Indole ketone derivative and its preparation method and application

Abstract

The present invention belongs to the technical field of organic synthesis, and provides an indole ketone derivative and a preparation method and application thereof. The present invention uses N-phenylmethacrylamide or its derivatives and phenylhydrazine as raw materials, and prepares the indole ketone derivative by photocatalytic reaction under an inert atmosphere, and the synthesis route is as follows; the method synthesizes the indole ketone derivative by free radical pathway by photochemical catalytic C-H / N-H activation; the photochemical catalytic system is efficient and environmentally friendly, avoids the use of chemical oxidants, has mild reaction conditions, and can obtain a good yield under room temperature conditions; the indole ketone derivative prepared by the present invention has certain anti-cancer cell proliferation activity and can be widely used in the pharmaceutical field.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to an indole ketone derivative and a preparation method and application thereof. Background Art

[0002] Indole and its derivatives are an important heterocyclic structure, with a typical structure shown in formula (I). They have good biological activity and can be used in anti-cancer, anti-HIV, antibacterial, antioxidant, anti-diabetic, analgesic and other drugs; their main activity is mainly affected by factors such as the configuration of the C-3 carbon on Oxindole, the presence of substituents, and the type and configuration of substituents.

[0003]

[0004] In view of the structural requirements of indole derivatives, different synthetic routes have also been derived; among them, free radical oxidative coupling reaction is an effective alternative to the mature method of forming CC and CX bonds, providing many important innovations in synthetic chemistry; usually such transformations are achieved through a single electron transfer process, requiring the use of transition metal catalysts (such as Ag, Fe or Cu) and free radical oxidants (such as TBHP, H2O2 or K2S2O8).

[0005] Due to the high efficiency of N-arylacrylamide as a substrate in free radical oxidative coupling reactions, the reaction route for synthesizing substituted indoles from N-arylacrylamide via transition metal catalysis is relatively mature. In 2013, Yang Shangdong's group (Angew. Chem. Int. Ed., 2013, 52, 3972-3976) reported the preparation of various diphenylphosphocarbonyl indoles by Ag-catalyzed carbonyl phosphorylation and CH functionalization cascade reaction of N-aryl acrylamide; Li Jinheng's group (Angew. Chem., 2013, 125, 3726-3729) developed a new Fe-catalyzed oxidation pathway, using TBHP as an oxidant, to prepare a variety of functionalized carbonyl indoles through 1,2-alkyl arylation of the C=C bond in N-aryl acrylamide; in 2014, Bruce H. Lipshutz's group (Chem. Commun., 2014, 50, 936-938) disclosed the copper-catalyzed trifluoromethylation reaction of N-aryl acrylamide, and synthesized a variety of carbonyl indoles containing -CF3 in the free radical process.

[0006] In 2017, Wang Lei's research group (Green Chemistry, 2017, 19(7): 1732-1739) reported a visible light-induced direct cyclization reaction of acrylamide and cyclic ether using EosinY as a photosensitizer and TBHP as an oxidant. The reaction conditions are mild, the operation is simple and environmentally friendly, and a variety of alkylated indolones can be prepared under metal-free conditions at room temperature. However, the oxidant is flammable, the operation is dangerous, and the reaction yield is relatively low.

[0007] At present, photocatalytic synthesis has become increasingly prominent as a viable platform for molecular synthesis and is considered to be an effective alternative method for activating CH bonds under mild conditions. Compared with transition metal catalysts, organic dyes are more excellent due to their low cost, non-toxicity and environmental friendliness, and can replace transition metal catalysts in photocatalytic synthesis reactions. Therefore, in order to develop a milder and high-yield method for preparing indolone derivatives, the synthetic route for preparing indolone derivatives through photocatalytic free radical oxidative coupling reaction using organic dyes as photosensitizers still needs to be further developed. Summary of the invention

[0008] In view of the problems in the prior art that the photocatalytic system needs to be carried out under the action of a transition metal catalyst or an oxidant and has a low yield, the present invention provides an indolinone derivative and a preparation method and application thereof. The method uses N-phenylmethyl acrylamide as a raw material, phenylhydrazine provides free radicals, and synthesizes the indolinone derivative under simple and mild conditions; and provides a new synthesis route of the indolinone derivative, which has mild reaction conditions and high yield.

[0009] The technical solution of the present invention is as follows:

[0010] A method for preparing an indolinone derivative, wherein the method uses N-phenylmethyl acrylamide or its derivatives and phenylhydrazine as raw materials, and prepares the indolinone derivative through a photocatalytic reaction under an inert atmosphere;

[0011] The synthetic route is as follows:

[0012]

[0013] Furthermore, the general structural formula of the N-phenylmethylacrylamide and its derivatives is as follows:

[0014]

[0015] Wherein, R1-R4 are each independently selected from at least one of H, C1-C5 alkyl, aryl, alkoxy, halogen and nitro; preferably at least one of -H, -CH3, -Cl and -OCH3.

[0016] R5 is selected from any one of H, C1-C5 alkyl, aryl, alkoxy, halogen and nitro; preferably -CH3 or phenyl.

[0017] Furthermore, the photocatalytic system includes: a light source, a photosensitizer and a solvent.

[0018] Furthermore, the light source is a blue light LED; preferably a 10W blue light LED.

[0019] Furthermore, the photosensitizer is at least one of Rose Bengal RB, Eosin Y, Eosin B, Rhodamine 6G and fluorescein; preferably at least one of Rose Bengal RB, Eosin Y, Eosin B and Rhodamine 6G; further preferably Rose Bengal RB or Rhodamine 6G; further preferably Rose Bengal RB.

[0020] Furthermore, the cobalt salt is at least one of Co(OAc)2, CoCl2, and CoSO4; preferably Co(OAc)2.

[0021] Furthermore, the base is at least one of NaOPiv, KOt-Bu, LiOt-Bu, K2CO3 and Cs2CO3; preferably NaOPiv.

[0022] Furthermore, the solvent is at least one of 1,2-dichloroethane, dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, dichloromethane and ethanol; preferably at least one of 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, dichloromethane and ethanol; further preferably at least one of acetonitrile, N,N-dimethylformamide, dichloromethane and ethanol; further preferably dichloromethane or ethanol; further preferably ethanol.

[0023] Furthermore, the inert atmosphere is nitrogen or argon, preferably nitrogen.

[0024] Further, the molar ratio of N-phenylmethylacrylamide or its derivative to phenylhydrazine is 1:0.6-3; preferably 1:0.8-2.8; further preferably 1:1.0-2.6; further preferably 1:1.2-2.4; further preferably 1:1.4-2.2; further preferably 1:1.5-2.0; further preferably 1:1.5-1.8.

[0025] Furthermore, the molar ratio of the N-phenylmethyl acrylamide or its derivative to the photosensitizer is 10-20:1; preferably 15-20:1; and more preferably 15-18:1.

[0026] Furthermore, the molar ratio of N-phenylmethyl acrylamide or its derivative to Co(OAc)2 is 4-10:1; preferably 5-10:1; and further preferably 8-10:1.

[0027] Furthermore, the molar ratio of the N-phenylmethylacrylamide or its derivative to NaOPiv is 0.5-3:1; preferably 1-2:1; and more preferably 1-1.5:1.

[0028] Furthermore, the photocatalytic reaction temperature is room temperature, and the reaction time is 10-15 hours, preferably 12 hours.

[0029] The present invention also provides an indole ketone derivative prepared by any of the above preparation methods.

[0030] The present invention also provides the use of the indole derivatives in the preparation of anticancer cell drugs.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] 1. The present invention provides a new synthesis route of indolone derivatives, which utilizes the photochemical catalytic CH / NH activation method, in the presence of cobalt salt and base, uses organic dye as a photosensitizer, provides free radicals through photocatalytic phenylhydrazine, and synthesizes indolone derivatives through a free radical pathway with N-phenylmethylacrylamide or its derivatives; the synthesis route is simple to operate; the product purity is high (all above 89%), and the yield is as high as above 90%;

[0033] 2. The photochemical catalysis of the present invention uses organic dyes as photosensitizers, avoiding the use of chemical oxidants, and has simple operation, mild reaction conditions, and is environmentally friendly and pollution-free;

[0034] 3. The present invention can greatly improve the yield of the reaction product by selecting an organic solvent;

[0035] 4. The indole derivatives prepared by the present invention have anticancer effect and are widely used in the pharmaceutical field. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 The H NMR spectrum of the compound prepared in Example 1 of the present invention;

[0037] Figure 2 The NMR carbon spectrum of the compound prepared in Example 1 of the present invention;

[0038] Figure 3 This is the H NMR spectrum of the compound prepared in Example 2 of the present invention;

[0039] Figure 4 The NMR carbon spectrum of the compound prepared in Example 2 of the present invention;

[0040] Figure 5 This is the H NMR spectrum of the compound prepared in Example 3 of the present invention;

[0041] Figure 6 The NMR carbon spectrum of the compound prepared in Example 3 of the present invention;

[0042] Figure 7 This is the H NMR spectrum of the compound prepared in Example 4 of the present invention;

[0043] Figure 8 The NMR carbon spectrum of the compound prepared in Example 4 of the present invention;

[0044] Fig. 9 This is the H NMR spectrum of the compound prepared in Example 5 of the present invention;

[0045] Fig.10 This is the NMR carbon spectrum of the compound prepared in Example 5 of the present invention;

[0046] Fig.11 This is the H NMR spectrum of the compound prepared in Example 6 of the present invention;

[0047] Fig.12 The NMR carbon spectrum of the compound prepared in Example 6 of the present invention;

[0048] Fig.13 This is the H NMR spectrum of the compound prepared in Example 7 of the present invention;

[0049] Fig.14 This is the NMR carbon spectrum of the compound prepared in Example 7 of the present invention;

[0050] Fig.15 This is the H NMR spectrum of the compound prepared in Example 8 of the present invention;

[0051] Fig.16 This is the NMR carbon spectrum of the compound prepared in Example 8 of the present invention;

[0052] Fig.17 This is the H NMR spectrum of the compound prepared in Example 9 of the present invention;

[0053] Fig.18 This is the NMR carbon spectrum of the compound prepared in Example 9 of the present invention;

[0054] Fig.19 This is the H NMR spectrum of the compound prepared in Example 10 of the present invention;

[0055] Fig. 20 The NMR carbon spectrum of the compound prepared in Example 10 of the present invention;

[0056] Fig.21This is the H NMR spectrum of the compound prepared in Example 11 of the present invention;

[0057] Fig. 22 This is the carbon NMR spectrum of the compound prepared in Example 11 of the present invention. DETAILED DESCRIPTION

[0058] The above-mentioned features mentioned in the present invention or the features mentioned in the embodiments can be combined arbitrarily; all the features explained in the specification of this case can be used in combination with any method form, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equal or similar purpose; therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features.

[0059] The present invention is further described below in conjunction with specific examples; these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. The following examples are implementation methods with specific conditions noted, usually according to conventional conditions or according to the conditions recommended by the manufacturer; unless otherwise defined, all professional and scientific terms used in the text have the same meanings as those known to those skilled in the art. In addition, any methods and materials similar or equivalent to the recorded contents can be applied to the method of the present invention. The preferred implementation methods and materials described in the text are only for demonstration purposes. It is worth noting that the raw materials used in the present invention are all common commercially available products, and their sources are not specifically limited.

[0060] Embodiment 1:

[0061] N-(2-dimethyl)-N-(2-phenyl)-2-acrylamide (0.3 mmol), phenylhydrazine (0.45 mmol), Co(OAc)2 (0.03 mmol), NaOPiv (0.6 mmol) and Bengal rose red RB (0.03 mmol) were added to EtOH (10 mL) at room temperature under N2 atmosphere and reacted for 12 h. After the reaction, the mixture was transferred to a flask; then the solvent was evaporated to dryness under reduced pressure, and the mixture was chromatographed on silica gel using a mixture of ethyl acetate / petroleum ether (20:1) as an eluent; a yellow solid was obtained with a yield of 81% (purity: 99%) and a melting point of 89.1-90.6°C.

[0062]

[0063] FT-IR(KBr): 2925,1711,1611,1485,1375,750cm -1 ;

[0064] 1H NMR (400MHz, CDCl3) δ (ppm) = 7.21-7.10 (m, 2H), 7.04 (dd, J = 10.1, 6.4Hz, 4H), 6.85(d,J=7.6Hz,2H),6.61(d,J=7.7Hz,1H),3.15-2.97(m,5H),1.48(s,3H);

[0065] 13 C NMR (100MHz, CDCl3) δ (ppm) = 180.0, 143.1, 136.1, 133.0, 129.8, 127.7, 127.4, 126.4, 123.3, 122.0, 107.7, 49.9, 44.5, 25.8, 22.7;

[0066] MS(EI,70eV)m / z:251.16,160.13,91.13.

[0067] Embodiment 2:

[0068] N-(2-dimethyl)-N-(2-methylphenyl)-2-acrylamide (0.3mmol), phenylhydrazine (0.18mmol), Co(OAc)2 (0.075mmol), NaOPiv (0.1mmol) and Bengal rose red RB (0.015mmol) were added to DCM (10mL) at room temperature under N2 atmosphere and reacted for 12h. After the reaction, the mixture was transferred to a flask; then the solvent was evaporated to dryness under reduced pressure, and a mixture of ethyl acetate / petroleum ether (20:1) was used as an eluent, and the mixture was chromatographed on silica gel to obtain a light oil with a yield of 75% (purity: 99%).

[0069]

[0070] FT-IR(KBr): 2975,1764,1707,1456,1243,1065,700cm -1 ;

[0071] 1 H NMR (400MHz, CDCl3): δppm=7.10-7.02(m,3H),7.00-6.94(m,1H),6.93-6.89(m,2H),6. 86-6.81(m,2H),3.26(s,3H),3.04(dd,J=49.7,12.9Hz,2H),2.40(s,3H),1.46(s,3H);

[0072] 13C NMR (100MHz, CDCl3): δppm=180.7,140.9,136.2,133.6,131.4,129.8,127.4,126.3,121.9,121.1,119.3,49.2,44.8,29.2,23.0,18.8;

[0073] MS (EI, 70eV) m / z: 265.21, 174.16, 91.14.

[0074] Embodiment 3:

[0075] N-(2-fluorophenyl)-N-(2-dimethyl)-2-acrylamide (0.3 mmol), phenylhydrazine (0.9 mmol), Co(OAc)2 (0.06 mmol), NaOPiv (0.15 mmol) and Rose Bengal RB (0.02 mmol) were added to EtOH (10 mL) at room temperature under N2 atmosphere and reacted for 12 h. After the reaction, the mixture was transferred to a flask; then the solvent was evaporated to dryness under reduced pressure, and a mixture of ethyl acetate / petroleum ether (20:1) was used as an eluent, and the mixture was chromatographed on silica gel to obtain a brown oily substance with a yield of 86% (purity: 99%).

[0076]

[0077] FT-IR(KBr): 2989,1764,1718,1242,1056,783cm -1 ;

[0078] 1 H NMR (400MHz, CDCl3): δ (ppm) = 7.08 (t, J = 6.1Hz, 3H), 6.95 (m,

[0079] 3H),6.83(d,J=6.5Hz,2H),3.19(d,J=2.3Hz,3H),3.06(dd,J=62.0,13.0Hz,2H),

[0080] 1.47(s,3H);

[0081] 13 C NMR (100MHz, CDCl3): δ (ppm) = 179.5, 148.7, 146.3, 136.0 (J = 11.8Hz), 135.8, 129.7, 127.6, 12 6.6, 122.5 (J = 25.3Hz), 119.1 (J = 12.3Hz), 115.7 (J = 76.9Hz), 50.3, 44.7, 28.3 (J = 23.3), 22.9;

[0082] HRMS(ESI)m / z:calcdfor C 17 H 17 FNO,270.1289; found,270.1288.

[0083] Embodiment 4:

[0084] N-(2-methoxyphenyl)-N-(2-dimethyl)-2-acrylamide (0.3 mmol), phenylhydrazine (0.78 mmol), Co(OAc)2 (0.045 mmol), NaOPiv (0.2 mol) and Bengal rose red RB (0.03 mmol) were added to DCM (10 mL) at room temperature under N2 atmosphere and reacted for 12 h. After the reaction, the mixture was transferred to a flask; then the solvent was evaporated to dryness under reduced pressure, and a mixture of ethyl acetate / petroleum ether (10:1) was used as an eluent, and the mixture was chromatographed on silica gel to obtain a brown oil with a yield of 78% (purity: 99%).

[0085]

[0086] FT-IR(KBr): 2928,1706,1463,1248,1046,737cm -1 ;

[0087] 1 H NMR (400MHz, CDCl3): δ (ppm) = 7.07 (d, J = 6.6Hz, 3H), 6.97 (t, J = 7.9Hz, 1H), 6.88-6.83 (m, 2H ),6.79-6.73(m,2H),3.74(s,3H),3.26(s,3H),3.05(dd,J=53.5,13.0Hz,2H),1.45(s,3H);

[0088] 13 C NMR (100MHz, CDCl3): δ (ppm) = 180.3, 145.1, 136.2, 134.7, 129.8, 127.5, 126.4, 122.6, 116.1, 115.3, 111.8, 56.0, 50.0, 44.6, 29.1, 23.1;

[0089] HRMS(ESI)m / z:calcdfor C 18 H 20 NO2,282.1489; found,282.1489.

[0090] Embodiment 5:

[0091] N,2-dimethyl-N-(4-methylphenyl)-2-acrylamide (0.3mmol), phenylhydrazine (0.45mmol), Co(OAc)2 (0.045mmol), NaOPiv (0.6mmol) and rhodamine 6G (0.3mmol) were added to EtOH (10mL) at room temperature under N2 atmosphere and reacted for 12h. After the reaction, the mixture was transferred to a flask; then the solvent was evaporated to dryness under reduced pressure, and a mixture of ethyl acetate / petroleum ether (20:1) was used as an eluent, and the mixture was chromatographed on silica gel to obtain a yellow oil with a yield of 84% (purity: 99%).

[0092]

[0093] FT-IR(KBr): 2924,1710,1498,1363,808cm -1 ;

[0094] 1 H NMR (400MHz, CDCl3): δ (ppm) = 7.06 (dd, J = 7.9, 2.7Hz, 3H), 7.00-6.93 (m, 2H), 6.88-6.83 (m, 2H) ),6.50(d,J=7.8Hz,1H),3.05(dd,J=41.8,13.0Hz,2H),2.96(s,3H),2.35(s,3H),1.46(s,3H);

[0095] 13 C NMR (100MHz, CDCl3): δ (ppm) = 179.9, 140.7, 136.2, 133.0, 131.4, 129.8, 127.9, 127.4, 126.3, 124.1, 107.4, 49.9, 44.5, 25.8, 22.7, 21.1;

[0096] MS(EI,70eV)m / z: 265.21,174.17,91.15.

[0097] Embodiment 6:

[0098] N-(4-fluorophenyl)-N-(2-dimethyl)-2-acrylamide (0.3 mmol), phenylhydrazine (0.45 mmol), Co(OAc)2 (0.045 mmol), NaOPiv (0.6 mmol) and rhodamine 6G (0.3 mmol) were added to EtOH (10 mL) at room temperature under N2 atmosphere and reacted for 12 h. After the reaction, the mixture was transferred to a flask; then the solvent was evaporated to dryness under reduced pressure, and a mixture of ethyl acetate / petroleum ether (20:1) was used as an eluent, and the mixture was chromatographed on silica gel to obtain a brown solid with a yield of 72% (purity: 98%) and a melting point of 104.2-105.3°C.

[0099]

[0100] FT-IR(KBr): 2927,1712,1494,1241,1054,699cm -1 ;

[0101] 1 H NMR (400MHz, CDCl3): δ (ppm) = 7.07 (dd, J = 5.0, 1.7Hz, 3H), 6.91-6.83 (m, 4H), 6.51 (dd, J = 9.2, 4.1Hz, 1H), 3.19-2.92 (m, 5H), 1.47 (s, 3H);

[0102] 13 C NMR (100MHz, CDCl3): δ (ppm) = 179.6, 159.0 (J = 954.0Hz), 139.0 (J = 7.2Hz), 135.8, 134.7 (J = 31.4Hz), 129.7,127.6,126.6,113.8(J=93.7Hz),111.4(J=97.8Hz),108.1(J=32.5Hz),50.4,44.4,26.0,22.6;

[0103] MS(EI,70eV)m / z: 269.19,178.12,91.12.

[0104] Embodiment 7:

[0105] N-(4-chlorophenyl)-N-(2-dimethyl)-2-acrylamide (0.3 mmol), phenylhydrazine (0.45 mmol), Co(OAc)2 (0.045 mmol), NaOPiv (0.6 mmol) and Bengal rose red RB (0.03 mmol) were added to EtOH (10 mL) at room temperature under N2 atmosphere and reacted for 12 h. After the reaction, the mixture was transferred to a flask; then the solvent was evaporated to dryness under reduced pressure, and a mixture of ethyl acetate / petroleum ether (20:1) was used as an eluent, and the mixture was chromatographed on silica gel to obtain a brown oil with a yield of 79% (purity: 98%).

[0106]

[0107] FT-IR(KBr): 2927,1715,1490,1350,882cm -1 ;

[0108] 1 H NMR (400MHz, CDCl3): δ (ppm) = 7.15 (dd, J = 8.2, 1.6Hz, 1H), 7.09 (t, J = 7.6Hz, 4H), 6.88-6. 82(m,2H),6.52(d,J=8.2Hz,1H),3.11(dd,J=47.5,34.4Hz,2H),2.96(s,3H),1.47(s,3H);

[0109] 13 C NMR (100MHz, CDCl3): δ (ppm) = 179.4, 141.7, 135.7, 134.8, 130.0, 127.6, 127.6, 127.5, 126.6, 123.8, 108.6, 50.2, 44.5, 26.0, 22.6;

[0110] MS (EI, 70eV) m / z: 285.13, 194.09, 91.10.

[0111] Embodiment 8:

[0112] N-(2-dimethyl)-N-(3-methylphenyl)-2-acrylamide (0.3 mmol), phenylhydrazine (0.45 mmol), Co(OAc)2 (0.03 mmol), NaOPiv (0.6 mmol) and Bengal rose red RB (0.03 mmol) were added to EtOH (10 mL) at room temperature under N2 atmosphere and reacted for 12 h. After the reaction, the mixture was transferred to a flask; then the solvent was evaporated to dryness under reduced pressure, and a mixture of ethyl acetate / petroleum ether (20:1) was used as an eluent, and the mixture was chromatographed on silica gel to obtain a yellow oil with a yield of 89% (purity: 98%).

[0113]

[0114] FT-IR(KBr): 2927,1712,1616,1460,1307,744cm -1 ;

[0115] 1 H NMR (400MHz, CDCl3): δ (ppm) = 7.12-6.96 (m, 4H), 6.91-6.77 (m, 3H), 6.49-6. 35(m,1H),3.30-2.85(m,5H),2.44(d,J=80.6Hz,3H),1.53(d,J=61.9Hz,3H);

[0116] 13 C NMR (100MHz, CDCl3): δ (ppm) = 180.2, 179.6, 143.3, 143.1, 137.6, 136.3, 136.3, 134.0, 129.9, 129.8, 129.7, 128.9, 127.5, 127.4,127.3,126.3,126.2,124.8,123.0,122.5,108.7,105.4,51.1,49.6,44.3,42.3,25.8,25.7,22.8,21.7,21.3,18.4;

[0117] MS(EI,70eV)m / z: 265.21,174.17,91.14.

[0118] Embodiment 9:

[0119] N-(2-dimethyl)-N-(3,4,5-trimethoxyphenyl)-2-acrylamide (0.3 mmol), phenylhydrazine (0.45 mmol), Co(OAc)2 (0.03 mmol), NaOPiv (0.6 mmol) and Bengal rose red RB (0.03 mmol) were added to EtOH (10 mL) at room temperature under N2 atmosphere and reacted for 12 h. After the reaction, the mixture was transferred to a flask; then the solvent was evaporated to dryness under reduced pressure, and a mixture of ethyl acetate / petroleum ether (5:1) was used as an eluent, and the mixture was chromatographed on silica gel to obtain a black solid with a yield of 93% (purity: 99%) and a melting point of 90.8-92.2°C.

[0120]

[0121] FT-IR(KBr): 2933,1710,1614,1466,1249,1021,703cm -1 ;

[0122] 1 H NMR (400MHz, CDCl3): δ (ppm) = 6.98 (d, J = 4.2Hz, 3H), 6.91-6.83 (m, 2H), 5.90 (s, 1H), 4.08 ( s,3H),3.82(s,3H),3.79(s,3H),3.19(dd,J=42.5,12.7Hz,2H),2.88(s,3H),1.55(s,3H);

[0123] 13 C NMR (100MHz, CDCl3): δ (ppm) = 180.2, 153.9, 150.5, 139.1, 137.3, 137.1, 1 29.1,127.3,126.1,115.2,89.1,60.9,60.8,56.3,51.1,42.7,25.9,22.4;

[0124] MS (EI, 70eV) m / z: 341.21, 250.19, 91.14.

[0125] Embodiment 10:

[0126] N-(2-dimethyl)-N-(1-naphthyl)-2-acrylamide (0.3 mmol), phenylhydrazine (0.45 mmol), Co(OAc)2 (0.045 mol), NaOPiv (0.6 mmol) and rhodamine 6G (0.3 mmol) were added to EtOH (10 mL) at room temperature under N2 atmosphere and reacted for 12 h. After the reaction, the mixture was transferred to a flask; then the solvent was evaporated to dryness under reduced pressure, and a mixture of ethyl acetate / petroleum ether (10:1) was used as an eluent, and the mixture was chromatographed on silica gel to obtain a red oil with a yield of 78% (purity: 98%).

[0127]

[0128] FT-IR(KBr): 2925,1710,1432,1373,1244,1053,700cm -1 ;

[0129] 1 H NMR (400MHz, CDCl3): δ (ppm) = 8.19 (dd, J = 35.1, 8.8Hz, 1H), 7.78 (dd, J = 29.9, 8.8Hz, 1H), 7.53-7.11 (m, 4H), 6.93(dd,J=17.4,4.1Hz,3H),6.84-6.71(m,2H),3.53(d,J=23.2Hz,3H),3.07(m,2H),1.45(d,J=6.5Hz,3H);

[0130] 13 C NMR (100MHz, CDCl3): δ (ppm) = 181.6, 181.5, 141.0, 138.0, 137.6, 136.1, 136.1, 134.9,134.3,132.2,130.2,129.8,129.7,129.3,128.8,128.3,128.2,127.5,1 27.5,127.4,127.2,126.5,126.4,125.5,125.4,125.2,125.1,122.6,122.3,121.6,121.4,121.1,121.0,120.8,49.8,49.8,44.5,44.5,30.6,30.3,23.0,22.9.

[0131] HRMS(ESI)m / z:calcdfor C 21 H 20 NO,302.1539;found,302.1540.

[0132] Embodiment 11:

[0133] N-(Benzyl-2-methyl)-N-phenyl-2-acrylamide (0.3 mmol), phenylhydrazine (0.45 mmol), Co(OAc)2 (0.03 mol), NaOPiv (0.6 mmol) and rhodamine 6G (0.3 mmol) were added to DCM (10 mL) at room temperature under N2 atmosphere and reacted for 12 h. After the reaction, the mixture was transferred to a flask; then the solvent was evaporated to dryness under reduced pressure, and a mixture of ethyl acetate / petroleum ether (10:1) was used as an eluent, and the mixture was chromatographed on silica gel to obtain a brown solid with a yield of 85% (purity: 99%).

[0134]

[0135] FT-IR(KBr): 2975,1709,1610,1460,1374,1236,750cm -1 ;

[0136] 1 H NMR (400MHz, CDCl3): δ (ppm) = 7.19 (dd, J = 13.2, 7.9Hz, 2H), 7.08-6.99 (m, 4H), 6.82 (dd, J = 7.5, 1.5Hz, 2H ),6.62(d,J=7.7Hz,1H),3.54(m,2H),3.08(dd,J=53.9,12.9Hz,2H),1.48(s,3H),0.86(t,J=7.2Hz,3H);

[0137] 13 C NMR (100MHz, CDCl3): δ (ppm) = 179.4, 142.2, 136.1, 133.3, 129.8, 127.7, 127.4, 126.3, 123.3, 121.9, 107.9, 49.8, 44.6, 34.1, 22.9, 12.1;

[0138] MS(EI,70eV)m / z: 265.20,174.15,91.13.

[0139] Comparative Example 1:

[0140] N-(2-dimethyl)-N-(2-phenyl)-2-acrylamide (0.3 mmol), phenylhydrazine (0.45 mmol), Co(OAc)2 (0.03 mmol), NaOPiv (0.6 mmol) and Ir(ppy)3 (0.03 mmol) were added to EtOH (10 mL) at room temperature under N2 atmosphere and reacted for 12 h. After the reaction, the mixture was transferred to a flask; then the solvent was evaporated to dryness under reduced pressure, and the mixture was chromatographed on silica gel using a mixture of ethyl acetate / petroleum ether (20:1) as an eluent; a yellow solid was obtained with a yield of 31% (purity: 95%).

[0141]

[0142] Comparative Example 2:

[0143] N-(2-dimethyl)-N-(2-phenyl)-2-acrylamide (0.3 mmol), phenylhydrazine (0.45 mmol), Co(OAc)2 (0.03 mmol), NaOPiv (0.6 mmol) and Rose Bengal RB (0.03 mmol) were added to toluene (10 mL) at room temperature under N2 atmosphere and reacted for 12 h. After the reaction, the mixture was transferred to a flask; then the solvent was evaporated to dryness under reduced pressure, and the mixture was chromatographed on silica gel using a mixture of ethyl acetate / petroleum ether (20:1) as an eluent; a yellow solid was obtained with a yield of 28% (purity: 97%).

[0144]

[0145] Test example:

[0146] The indolinone compounds prepared in Example 3, Example 4, and Example 11 were selected for MTT test, osimertinib (AZD-9291) was used as a positive control drug, and HepG2 (human liver cancer cells) and HeLa (cervical cancer cells) were selected as cells.

[0147] The specific operation method is as follows:

[0148] (1) Cell recovery, culture and subculture

[0149] After taking the frozen cells out of the refrigerator, quickly thaw them in a 37.5℃ constant temperature water bath. Then add the thawed cells to an ep tube containing 1mL DMEM in a clean bench, put it in a centrifuge, and centrifuge it at 1000rpm for 3 minutes. After completion, discard the supernatant, add complete culture medium, blow it evenly, and take it to the culture bottle. When the color of the culture medium changes, replace the culture medium. When the cells grow to 90% of the culture bottle, pass them on. First, pour out the old culture medium, slowly add 2mL PBS to wash the culture bottle, and then add 0.5mL trypsin to digest. When the cells begin to fall off, add culture medium and blow it gently until the cells fall off completely. Then collect the cell suspension and centrifuge it at 1000rpm for 3 minutes, discard the supernatant, add complete culture medium, blow it evenly, and divide it into two culture bottles.

[0150] (2) MTT method

[0151] Take the logarithmically growing cells, digest them and pipette to evenly distribute the cells, then count the cells and dilute them to 6×10 3 (cell / mL), evenly add 100μL of cell suspension to the 96-well plate (not added to the 36 wells on the edge), place it in the incubator, and give the drug after the cells adhere to the wall for 12 hours. The drug is set to 5 concentrations (90μM, 30μM, 10μM, 3.3μM, 1.1μM) and 3 replicates are set. After giving the drug, continue to incubate in the incubator for 48 hours. After the incubation is completed, discard the original solution, add 10μL of MTT solution (5mg / mL) and 90μL of blank culture medium, continue to culture for 4 hours, then discard the original solution, add 100μL of DMSO solution to dissolve, shake on a shaker for 15 minutes, and use an enzyme reader to measure the absorbance value of each well at a wavelength of 490nm.

[0152] Finally, the cell survival rate was calculated using the following formula:

[0153]

[0154] IC of analyzed compounds 50 The values ​​show that this series of compounds has certain inhibitory activity against the above cell lines. The results are as follows:

[0155] Table 1 In vitro antiproliferative activity of the compounds prepared in the examples and the positive control

[0156]

[0157]

[0158] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing an indole derivative, characterized in that: Indolone derivatives are prepared by photocatalytic reaction under inert atmosphere using N-phenylmethacrylamide derivatives and phenylhydrazine as raw materials. The synthetic route is as follows: The indolinone derivative is The power of the blue light LED is 10-20W, the photosensitizer is Bengal Rose Red RB or Rhodamine 6G, and the solvent is dichloromethane or ethanol.

2. The preparation method according to claim 1, characterized in that: The cobalt salt is at least one of Co(OAc)2, CoCl2, and CoSO4; the base is at least one of NaOPiv, KOt-Bu, LiOt-Bu, K2CO3, and Cs2CO3.

3. The preparation method according to any one of claims 1-2, characterized in that: The molar ratio of the N-phenylmethylacrylamide derivative to phenylhydrazine is 1:0.6-3; the molar ratio of the N-phenylmethylacrylamide derivative to the photosensitizer is 10-20:1; the molar ratio of the N-phenylmethylacrylamide derivative to the cobalt salt is 4-10:1; and the molar ratio of the N-phenylmethylacrylamide derivative to the base is 0.5-3:1.

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