embodiments, the reaction is carried out under the protection of an inert gas.

[0049] In some of the embodiments, the molar ratio of the indole derivative, the aromatic formic acid compound, the photocatalyst, Ph3P and the base is 1:1.2-2:0.005-0.04:1.2-2:1.0-2.

[0050] In some of the embodiments, the molar ratio of the indole derivative, the aromatic carboxylic acid compound, the photocatalyst, Ph3P and the base is 1:1.4-1.8:0.008-0.012:1.4-1.8:1.0-1.5.

[0051] The present invention also provides the use of the 2-acylindoline derivative or its stereoisomer or its pharmaceutically acceptable salt in the preparation of a drug for preventing and / or treating tumors, wherein the tumor is preferably colon cancer, liver cancer, prostate cancer, lung cancer, or pancreatic cancer.

[0052] The present invention also provides a drug for preventing and / or treating tumors, which is prepared from active ingredients and pharmaceutically acceptable excipients, wherein the active ingredient comprises the 2-acylindoline derivative or its stereoisomer or its pharmaceutically acceptable salt described in the present invention.

[0053] The present invention has the following beneficial effects:

[0054] The present invention uses indole derivatives as raw materials, and carries out a hydroacylation dearomatization reaction with an aryl formic acid compound under the action of a photocatalyst, Ph3P and a base, so as to obtain 2-acylindoleline derivatives efficiently and in high yield. The synthesis method uses green and sustainable visible light as reaction energy, and the raw materials carboxylic acid and indole used are both stable bulk raw material chemicals, which are cheap and easy to obtain. The synthesis method of the present invention has many advantages such as simplicity, high efficiency, high chemical selectivity, high yield, mild reaction conditions, green environmental protection, and low synthesis cost.

[0055] 2-Acyl indole derivatives are widely present in biologically active molecules such as natural products and drugs, and have important pharmaceutical activities. The synthesis method of the present invention can prepare a series of 2-acyl indole derivatives with high efficiency and high yield, providing a simple and effective synthesis strategy and method for developing more biologically active drug molecules, and playing an important role in the development and discovery of new drugs.

[0056] The 2-acyl indoline derivatives prepared by the invention have certain anti-tumor activity, and some compounds have excellent anti-tumor activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 The inhibitory activity of compounds 7-1 to 7-13 on tumor cells.

[0058] Figure 2 is the inhibition rate of compound 7-4 on colon cancer HCT116 cells.

[0059] Figure 3 is the inhibition rate of compound 7-4 on liver cancer HepG2 cells.

[0060] Figure 4 is the inhibition rate of compound 7-4 on pancreatic cancer BxPC3 cells. DETAILED DESCRIPTION

[0061] In order to facilitate the understanding of the present invention, the present invention will be described more fully below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0062] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0063] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used in the present invention includes any and all combinations of one or more of the related listed items.

[0064] In addition, as used in the present invention, the term "or" is an inclusive "or" symbol and is equivalent to the term "and / or", unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for being based on other factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meanings of "a", "an", and "the" include plural referents. The meaning of "in..." includes "in..." and "on...".

[0065] In the compounds described in the present invention, when any variable (such as R 5 If a (, etc.) compound occurs more than once in any component, its definition at each occurrence is independent of its definition at every other occurrence. Likewise, combinations of substituents and variables are permitted so long as such combinations render the compound stable. A line drawn from a substituent into a ring system or carbon chain indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, this means that such bonds are attached only to any suitable carbon atom of an adjacent ring. It is to be understood that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the invention to provide compounds that are chemically stable and that can be readily synthesized from readily available raw materials by techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it is to be understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0066] The term "alkyl" as used herein is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, the definition of "C1-C6" in "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched chain. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0067] The term "alkoxy" used in the present invention refers to a group having an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, etc.

[0068] The term "halogen" as used herein refers to chlorine, fluorine, bromine and iodine.

[0069] The room temperature described in the present invention refers to 23°C-25°C.

[0070] The present invention is further described in detail below with reference to specific embodiments.

[0071] The starting materials and reagents used in the following examples are all commercially available conventional materials and reagents, or can be synthesized by known methods reported in the literature.

[0072] Example 1

[0073]

[0074] Among them, the structure of the catalyst [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 is as follows:

[0075]

[0076] In a 10 mL glass flask equipped with a magnetic stir bar, dry MeCN (2 mL),

[0077] [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (0.002mmol, 1mol%, 2.2mg), aryl formic acid derivative 2a (0.3mmol, 1.5equiv), PPh3 (0.3mmol, 1.5equiv, 63mg) and K2HPO4 (0.2mmol, 1.0equiv, 35mg), indole derivative 1a (0.2mmol, 1equiv) was added to the resulting mixture. Nitrogen protection was performed by evacuating the flask and backfilling it with nitrogen three times, and then placing it in an irradiation device equipped with a 10W blue light emitting diode (LED) bar (whose wavelength is 454nm). The resulting mixture was stirred at room temperature for 24 hours. The crude product was purified by column chromatography (silica gel, EtOAc:n-hexane=1:10~1:5) to obtain a yellow solid product 7-1 with a yield of 76% and dr=2 / 1.

[0078] 1 H NMR (400MHz, CDCl3) δ7.65 (dd, J=8.2, 1.2Hz, 2H), 7.59 (s, 5H), 7.53-7.39 (m, 4H), 7.3 2(d,J=4.0Hz,2H),7.17(d,J=8.4Hz,1H),6.87(dt,J=8.6,4.4Hz,1H),3.61(s,3H)ppm;

[0079] 13 C NMR (100MHz, CDCl3) δ155.1,138.4,132.5,131.5,131.1,130.5,130.4,130.0,129.7,1 29.6,128.5,128.0,127.1,123.7,122.3,119.8,118.5,115.8,115.0,101.4,28.9ppm;

[0080] HRMS(ESI):exact mass calculated for[M+H] + (C 23 H 24 NO7 + )requires m / z426.1547, found m / z426.1544.

[0081] Example 2

[0082] Compound 2b, compound 2c, compound 2d, compound 2e, compound 2f, compound 2g, compound 2h, compound 2i, and compound 2j were used as raw materials to replace compound 2a in Example 1, and compounds 7-2 to 7-7, compound 7-9, compound 7-10, and compound 7-13 were prepared according to the method and conditions of Example 1.

[0083]

[0084] Compound 1b, compound 1c and compound 1d were used as raw materials to replace compound 1a in Example 1, and compound 2j was used to replace compound 2a. Compound 7-8, compound 7-11 and compound 7-12 were prepared according to the method and conditions of Example 1.

[0085]

[0086] Wherein, compound 1b can be prepared by the following method:

[0087]

[0088] To a solution of N-Boc-indole-3-carboxylic acid in anhydrous dichloromethane (10 mL) were added TEA (2 mmol, 0.266 mL), DMAP (0.5 mmol, 61 mg), EDC (1.2 mmol, 0.23 g), (1R)-(+)-2,10-camphorsulfonamide (0.6 mmol, 130 mg). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was purified by column chromatography to obtain the desired indole derivative 1b.

[0089] The following are the structural formulas and characterization data of compounds 7-2 to 7-13.

[0090] 1. According to the synthesis steps of Example 1, a yellow solid product 7-2 (yield 72%) was obtained, dr = 2 / 1, and its structure is as follows:

[0091]

[0092] 1H NMR (400MHz, CDCl3): δ8.38(d,J=10.9Hz,1H),8.30(s,1H),8.15(d,J=7.8Hz,1 H),8.03(d,J=8.0Hz,0.61H),7.93(d,J=8.1Hz,1H),7.66-7.51(m,0.36H),7.3 4(t,J=7.8Hz,2H),7.01(t,J=7.5Hz,1H),6.46(s,0.34H),6.38(d,J=3.9Hz,0. 67H), 4.09 (d, J = 11.4Hz, 1H), 3.85 (s, 3H), 1.62 (s, 2.75H), 1.35 (s, 6.23H) ppm;

[0093] 13 C NMR (100MHz, CDCl3): δ194.1,170.6,155.5,151.1,150.1,144.6,142.8,131.8,129.7,125.6,125.4,12 4.5,122.6,121.1,114.9,114.1,112.2,111.9,82.8,81.8,64.7,64.5,53.3,49.5,48.7,28.4,28.1ppm;

[0094] HRMS(ESI):exact mass calculated for[M+H] + (C 23 H 23 N2O6 + )requires m / z423.1551, found m / z 423.1554.

[0095] 2. According to the synthesis steps of Example 1, a yellow solid product 7-3 (yield 80%) was obtained, dr = 2.5 / 1, and its structure is as follows:

[0096]

[0097] 1H NMR (400MHz, CDCl3): δ8.99(s,1H),8.31(d,J=18.2Hz,1H),7.95(d,J=8.0Hz,0.63H),7.80(d,J=8.4H z,0.68H),7.71(s,0.28H),7.52(s,0.27H),7.34(d,J=8.5Hz,0.61H),7.22(dd,J=7.6,3.8Hz,1.82H), 7.16(d,J=19.0Hz,1.64H),6.88(td,J=7.5,0.6Hz,1H),6.58(s,0.65H),6.51(s,0.28H),6.45(s,0.27 H),6.36(d,J=3.6Hz,0.67H),4.03(t,J=5.8Hz,1H),3.72(s,3H),1.52(s,2.58H),1.25(s,6.42H)ppm;

[0098] 13 C NMR (100MHz, CDCl3): δ195.3,171.0,151.6,143.1,139.0,129.6,127.7,126.3,126.1,126.0,125.7, 125.5,125.1,123.2,122.5,122.5,114.9,111.8,104.3,82.6,81.6,64.6,53.1,49.9,49.2,28.1ppm;

[0099] HRMS(ESI):exact mass calculated for[M+H] + (C 24 H 25 N2O5 + )requires m / z421.1758, found m / z 421.1754.

[0100] 3. According to the synthesis steps of the embodiment, a yellow solid product 7-4 (yield 73%) was obtained, dr = 1.5 / 1, and its structure is as follows:

[0101]

[0102] 1H NMR (400MHz, CDCl3): δ9.17(s,0.38H),8.93(s,0.56H),8.75(s,0.57H),8.26(s,0.38H),8.16-7.91( m,1.77H),7.83(d,J=7.9Hz,0.43H),7.62(dd,J=39.6,7.4Hz,0.82H),7.43-7.29(m,2.61H),7.21(dd ,J=14.5,7.0Hz,2.60H),7.16(s,0.51H),7.08(d,J=8.1Hz,0.29H),6.89(t,J=7.5Hz,1H),6.49-6.22 (m,1H),4.09(s,0.58H),4.01(s,0.38H),3.73(d,J=8.0Hz,3H),1.59(s,3.59H),1.25(s,5.37H)ppm;

[0103] 13 C NMR (400MHz, CDCl3): δ194.7,193.6,171.0,170.8,152.7,151.6,143.1,143.0,140.2,129.6,126.9,126.6,126.5,126.1,125.5,125.1, 123.4,123.2,122.6,122.2,121.8,120.5,120.1,115.1,114.9,111.3,111.1,110.7,82.9,81.6,64.6,53.2,50.0,49.2,28.5,28.1ppm;

[0104] HRMS(ESI):exact mass calculated for[M+H] + (C 28 H 27 N2O5 + )requires m / z471.1914, found m / z 471.1921.

[0105] 4. According to the synthesis steps of Example 1, a yellow solid product 7-5 (yield 69%) was obtained, dr = 2 / 1, and its structure is as follows:

[0106]

[0107] 1H NMR (400MHz, CDCl3): δ8.04-7.84(m,3H),7.58-7.44(m,0.55H),7.44-7.31(m,3.65H),7.19(t,J=6.2Hz,1H),6.87(t,J=7.4Hz,1H ),6.25(s,0.31H),6.12(d,J=4.1Hz,0.62H),4.31-3.99(m,1H),3.78(s,3H),2.64(d,J=4.8Hz,3H),1.55(s,3H),1.36(s,6H)ppm;

[0108] 13 C NMR (400MHz, CDCl3): δ190.4,171.2,159.1,156.2,151.6,143.2,132.7,130.9,129. 5,128.9,126.6,126.4,124.6,122.4,115.1,81.2,67.1,52.8,49.7,28.4,28.2ppm;

[0109] HRMS(ESI):exact mass calculated for[M+H] + (C 26 H 27 N2O6 + )requires m / z463.1864,found m / z463.1869.

[0110] 5. According to the synthesis steps of Example 1, a yellow solid product 7-6 (yield 71%) was obtained, dr = 1.8 / 1, and its structure is as follows:

[0111]

[0112] 1 H NMR (400MHz, CDCl3): δ7.91 (d, J=7.8Hz, 0.60H), 7.58-7.37 (m, 1.38H), 7.25 (dd, J=15.3, 7.5Hz, 2H), 7.11-6.80 (m, 2H), 5.98 (s,0.34H),5.89(d,J=3.7Hz,0.63H),4.11(s,3H),4.01(d,J=11.3Hz,1H),3.75(s,3H),1.53(s,3.21H),1.28(s,5.77H)ppm;

[0113] 13C NMR (400MHz, CDCl3): δ186.8,170.5,151.0,142.7,138.2,135.4,129.7,125.4,12 4.5,122.8,114.8,111.6,82.9,81.8,66.2,53.2,49.8,49.0,40.3,28.4,28.1ppm;

[0114] HRMS(ESI):exact mass calculated for[M+H] + (C 20 H 24 N3O5 + )requires m / z386.1710,found m / z 386.1713.

[0115] 6. According to the synthesis steps of Example 1, a yellow solid product 7-7 (yield 85%) was obtained, dr = 2.2 / 1, and its structure is as follows:

[0116]

[0117] 1 H NMR (400MHz, CDCl3): δ8.76 (t, J=12.1Hz, 1.28H), 8.63 (s, 0.73H), 8.06 (d, J=7.7H z,0.67H),7.92(d,J=7.6Hz,1H),7.63(s,0.29H),7.50(dd,J=13.8,7.6Hz,2H),7.3 6(dd,J=15.5,7.5Hz,2H),7.02(t,J=7.4Hz,1H),6.37(s,0.31H),6.25(d,J=3.5Hz ,0.68H),4.19(d,J=21.2Hz,1H),3.85(s,3H),1.64(s,2.69H),1.33(s,6.44H)ppm;

[0118] 13 C NMR (400MHz, CDCl3): δ190.3,171.0,151.2,142.9,142.0,139.8,138.4,137.7,137.0,131.8,129.6, 126.1,125.8,125.6,124.6,122.6,122.3,114.9,82.7,81.7,65.7,53.2,50.0,49.2,28.4,28.0ppm;

[0119] HRMS(ESI):exactmass calculated for[M+H] + (C 24 H 24 NO5S + ) requires m / z

[0120] 438.1370, found m / z 438.1364.

[0121] 7. According to the synthesis steps of Example 1, a yellow solid product 7-8 (yield 71%) was obtained, dr = 2.3 / 1, ee = 98.0%; its structure is as follows:

[0122]

[0123] 1 H NMR (400MHz, CDCl3): δ8.08-8.00(m,0.35H),7.95(d,J=8.1Hz,0.66H),7.84(dd,J=13.2,7.9Hz,2H),7.59-7.47 (m,1H),7.46-7.31(m,3H),7.28-7.16(m,1H),6.84(t,J=7.5Hz,1H),6.23(d,J=2.5Hz,0.29H),6.15(d,J=3.3Hz, 0.67H), 4.62 (t, J=9.7Hz, 1H), 3.91 (dd, J=7.4, 4.2Hz, 1H), 3.42 (dd, J=33.7, 13.9Hz, 2H), 1.86 (ddd, J=38.1, 21. 2,11.9Hz,5H),1.53(s,2.22H),1.39(t,J=10.0Hz,1H),1.28(d,J=11.7Hz,7.81H),1.11(s,3H),0.89(s,3H)ppm;

[0124] 13 C NMR (400MHz, CDCl3): δ194.6,170.6,151.2,143.3,133.9,133.8,133.6,130.2,129.8,129.6,129.1,128.8,128.7,128.5,12 5.6,125.1,122.5,115.2,82.5,81.5,65.5,65.1,53.1,50.2,48.5,47.8,44.3,37.9,32.8,28.4,28.1,26.5,20.8,19.8ppm;

[0125] HRMS(ESI):exact mass calculated for[M+H] + (C 31 H 37 N2O6S + ) requires m / z

[0126] 565.2367, found m / z 565.2372.

[0127] Chiral HPLC: Daicel IC, AD-H; detected at 254nm; n-hexane / i-propanol=95 / 5; flow=1mL / min; Retention time: 16.757min, 24.315min.

[0128] 8. According to the synthesis steps of Example 1, a yellow solid product 7-9 (yield 65%) was obtained, dr = 2.2 / 1, and its structure is as follows:

[0129]

[0130] 1 H NMR (400MHz, CDCl3): δ8.80(d,J=15.6Hz,1H),8.37(d,J=7.2Hz,1H),8.16(d t,J=15.9,4.9Hz,2H),7.95(d,J=7.9Hz,0.59H),7.66-7.48(m,2.52H),7.38 -7.16(m,4H),6.92(t,J=7.4Hz,1H),6.37(s,0.32H),6.28(d,J=3.7Hz,0.71 H),4.03(d,J=17.8Hz,1H),3.78(s,3H),1.54(s,2.85H),1.28(s,6.16H)ppm;

[0131] 13C NMR (400MHz, CDCl3): δ194.4,173.2,170.5,167.9,162.1,159.5,151.2,142.9,134.9-134.7(m),132.5,131.1,131.0,129.7(d,J=9.0Hz ),128.1-127.8(m),125.5,124.8(d,J=3.7Hz),122.6,117.3,117.1,115.0,112.7(d,J=11.2Hz),81.8,64.9,53.3,49.5,28.4,28.1ppm;

[0132] 19 F NMR(376MHz, CDCl3)δ-108.09(s)ppm;

[0133] HRMS(ESI):exact mass calculated for[M+H] + (C 30 H 27 FN3O6 + )requires m / z544.1878, found m / z 544.1882.

[0134] 9. According to the synthesis steps of Example 1, a yellow solid product 7-10 (yield 69%) was obtained, dr = 2.5 / 1, and its structure is as follows:

[0135]

[0136] 1 H NMR (400MHz, CDCl3): δ8.56 (d, J = 20.1Hz, 1H), 8.14-7.85 (m, 4.75H), 7.76 (d, J = 8.2Hz, 1H) ,7.53(d,J=2.2Hz,1.24H),7.48(dd,J=8.4,2.2Hz,1H),7.25(d,J=7.4Hz,2H),6.92(dd,J= 12.6,7.9Hz,2H),6.50(s,0.28H),6.40(d,J=3.7Hz,0.71H),4.34-3.97(m,1H),3.83(s,3H ),3.75(s,3H),2.11(s,6H),2.03(s,3H),1.73(s,6H),1.26(s,5.95H),1.18(s,3.35H)ppm;

[0137] 13C NMR (400MHz, CDCl3): δ194.9,170.8,159.1,151.3,142.2,139.1,136.4,132.3,131.3,130.9,130.4,130.2,129.6,129.0,126.9,1 26.0,125.8,125.5,124.7,124.5,122.5,115.0,114.1,112.2,81.7,64.6,55.2,53.2,49.7,40.6,37.2,37.1,29.7,29.1,28.1ppm;

[0138] HRMS(ESI):exact mass calculated for[M+H] + (C 43 H 46 NO6 + )requires m / z672.3320,found m / z 672.3324.

[0139] 10. According to the synthesis steps of Example 1, a white solid product 7-11 (yield 66%) was obtained, dr = 2.3 / 1, and its structure is as follows:

[0140]

[0141] 1 H NMR (400MHz, CDCl3): δ8.08-7.82(m,2.78H),7.54(d,J=6.9Hz,1.35H),7.44(d,J=6.9Hz,2H),7.24(d,J=7.7Hz, 2H),6.91(d,J=6.7Hz,1H),6.29(s,0.30H),6.21(d,J=3.3Hz,0.70H),5.49-5.14(m,1H),4.80-4.49(m,1H),3.9 3(d,J=15.3Hz,1H),2.46(t,J=8.6Hz,1H),2.25(dd,J=21.9,14.2Hz,2H),2.11(d,J=9.9Hz,1H),2.05(s,3H),1. 89-1.72(m,2H),1.69-1.34(m,12.37H),1.26(s,6.70H),1.16-1.02(m,3H),0.95-0.91(m,4H),0.56(s,3H)ppm;

[0142] 13C NMR (400MHz, CDCl3): δ209.6,195.1,169.6,151.2,142.9,139.2,139.1,134.1,133. 9,129.8,129.6,129.1,129.0,128.7,128.5,128.2,128.2,127.8,127.3,127.1,125. 1,122.8,122.5,114.9,81.6,76.0,63.7,56.8,49.8,49.7,44.0,38.8,38.0,37.8,3 6.9,36.8,36.6,31.8,31.6,28.4,28.0,27.7,27.6,24.5,22.8,21.0,19.3,13.2ppm;

[0143] HRMS(ESI):exact mass calculated for[M+H] + (C 42 H 52 NO6 + )requires m / z666.3789,found m / z 666.3793.

[0144] 11. According to the synthesis steps of Example 1, a yellow solid product 7-12 (yield 76%) was obtained, dr = 2.4 / 1, and its structure is as follows:

[0145]

[0146] 1H NMR (400MHz, CDCl3): δ7.94 (t, J=9.1Hz, 2.72H), 7.53 (d, J=7.1Hz, 1.30H), 7.42 (dd, J=13.4, 6.7Hz, 2H), 7.19 (dd, J=8. 4,4.7Hz,2H),6.88(dd,J=14.0,7.0Hz,1H),6.27(d,J=11.5Hz,0.29H),6.21(d,J=4.3Hz,0.71H),4.73(dtd,J=15.3,10 .9,4.3Hz,1H),3.94(d,J=3.4Hz,1H),1.87(dd,J=38.0,11.8Hz,1H),1.72-1.49(m,6.23H),1.47-1.15(m,8.60H),1.07 -0.89(m,2.17H),0.87-0.77(m,4H),0.74(d,J=6.9Hz,3.21H),0.68(d,J=6.8Hz,1.88H),0.57(d,J=6.9Hz,1.19H)ppm;

[0147] 13 C NMR (400MHz, CDCl3): δ195.0,194.9,169.9,151.3,142.9,134.0,133.8,129. 5,128.9,128.6,128.6,125.3,125.1,125.0,124.8,122.5,122.3,115.0,114 .9,82.5,81.5,76.4,76.2,64.9,49.9,49.8,47.1,40.8,40.6,34.1,34.1,31 .4,28.4,28.1,26.4,25.8,23.5,22.9,22.0,22.0,20.8,20.6,16.4,15.8ppm;

[0148] HRMS(ESI):exact mass calculated for[M+H] + (C 31 H 40 NO5 + )requires m / z506.2901,found m / z 506.2905.

[0149] 12. According to the synthesis steps of Example 1, a yellow solid product 7-13 (yield 77%) was obtained, dr = 2 / 1, and its structure is as follows:

[0150]

[0151] 1 H NMR (400MHz, CDCl3): δ8.13 (dd, J=5.2, 3.3Hz, 0.85H), 8.10-8.01 (m, 1.89H), 7.62 (ddd ,J=8.6,2.5,1.3Hz,1.58H),7.56-7.49(m,2.16H),7.49-7.43(m,0.71H),7.32(t,J=9. 1Hz,1.66H),6.99(t,J=7.4Hz,0.93H),6.44(s,0.29H),6.34(d,J=3.8Hz,0.63H),4.08 (t,J=9.4Hz,1H),3.82(s,2.78H),3.70(s,0.15H),1.63(s,2.43H),1.36(s,6.33H)ppm;

[0152] 13 C NMR (100MHz, CDCl3): δ171.6,170.7,152.2,151.2,142.9,133.9,133.7,130.2,129.6,129.4,129.1,128.6,128.5 ,127.8,126.1,126.0,125.5,124.7,124.6,122.6,114.9,82.6,81.7,64.6,53.2,49.4,48.6,28.4,28.0,27.5ppm;

[0153] HRMS(ESI):exact mass calculated for[M+H] + (C 22 H 24 NO5 + )requires m / z382.1649, found m / z 382.1651.

[0154] Example 3 Synthesis of Compounds 7-13 under Different Reaction Conditions

[0155] Compound 2j was used as a raw material to replace compound 2a in Example 1, and compound 7-13 was prepared according to the method of Example 1 under the conditions shown in Table 1 below, and the yields were shown in Table 1. The preparation method and reaction conditions of this example are the same as those of Example 1 except for the differences shown in Table 1.

[0156] Table 1

[0157]

[0158]

[0159] The structures of the catalysts (cat-I to cat-V) are as follows:

[0160]

[0161] From the reaction yields in the table, we can see that the photocatalyst has a great influence on the reaction effect. 4CzIPN (III) can only obtain a lower product yield. Other dye-based photocatalysts, such as methylene blue (II), eosin Y (IV) and Mes-Acr + ClO4 - (V), failed to obtain the product. In addition, the solvent also has a great influence on the reaction. The yield is reduced in CH2Cl2; the yield is significantly reduced in N, N-dimethylacetamide (DMA); and only trace amounts of the product are obtained in 1,4-dioxane. Inorganic bases Na2CO3 or Cs2CO3 or organic bases 2,6-lutidine instead of K2HPO4 reduce the reaction yield. Control experiments show that Ph3P, photocatalysts and visible light are crucial to the success of the hydroacylation dearomatization reaction.

[0162] In addition, the present invention has found that according to the reaction conditions of Example 1, the reaction cannot occur when the hydrogen on the N of the indole derivative is not substituted or the substituent is a methyl group.

[0163] Example 4 Antitumor Activity Test

[0164] 1. Inhibitory activity of compounds on different tumor cells

[0165] Compounds 7-1 to 7-12 were tested for anti-tumor activity, and human colon cancer cells HCT116, liver cancer cells HepG2, prostate cancer cells DU145, lung cancer cells A549 and pancreatic cancer cells BxpC3 were selected. These cell lines were purchased from the American Type Culture Collection (ATCC). HepG2 and DU145 were cultured in DMEM medium, HCT116 was cultured in McCoy's 5A medium, A549 was cultured in F12K medium, and BxpC3 was cultured in RPMI1640 medium. All culture media were supplemented with 10% fetal bovine serum (FBS) to provide growth factors required for cell growth, and the cell culture conditions were a constant temperature incubator at 37°C and 5% CO2. The culture steps are as follows:

[0166] (1) Tumor cells in the logarithmic growth phase were digested with trypsin and resuspended in complete medium. The cell concentration was measured using a cell counter and the cells were diluted to 3×10 4 Pieces / mL;

[0167] (2) Inoculate 100 μL of cell suspension in each well of a 96-well plate and incubate overnight in a cell culture incubator;

[0168] (3) Compounds 7-1 to 7-12 were diluted to 20 μM with the complete culture medium of the corresponding cells, and 100 μL of the compound dilution was added to each well of a 96-well plate to make the final concentration of the compound 10 μM. Each compound was added to 3 replicates, and the control group was DMSO with the same volume as the compound. The cells were returned to the cell culture incubator and cultured for 72 hours;

[0169] (4) The inhibitory effects of compounds 7-1 to 7-12 on the survival of various tumor cells were detected by MTT assay. After the tumor cells were treated with the compounds for 72 hours, 20 μL of 5 mg / mL MTT solution was added to each well and incubated at 37°C for another 4 hours;

[0170] (5) Discard the cell culture medium, add 150 μL DMSO to dissolve the cells, and measure the OD value at 570 nm (OD570) using a microplate reader;

[0171] (6) Data processing: relative survival rate was calculated based on OD570 of the compound-treated group and the control-treated group. Cell survival rate = OD570 化合物 / OD570 DMSO .

[0172] The experimental results are as follows Figure 1 As shown: the 2-acylindoline derivatives prepared by the present invention have certain anti-tumor effects, and most of the compounds have a certain degree of inhibitory effect on the proliferation of BxPC3 cells, especially compound 7-4 has a good inhibitory effect on the growth of colon cancer cells HCT116, liver cancer cells HepG2, prostate cancer cells DU145, lung cancer cells A549 and pancreatic cancer cells BxpC3, especially has excellent inhibitory effect on colon cancer cells, liver cancer cells, prostate cancer and pancreatic cancer cells.

[0173] 2. Effects of different concentrations of compound 7-4 on the survival of colon cancer, liver cancer, and pancreatic cancer cells

[0174] HCT116, HepG2 and BxPC3 cells were diluted with McCoy's 5A medium, DMEM and RPMI1640 medium containing 10% FBS, respectively, to a final cell concentration of 2×10 4 / mL, and then inoculated 100 μL of cell suspension into 96-well plates respectively. After the cells adhered, compound 7-4 was added to make the final concentrations of 0 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM, and 20 μM, and 5 replicates were added for each concentration. After 72 hours of compound treatment, the MTT method was used to detect the effects of different concentrations of compound 7-4 on the survival ability of HCT116, HepG2 and BxPC3 cells.

[0175] The experimental results are as follows Figure 2-Figure 4 As shown, with the increase of compound concentration, the survival ability of the three cancer cells decreased significantly, indicating that compound 7-4 has considerable inhibitory activity against the three tumor cells. The half lethal concentrations of compound 7-4 for colon cancer HCT116, liver cancer HepG2, and pancreatic cancer BxPC3 are 1.7μM, 4.4μM, and 2.0μM, respectively.

[0176] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for synthesizing a 2-acylindoline derivative, characterized in that: The steps include: Under the irradiation of visible light, the indole derivative shown in Formula 1 reacts with the aryl formic acid compound shown in Formula 2 under the action of a photocatalyst, Ph3P and a base to obtain a 2-acylindole derivative shown in Formula (I); The photocatalyst is: and / or, The reaction formula is: Among them, R 1 and R 2 are each independently selected from: electron-withdrawing substituents; R 3 is selected from: hydrogen, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, cyano, C1-C6 alkylamino, C1-C6 alkylthio, halogen-substituted C1-C6 alkylthio, or two adjacent R 3 Together with the carbon atoms on the benzene ring, it forms a 5-8 membered heterocyclic group; R 4 Selected from: substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

2. The method for synthesizing a 2-acylindoline derivative according to claim 1, characterized in that: R 1 Selected from: tert-butyloxycarbonyl, p-toluenesulfonyl, acetyl, benzyloxycarbonyl, benzoyl.

3. The method for synthesizing a 2-acylindoline derivative according to claim 1, characterized in that: R 2 Selected from: ester group, amide group; preferably selected from: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, or the following groups:

4. The method for synthesizing a 2-acylindoline derivative according to claim 1, characterized in that: R 3 Selected from: hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkoxy, cyano, C1-C3 alkylamino, C1-C3 alkylthio, halogen-substituted C1-C3 alkylthio.

5. The method for synthesizing 2-acylindoline derivatives according to claim 1, characterized in that: R 4 Select from: 1 or more R 5 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 5 a substituted or unsubstituted 5-14 membered heteroaryl group; Each R 5 are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, cyano, C1-C6 alkylamino, C1-C6 alkylthio, halogen-substituted C1-C6 alkylthio, C3-C 12 Cycloalkyl, halogen-substituted C3-C 12 Cycloalkyl, 1 or more R 6 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 6 Substituted or unsubstituted 5-10 membered heteroaryl, or two adjacent R 5 Together they form a 5-8 membered heterocyclic group; Each R 6 are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, cyano, C1-C6 alkylamino, C1-C6 alkylthio, halogen-substituted C1-C6 alkylthio, C3-C 12 Cycloalkyl, halogen-substituted C3-C 12 Cycloalkyl, 1 or more R 7 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 7 Substituted or unsubstituted 5-10 membered heteroaryl, or two adjacent R 5 Together they form a 5-8 membered heterocyclic group; Each R 7 are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, cyano, C1-C6 alkylamino, C1-C6 alkylthio, halogen-substituted C1-C6 alkylthio, C3-C 12 Cycloalkyl; Preferably, R 4 Select from: 1 or more R 5 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 5 a substituted or unsubstituted 5-12 membered heteroaryl group; Each R 5 R is independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkoxy, cyano, C1-C3 alkylamino, C1-C3 alkylthio, halogen-substituted C1-C3 alkylthio, adamantyl, one or more R 6 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 6 Substituted or unsubstituted 5-10 membered heteroaryl, or two adjacent R 5 Together they form a 5-8 membered oxygen-containing heterocyclic group; Each R 6 R is independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkoxy, cyano, C1-C3 alkylamino, C1-C3 alkylthio, halogen-substituted C1-C3 alkylthio, adamantyl, one or more R 7 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 7 Substituted or unsubstituted 5-10 membered heteroaryl, or two adjacent R 5 Together they form a 5-8 membered oxygen-containing heterocyclic group; Each R 7 are independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkoxy, cyano, C1-C3 alkylamino, C1-C3 alkylthio, halogen-substituted C1-C3 alkylthio, and adamantyl; Preferably, R 4 Selected from:

6. The method for synthesizing 2-acylindoline derivatives according to claim 1, characterized in that: The indole derivatives shown in Formula 1 are selected from: The aryl formic acid compound shown in Formula 2 is selected from: The 2-acylindole derivative represented by formula (I) is selected from:

7. The method for synthesizing a 2-acyl indoline derivative according to any one of claims 1 to 6, characterized in that: The base is selected from at least one of K2HPO4, Cs2CO3, Na2CO3 and 2,6-lutidine, preferably K2HPO4 and / or Na2CO3; and / or The reaction is carried out in an organic solvent, wherein the organic solvent is selected from at least one of MeCN, dichloromethane, and N,N-dimethylacetamide, preferably MeCN; and / or, The visible light is blue light, and the wavelength of the blue light is preferably 430nm to 460nm; and / or, The reaction temperature is 15°C to 40°C, and the reaction time is 8 hours to 36 hours, preferably 20 hours to 28 hours; and / or, The reaction is carried out under the protection of an inert gas; and / or, The molar ratio of the indole derivative, the aromatic formic acid compound, the photocatalyst, Ph3P and the base is 1:1.2-2:0.005-0.04:1.2-2:1.0-2.

8. The 2-acylindoline derivative according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

9. Use of the 2-acylindoline derivative or its stereoisomer or its pharmaceutically acceptable salt as claimed in any one of claims 1 to 6 in the preparation of a medicament for preventing and / or treating tumors, wherein the tumor is preferably colon cancer, liver cancer, prostate cancer, lung cancer or pancreatic cancer.

10. A drug for preventing and / or treating tumors, characterized in that: The invention is prepared from active ingredients and pharmaceutically acceptable excipients, wherein the active ingredient comprises the 2-acyl indole derivative or its stereoisomer or pharmaceutically acceptable salt as described in any one of claims 1 to 6.

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