3-aryl-4-sulfonyl-1, 3, 4, 5-tetrahydrobenzo [cd]-indole compound as well as preparation method and application thereof

Abstract

The invention discloses a 3-aryl-4-sulfonyl-1, 3, 4, 5-tetrahydrobenzo [cd]-indole compound in the technical field of organic chemical synthesis, and the structural formula of the 3-aryl-4-sulfonyl-1, 3, 4, 5-tetrahydrobenzo [cd]-indole compound is as follows: # imgabs0 # is prepared by the following steps: sequentially adding beta-4 '-methylindole aryl ethylene, alkyl or aryl sulfonyl chloride and a solvent into a Schlenk tube with a stirrer; the 3-aryl-4-sulfonyl-1, 3, 4, 5-tetrahydrobenzo [cd]-indole compound is prepared by a one-pot method under the condition of constant-temperature organic photocatalysis. The method has the advantages of mild conditions and no need of additional oxidant, and provides a green and efficient preparation method for the sulfonyl-modified 1, 3, 4, 5-tetrahydrobenzo [cd]-indole compound. Meanwhile, according to verification, the 3-aryl-4-sulfonyl-1, 3, 4, 5-tetrahydrobenzo [cd]-indole compound has certain anti-hepatoma activity and can be applied to preparation of anti-hepatoma drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemical synthesis, and particularly relates to a 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]indole compound, a preparation method thereof, and an application thereof. Background Art

[0002] As a compound with a unique structure, 1,3,4,5-tetrahydrobenzo[cd]indole shows great potential in drug development. Nicergoline for treating cerebrovascular diseases, Methysergide for preventing migraine, and Metoclopramide with anti-anxiety and sedative effects are all closely related to the structure of 1,3,4,5-tetrahydrobenzo[cd]indole. At the same time, as a common synthetic intermediate, the sulfonyl group can significantly improve the solubility and biocompatibility of compounds. Introducing the sulfonyl group into drug molecules can enhance their pharmacokinetic properties. In view of the unique structures and importance of 1,3,4,5-tetrahydrobenzo[cd]indole and the sulfonyl group, developing an efficient and practical synthesis method for sulfonyl-modified 1,3,4,5-tetrahydrobenzo[cd]indole compounds is of great significance for the discovery of drug lead compounds and new drug development. Currently, the acid-catalyzed cyclization reaction is one of the main methods for constructing the indole polycyclic structure (Organic Letters, 2019, 21, 1574-1577), but these methods usually have problems such as high temperature and strong acid, narrow substrate scope, and environmental pollution. In addition, 1,3,4,5-tetrahydrobenzo[cd]indole compounds can also be constructed by using appropriate ketones and amines for reductive amination reactions (CN1036566A, J. Am. Chem. Soc., 2006, 128, 4946–4947). However, since the preparation of the ketone precursor is relatively complex and requires multiple steps to complete, and the reaction conditions are harsh, to a certain extent, it limits the synthesis of diverse products and related industrial applications. Summary of the Invention

[0003] Aiming at the deficiencies of the prior art, the present invention designs a method for preparing 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]indole compounds in one step under the conditions of organic photocatalytic synthesis.

[0004] One of the purposes of the present invention is to provide a 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]indole compound, and its structural formula is as follows:

[0005]

[0006] Ar is 4-methylphenyl, biphenyl, 2-naphthyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-i-propoxyphenyl, 4-butoxyphenyl, 4-phenoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, 3-methyl-4-methoxyphenyl or 2,3-dihydrobenzofuran-5-yl;

[0007] R is methyl, ethyl, propyl, cyclopropyl, phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-butoxyphenyl, 4-phenoxyphenyl, 4-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, biphenyl, 2-naphthyl, 2-thienyl, 2-furyl or 2-benzofuryl;

[0008] R' is hydrogen, methyl or benzyl.

[0009] The second object of the present invention is to provide a preparation method of 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds. β-4'-methylindole aryl ethylene, alkyl or aryl sulfonyl chloride, and a solvent are sequentially added into a reaction vessel, and 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds are prepared by a one-pot method under constant-temperature organic photocatalytic conditions. The reaction general formula is as follows:

[0010]

[0011] The working principle and beneficial effects of the present invention: The present invention innovatively uses β-4'-methylindole aryl ethylene and alkyl or aryl sulfonyl chloride as raw materials, and 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds are obtained through an organic photocatalytic synthesis reaction and subsequent purification process. This reaction makes full use of the EDA complex (electron donor-acceptor complex) to develop a new reaction mode for synthesizing novel and diverse 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds.

[0012] Further, the molar ratio of each substance in the reaction: β-4'-methylindole aryl ethylene: sulfonyl chloride = 1:0.5 - 5, preferably 1:1.5.

[0013] Further, the solvent is selected from one or more of ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, acetone, 1,2-dichloroethane, toluene, dimethyl sulfoxide, methanol, 1,4-dioxane or N,N-dimethylformamide, preferably ethyl acetate.

[0014] Further, in the above solution, the light source is selected from violet light (5 - 50 W), blue light (5 - 50 W), white light (5 - 50 W), and red light (5 - 50 W), preferably violet light (40 W).

[0015] Further, the temperature used is 0 - 60 °C, preferably 25 °C; the reaction time is 0.5 - 24 h, preferably 12 h; the gas atmosphere is selected from air, argon, nitrogen, and oxygen, preferably argon; the separation and purification method is selected from column chromatography and recrystallization, preferably column chromatography.

[0016] The third object of the present invention is to provide the application of C-3 benzylated indole compounds in the preparation of anti-hepatocellular carcinoma drugs. After verification, the described 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds have certain anti-cancer (human hepatocellular carcinoma SMMC-7721 cells) drug activities.

[0017] The present invention uses β-4'-methylindole aryl ethylene, alkyl or aryl sulfonyl chloride as raw materials, and under the conditions of organic photocatalytic synthesis, prepares 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds in one step. This method has the characteristics of easy availability of raw materials, mild reaction conditions, no need to add metals and oxidants, and easy derivatization and transformation of products, providing a green and efficient synthetic route for 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds. Description of the Drawings

[0018] Figure 1 Single crystal drawing of compound 1f prepared in Example 6;

[0019] Figure 2 For the 1 H NMR spectrum of compound 1a prepared in Example 1;

[0020] Figure 3 For the 13 C NMR spectrum of compound 1a prepared in Example 1;

[0021] Figure 4 For the 1 H NMR spectrum of compound 1b prepared in Example 2;

[0022] Figure 5 For the 13 C NMR spectrum of compound 1b prepared in Example 2;

[0023] Figure 6 For the 1 H NMR spectrum of compound 1d prepared in Example 4;

[0024] Figure 71H NMR spectrum of compound 1d prepared in Example 4; 13 13C NMR spectrum;

[0025] Figure 8 1H NMR spectrum of compound 1e prepared in Example 5; 1 13C NMR spectrum;

[0026] Figure 9 1H NMR spectrum of compound 1e prepared in Example 5; 13 13C NMR spectrum;

[0027] Figure 10 1H NMR spectrum of compound 1f prepared in Example 6; 1 13C NMR spectrum;

[0028] Figure 11 1H NMR spectrum of compound 1f prepared in Example 6; 13 13C NMR spectrum;

[0029] Figure 12 1H NMR spectrum of compound 1g prepared in Example 7; 1 13C NMR spectrum;

[0030] Figure 13 1H NMR spectrum of compound 1g prepared in Example 7; 13 13C NMR spectrum;

[0031] Figure 14 1H NMR spectrum of compound 1i prepared in Example 9; 1 13C NMR spectrum;

[0032] Figure 15 1H NMR spectrum of compound 1i prepared in Example 9; 13 13C NMR spectrum;

[0033] Figure 16 1H NMR spectrum of compound 1j prepared in Example 10; 1 13C NMR spectrum;

[0034] Figure 17 1H NMR spectrum of compound 1j prepared in Example 10; 13 13C NMR spectrum;

[0035] Figure 18 1H NMR spectrum of compound 1k prepared in Example 11; 1 13C NMR spectrum;

[0036] Figure 19 1H NMR spectrum of compound 1k prepared in Example 11; 13 13C NMR spectrum;

[0037] Figure 20Schematic diagram of the inhibitory effect of some compounds on the proliferation of human hepatocellular carcinoma cells (SMMC-7721 cells). Detailed implementation manners

[0038] The following is a further detailed description through specific implementation manners:

[0039] Example 1:

[0040] Using 4-(2E)-(3-(4-methoxyphenyl)allyl)-1-methyl-indole as the olefin substrate and 3-methylbenzenesulfonyl chloride as the sulfonylation reagent, prepare 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound 1a (Reaction Scheme 1)

[0041]

[0042] Add 4-(2E)-(3-(4-methoxyphenyl)allyl)-1-methyl-indole (0.2 mmol, 1.0 equiv.) and 3-methylbenzenesulfonyl chloride (0.3 mmol, 1.5 equiv.) to a 25 mL Schlenk tube equipped with a magnetic stir bar. Evacuate the Schlenk tube and refill it with argon three times. Subsequently, add ultra-dry ethyl acetate (EA) (2.0 mL, 0.1 M) to the Schlenk tube under argon protection. Seal the reaction mixture and place it in a fan-cooled environment at room temperature, while irradiating with ultraviolet light and stirring the reaction for 12 h. After the reaction is completed, monitor by thin-layer chromatography plate (TLC) spotting. After concentration under reduced pressure, the crude product is obtained by column chromatography (using petroleum ether and ethyl acetate as eluents, petroleum ether / ethyl acetate = 15:1 - 5:1) to obtain a dark green solid 1a (dr > 20:1, 52.6 mg, 61%).

[0043] The detection data of product 1a are as follows:

[0044] mp: 82.5 - 83.8 °C

[0045] 1 H NMR (400 MHz, CDCl 3 ) δ 7.27 (d, J = 7.9 Hz, 2H), 7.10 (t, J = 7.6 Hz, 1H), 6.99–6.93 (m, 3H), 6.81 (d, J = 7.3 Hz, 1H), 6.78 (d, J = 7.8 Hz, 2H), 6.71 (d, J = 8.1 Hz, 2H), 6.48 (s, 1H), 4.97 (d, J = 2.6 Hz, 1H), 3.74 (s, 4H), 3.62 (s, 3H), 3.52–3.45 (m, 1H), 3.38–3.30 (m, 1H), 2.23 (s, 3H).

[0046] 13 C NMR (101 MHz, CDCl 3 ) δ 158.4, 143.2, 135.3, 134.7, 134.2, 129.1, 128.1, 127.9, 126.6, 126.2, 124.4, 122.6, 116.1, 113.8, 111.4, 106.8, 68.8, 55.2, 38.6, 32.7, 25.0, 21.4.

[0047] HRMS (ESI, Q-TOF) m / z: [M+Na + Calcd for NaC 26 H 25 O 3 NS, 454.1447. Found: 454.1445.

[0048] Example 2:

[0049] Preparation of 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound 1b with the following structural formula (Reaction Scheme 2)

[0050]

[0051] Replace 4-(2E)-(3-(4-methoxyphenyl)allyl)-1-methyl-indole in Example 1 with 4-(2E)-(3-(3,4,5-trimethoxyphenyl)allyl)-1-methyl-indole, and replace 3-methylbenzenesulfonyl chloride with 4-methylbenzenesulfonyl chloride. Other conditions are the same as in Example 1, and finally obtain a dark green solid 1b (dr > 20:1, 38.3 mg, 39%).

[0052] The detection data of product 1b are as follows:

[0053] mp: 178.4 - 179.5 °C

[0054] 1 H NMR (400 MHz, CDCl 3 ) δ 7.25 (d, J = 8.3 Hz, 2H), 7.14–7.09 (m, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 7.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 2H), 6.45 (s, 1H), 6.25 (s, 2H), 4.88 (d, J = 5.0 Hz, 1H), 3.85–3.82 (m, 1H), 3.80 (s, 3H), 3.66 (s, 6H), 3.63 (s, 3H), 3.54–3.47 (m, 2H), 2.23 (s, 3H).

[0055] 13 C NMR(101MHz,CDCl 3 ) δ 153.2, 143.4, 138.5, 136.8, 135.5, 134.4, 128.11, 128.09, 126.7, 126.4, 124.7, 122.8, 116.4, 112.1, 107.1, 105.4, 68.5, 60.9, 56.2, 40.7, 32.9, 29.8, 25.8, 21.5.

[0056] HRMS(ESI, Q-TOF) m / z: [M+Na + Calcd for NaC 27 H 27 O 5 NS, 514.1659. Found: 514.1658.

[0057] Example 3:

[0058] Prepare 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound 1c with the following structural formula (Reaction Scheme 3)

[0059]

[0060] Replace 4-(2E)-(3-(4-methoxyphenyl)allyl)-1-methyl-indole in Example 1 with 4-(2E)-(3-(5-benzo[d][1,3]dioxolyl)allyl)-1-methyl-indole, and 3-methylbenzenesulfonyl chloride with hydroiodic acid. Other conditions are the same as in Example 1, and finally obtain a dark green oily liquid 1c (18.1 mg, 31%).

[0061] The detection data of product 1c are as follows:

[0062] 1 H NMR(400MHz, CDCl 3 ) δ 7.23–7.18(m, 1H), 7.15(d, J = 8.0Hz, 1H), 6.90(d, J = 6.6Hz, 1H), 6.79(s, 3H), 6.58(s, 1H), 5.96(s, 2H), 4.21(d, J = 6.5Hz, 1H), 3.76(s, 3H), 3.09–2.97(m, 2H), 2.33–2.26(m, 1H), 2.13–2.05(m, 1H).

[0063] 13 C NMR(101MHz, CDCl 3) δ 147.6, 146.0, 140.1, 135.0, 132.0, 127.7, 123.3, 122.4, 121.0, 116.4, 115.5, 108.4, 108.1, 106.5, 100.9, 40.1, 34.6, 32.9, 27.0.

[0064] HRMS(ESI, Q-TOF) m / z: [M+H + Calcd for C 19 H 18 O 2 N, 292.1332. Found: 292.1337.

[0065] Example 4:

[0066] Prepare 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound 1d with the following structural formula (Reaction Formula 4)

[0067]

[0068] Replace 3-methylbenzenesulfonyl chloride in Example 1 with cyclopropylsulfonyl chloride, and keep other conditions the same as in Example 1. Finally, obtain a dark green solid 1d (dr > 20:1, 31.3 mg, 41%).

[0069] The detection data of product 1d are as follows:

[0070] mp: 166.1 - 167.0 °C

[0071] 1 H NMR (400 MHz, CDCl 3 ) δ 7.25–7.20 (m, 1H), 7.20–7.13 (m, 3H), 6.95 (d, J = 6.5 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H), 6.64 (s, 1H), 4.95 (d, J = 5.0 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.68–3.64 (m, 1H), 3.52–3.44 (m, 2H), 1.27–1.18 (m, 1H), 0.98–0.92 (m, 1H), 0.84 (m, 1H), 0.33–0.21 (m, 2H).

[0072] 13 C NMR (101 MHz, CDCl 3) δ 158.8, 135.4, 134.6, 129.6, 127.3, 127.2, 124.5, 123.0, 116.3, 114.1, 112.7, 107.4, 68.4, 55.4, 39.6, 33.1, 29.5, 25.4, 5.0.

[0073] HRMS(ESI, Q-TOF) m / z: [M+Na + Calcd for NaC 22 H 23 O 3 NS, 404.1291. Found: 404.1295.

[0074] Example 5:

[0075] Prepare 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound 1e with the following structural formula (Reaction Scheme 5)

[0076]

[0077] Replace 3-methylbenzenesulfonyl chloride in Example 1 with morpholinesulfonyl chloride, and keep other conditions the same as in Example 1. Finally, obtain dark green solid 1e (dr > 20:1, 19.6 mg, 23%).

[0078] The test data of product 1e are as follows:

[0079] mp: 172.1 - 173.4 °C

[0080] 1 H NMR (400 MHz, CDCl 3 ) δ 7.23 (d, J = 3.5 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 6.94–6.90 (m, 1H), 6.79 (d, J = 8.6 Hz, 2H), 6.71 (s, 1H), 4.94 (d, J = 2.6 Hz, 1H), 3.80 (s, 3H), 3.77 (s, 4H), 3.48–3.41 (m, 1H), 3.34–3.27 (m, 1H), 3.11–3.02 (m, 4H), 2.63–2.48 (m, 4H).

[0081] 13 C NMR (101 MHz, CDCl 3)δ158.6,136.3,134.6,129.0,126.9,126.8,124.2,123.2,116.2,114.0,111.6,107.7,67.8,66.6,55.4,45.9,38.8,33.2,25.3.

[0082] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 23 H 26 O 4 N 2 S,449.1505.Found:449.1507.

[0083] Example 6:

[0084] Prepare 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound 1f with the following structural formula (Reaction Scheme 6)

[0085]

[0086] Replace 3-methylbenzenesulfonyl chloride in Example 1 with 4-cyanophenylsulfonyl chloride, and other conditions are the same as in Example 1. Finally, a dark green solid 1f (dr > 20:1, 52.2 mg, 59%) is obtained.

[0087] The detection data of product 1f are as follows:

[0088] mp:194.5 - 194.7 °C

[0089] 1 H NMR(400MHz,CDCl 3 )δ7.39(d,J = 8.3Hz,2H),7.14–7.06(m,3H),6.99–6.90(m,3H),6.81(d,J = 7.0Hz,1H),6.72(d,J = 8.6Hz,2H),6.55(s,1H),5.03(d,J = 2.1Hz,1H),3.74(s,4H),3.64(s,3H),3.57–3.48(m,1H),3.37–3.28(m,1H).

[0090] 13 C NMR(101MHz,CDCl 3)δ158.6,141.5,134.7,134.1,129.9,129.0,128.2,126.5,125.6,124.6,122.9,117.3,116.7,115.3,113.9,110.3,107.31,69.7,55.3,38.5,32.8,24.4.

[0091] HRMS(ESI,Q - TOF)m / z:[M + Na + Calcd for NaC 26 H 22 O 3 N 2 S,465.1243.Found:465.1245.

[0092] The single crystal of product 1f is as Figure 1 shown, and the specific data is as follows in Table 1:

[0093]

[0094]

[0095] Example 7:

[0096] Prepare 3 - aryl - 4 - sulfonyl - 1,3,4,5 - tetrahydrobenzo[cd] - indole compound 1g with the following structural formula (Reaction Scheme 7)

[0097]

[0098] Replace 3 - methylbenzenesulfonyl chloride in Example 1 with 4 - nitrophenylsulfonyl chloride, and keep other conditions the same as in Example 1. Finally, a dark green solid 1g (dr > 20:1, 44.4 mg, 48%) is obtained.

[0099] The detection data of product 1g is as follows:

[0100] mp:147.5 - 148.6 °C

[0101] 1 H NMR(400MHz,CDCl 3)δ7.58(d,J=8.0Hz,2H),7.45(d,J=8.1Hz,2H),7.07(t,J=7.6Hz,1H),6.95(d,J=8.1Hz,2H),6.83–6.77(m,2H),6.73(d,J=8.0Hz,2H),6.60(s,1H),5.09–5.05(m,1H),3.74(s,4H),3.60(s,3H),3.55–3.49(m,1H),3.37–3.28(m,1H).

[0102] 13 C NMR(101MHz,CDCl 3 )δ158.7,149.4,142.6,134.8,134.1,129.1,128.8,126.6,125.7,124.7,123.0,121.0,116.9,114.0,110.3,107.2,69.9,55.3,38.5,32.8,24.4.

[0103] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 25 H 22 O 5 N 2 S,485.1142.Found:485.1142.

[0104] Example 8:

[0105] Preparation of 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds 1h, 1h' with the following structural formula (Reaction Scheme 8)

[0106]

[0107] Replace the 3-methylbenzenesulfonyl chloride in Example 1 with thiophene sulfonyl chloride, and keep other conditions the same as in Example 1. Finally, a dark green solid 1h (dr>20:1, 47.4 mg, 56%) + 1h' (dr>20:1, 23.7 mg, 28%) is obtained.

[0108] The detection data of product 1h are as follows:

[0109] mp: 144.3–145.7 °C

[0110] 1 H NMR(400MHz,CDCl 3)δ 7.35 (d, J = 4.9 Hz, 1H), 7.17–7.12 (m, 1H), 7.07–6.98 (m, 4H), 6.85 (d, J = 7.0 Hz, 1H), 6.76 (d, J = 8.6 Hz, 2H), 6.69–6.63 (m, 1H), 6.54 (s, 1H), 5.01 (d, J = 3.9 Hz, 1H), 3.87–3.82 (m, 1H), 3.77 (s, 3H), 3.68 (s, 3H), 3.59–3.52 (m, 1H), 3.45–3.38 (m, 1H).

[0111] 13 C NMR (101 MHz, CDCl 3 )δ 158.6, 139.0, 135.4, 134.52, 134.47, 133.5, 129.2, 126.8, 126.1, 124.6, 122.8, 116.3, 112.0, 111.6, 107.3, 69.9, 55.4, 39.0, 32.9, 25.5.

[0112] HRMS (ESI, Q-TOF) m / z: [M+Na + Calcd for NaC 23 H 21 O 3 NS 2 , 446.0855. Found: 446.0854.

[0113] The detection data of product 1h' are as follows:

[0114] mp: 218.0 - 218.9 °C

[0115] 1 H NMR (400 MHz, CDCl 3 )δ 7.70–7.65 (m, 1H), 7.64–7.59 (m, 1H), 7.13 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 3.0 Hz, 1H), 7.07–7.03 (m, 1H), 6.93 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 6.70 (d, J = 8.4 Hz, 1H), 6.41 (d, J = 2.6 Hz, 1H), 5.00 (d, J = 5.9 Hz, 1H), 4.19–4.12 (m, 1H), 3.83–3.77 (m, 3H), 3.77–3.72 (m, 4H), 3.69–3.62 (m, 1H).

[0116] 1313C NMR (101 MHz, CDCl 3 ) δ 158.5, 139.1, 136.5, 136.1, 134.8, 134.5, 134.3, 130.8, 129.5, 129.1, 127.8, 124.5, 118.5, 114.0, 109.2, 99.0, 73.7, 55.3, 52.3, 33.3, 32.4.

[0117] HRMS (ESI, Q-TOF) m / z: [M+Na + Calcd for NaC 23 H 21 O 3 NS 2 , 446.0855. Found: 446.0851.

[0118] Example 9:

[0119] Prepare 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound 1i with the following structural formula (Reaction Formula 9)

[0120]

[0121] Product 1i detection data Replace 3-methylbenzenesulfonyl chloride in Example 1 with benzofuranyl sulfonyl chloride, and other conditions are the same as in Example 1. Finally, a dark green solid 1i (dr > 20:1, 54.2 mg, 59%) is obtained.

[0122] The detection data of product 1i are as follows:

[0123] mp: 163.4 - 164.5 °C

[0124] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.22 (d, J = 8.4 Hz, 1H), 7.11–7.06 (m, 1H), 7.02 (s, 1H), 6.97 (d, J = 8.1 Hz, 3H), 6.82 (d, J = 7.0 Hz, 1H), 6.72 (d, J = 8.6 Hz, 2H), 6.49 (s, 1H), 6.30 (d, J = 8.4 Hz, 1H), 4.98 (d, J = 3.2 Hz, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.75 (s, 3H), 3.73–3.68 (m, 1H), 3.65 (s, 3H), 3.54–3.47 (m, 1H), 3.38–3.30 (m, 1H), 2.91 (t, J = 8.8 Hz, 2H).

[0125] 13 C NMR (101 MHz, CDCl 3 ) δ 163.7, 158.4, 135.5, 134.3, 130.0, 129.1, 129.0, 126.6, 126.5, 126.4, 125.5, 124.4, 122.7, 116.2, 113.8, 111.5, 107.7, 106.8, 72.2, 69.1, 55.3, 38.8, 32.8, 28.6, 25.0.

[0126] HRMS (ESI, Q-TOF) m / z: [M+Na + Calcd for NaC 27 H 25 O 4 NS, 482.1397. Found: 482.1397.

[0127] Example 10:

[0128] Prepare 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound 1j with the following structural formula (Reaction Formula 10)

[0129]

[0130] Replace 3-methylbenzenesulfonyl chloride in Example 1 with benzothiazole-5-sulfonyl chloride, and keep other conditions the same as in Example 1. Finally, a dark green solid 1j (dr > 20:1, 38.9 mg, 41%) is obtained.

[0131] The detection data of product 1j are as follows:

[0132] mp: 199.0 - 199.4 °C

[0133] 1 H NMR (400 MHz, CDCl 3 ) δ 9.08 (s, 1H), 7.88 (d, J = 1.4 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.50–7.47 (m, 1H), 6.97–6.91 (m, 3H), 6.80 (d, J = 7.0 Hz, 1H), 6.69–6.64 (m, 3H), 6.45 (s, 1H), 5.05 (d, J = 3.1 Hz, 1H), 3.82–3.78 (m, 1H), 3.70 (s, 3H), 3.61–3.54 (m, 1H), 3.41 (s, 3H), 3.39–3.33 (m, 1H).

[0134] 13 C NMR (101 MHz, CDCl3 )δ158.6,157.8,155.3,135.1,134.9,134.1,132.2,129.2,126.5,126.0,125.8,124.3,123.4,123.0,121.9,116.5,113.9,111.1,107.3,69.8,55.3,38.9,32.6,24.9.

[0135] HRMS(ESI,Q - TOF)m / z:[M + Na + Calcd for NaC 26 H 22 O 3 N 2 S 2 ,497.0964.Found:497.0963.

[0136] Example 11:

[0137] Prepare 3 - aryl - 4 - sulfonyl - 1,3,4,5 - tetrahydrobenzo[cd] - indole compound 1k with the following structural formula (Reaction Formula 11)

[0138]

[0139] Replace 3 - methylbenzenesulfonyl chloride in Example 1 with phenylsulfonyl chloride, and keep other conditions the same as in Example 1. Finally, obtain dark green solid 1k (dr > 20:1, 49.3 mg, 59%).

[0140] The detection data of product 1k are as follows:

[0141] mp: 140.3 - 141.2 °C

[0142] 1 H NMR(400 MHz, CDCl 3 )δ7.40(d, J = 7.5 Hz, 2H), 7.25–7.20(m, 1H), 7.13–7.07(m, 1H), 7.03–6.93(m, 5H), 6.83(d, J = 6.8 Hz, 1H), 6.71(d, J = 8.1 Hz, 2H), 6.48(s, 1H), 4.99(d, J = 1.4 Hz, 1H), 3.75(s, 4H), 3.62(s, 3H), 3.55–3.48(m, 1H), 3.40–3.33(m, 1H).

[0143] 13 C NMR(101 MHz, CDCl 3)δ158.5,138.1,135.2,134.3,132.4,129.2,128.2,127.4,126.7,126.2,124.4,122.7,116.3,113.9,111.5,107.3,69.1,55.3,38.8,32.8,25.1.

[0144] HRMS(ESI,Q - TOF)m / z:[M + Na + Calcd for NaC 25 H 23 O 3 NS,440.1291.Found:440.1293.

[0145] Example 12:

[0146] Prepare 3 - aryl - 4 - sulfonyl - 1,3,4,5 - tetrahydrobenzo[cd] - indole compound 1l with the following structural formula (Reaction Formula 12)

[0147]

[0148] Replace 3 - methylbenzenesulfonyl chloride in Example 1 with dimethylaminosulfonyl chloride, and keep other conditions the same as in Example 1. Finally, obtain dark green solid 1l (dr > 20:1, 22.3 mg, 29%).

[0149] The test data of product 1l are as follows:

[0150] mp:102.4 - 104.2 °C

[0151] 1 H NMR(400 MHz,CDCl 3 )δ7.21(d,J = 6.1 Hz,2H),7.05(d,J = 8.6 Hz,2H),6.93(d,J = 5.8 Hz,1H),6.80(d,J = 8.7 Hz,2H),6.65(s,1H),4.91(d,J = 3.8 Hz,1H),3.84–3.81(m,1H),3.78(s,3H),3.78(s,3H),3.49–3.42(m,1H),3.37–3.30(m,1H),2.15(s,6H).

[0152] 13 C NMR(101 MHz,CDCl 3)δ158.5,136.2,134.6,129.1,127.3,126.7,124.4,123.0,116.2,114.0,112.4,107.4,67.5,55.4,39.3,36.9,33.1,25.9.

[0153] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 21 H 24 O 3 N 2 S,407.1400.Found:407.1403.

[0154] Example 13:

[0155] Prepare 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound 1m with the following structural formula (Reaction Formula 13)

[0156]

[0157] Replace the 3-methylbenzenesulfonyl chloride in Example 1 with 4-fluorophenylsulfonyl chloride, and keep other conditions the same as in Example 1. Finally, obtain a dark green solid 1m (dr>20:1, 47.9 mg, 55%).

[0158] The test data of product 1m are as follows:

[0159] mp:149.4 - 150.5 °C

[0160] 1 H NMR(400MHz,CDCl 3 )δ7.36–7.29(m,2H),7.10(t,J = 7.6Hz,1H),6.99–6.93(m,3H),6.81(d,J = 7.0Hz,1H),6.73(d,J = 8.4Hz,2H),6.56(d,J = 8.5Hz,2H),6.52(s,1H),5.01(d,J = 2.3Hz,1H),3.75(s,3H),3.73–3.69(m,1H),3.63(s,3H),3.55–3.47(m,1H),3.37–3.30(m,1H).

[0161] 13 C NMR(101MHz,CDCl 3) δ 164.9 (d, J = 254.8 Hz), 158.6, 135.2, 134.3, 133.6 (d, J = 3.1 Hz), 130.8 (d, J = 9.7 Hz), 129.1, 126.6, 126.0, 124.5, 122.9, 116.5, 114.1 (d, J = 22.6 Hz), 114.0, 110.9, 107.2, 69.4, 55.4, 38.7, 32.8, 24.8.

[0162] 19 F NMR (376 MHz, CDCl 3 ) δ -105.50.

[0163] HRMS (ESI, Q-TOF) m / z: [M+Na + Calcd for NaC 25 H 22 O 3 FNS, 458.1197. Found: 458.1196.

[0164] Example 14:

[0165] Prepare 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound 1n with the following structural formula (Reaction Scheme 14)

[0166]

[0167] Replace 4-(2E)-(3-(3,4,5-trimethoxyphenyl)allyl)-1-methyl-indole in Example 2 with 4-(2E)-(3-(4-methoxyphenyl)allyl)-1-benzyl-indole, and keep other conditions the same as in Example 2. Finally, a dark green solid 1n (dr > 20:1, 53.8 mg, 53%) was obtained.

[0168] The detection data of product 1n are as follows:

[0169] mp: 76.6 - 77.6 °C

[0170] 1 H NMR (400 MHz, CDCl 3)δ 7.36–7.27 (m, 5H), 7.14 (d, J = 6.8 Hz, 2H), 7.07–7.02 (m, 1H), 6.98 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.3 Hz, 1H), 6.81–6.75 (m, 3H), 6.72 (d, J = 8.7 Hz, 2H), 6.62 (s, 1H), 5.14 (s, 2H), 5.00 (d, J = 4.0 Hz, 1H), 3.81–3.77 (m, 1H), 3.76 (s, 3H), 3.52–3.45 (m, 1H), 3.41–3.34 (m, 1H), 2.21 (s, 3H).

[0171] 13 C NMR (101 MHz, CDCl 3 )δ 158.4, 143.3, 137.5, 135.2, 134.9, 133.9, 129.1, 128.8, 128.21, 128.17, 127.7, 127.1, 126.8, 126.4, 123.7, 122.7, 116.5, 113.8, 112.4, 107.3, 68.7, 55.2, 50.3, 38.9, 25.2, 21.4.

[0172] HRMS (ESI, Q-TOF) m / z: [M+Na + Calcd for NaC 32 H 29 O 3 NS, 530.1760. Found: 530.1760.

[0173] Example 15:

[0174] Prepare 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound 1o with the following structural formula (Reaction Scheme 15)

[0175]

[0176] Replace 4-(2E)-(3-(3,4,5-trimethoxyphenyl)allyl)-1-methyl-indole in Example 2 with 4-(2E)-(3-(4-methoxyphenyl)allyl)-1H-indole, and keep other conditions the same as in Example 2. Finally, obtain a dark green oily liquid 1o (dr > 20:1, 32.6 mg, 39%).

[0177] The detection data of product 1o are as follows:

[0178] 11H NMR (400 MHz, DMSO-d6) δ 10.68 (d, J = 1.2 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.03–6.94 (m, 3H), 6.91 (t, J = 7.6 Hz, 1H), 6.77 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 7.0 Hz, 1H), 6.64 (d, J = 8.8 Hz, 3H), 4.64 (d, J = 4.5 Hz, 1H), 3.87–3.81 (m, 1H), 3.60 (s, 3H), 3.26–3.19 (m, 1H), 3.17–3.10 (m, 1H), 2.19 (s, 3H).

[0179] 13 13C NMR (101 MHz, DMSO-d6) δ 157.9, 143.3, 135.2, 135.0, 133.2, 128.9, 128.6, 127.8 126.0, 125.6, 121.9, 120.4, 115.5, 113.7, 112.0, 109.0, 66.7, 55.0, 38.5, 24.9, 21.0.

[0180] HRMS (ESI, Q-TOF) m / z: [M+Na + Calcd for NaC 25 H 23 O 3 NS, 440.1291. Found: 440.1293.

[0181] Example 16:

[0182] Preparation of 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound 1p with the following structural formula (Reaction Scheme 16)

[0183]

[0184] Replace 4-(2E)-(3-(3,4,5-trimethoxyphenyl)allyl)-1-methyl-indole in Example 2 with 4-(2E)-(3-(3,4-dimethoxyphenyl)allyl)-1-methyl-indole, and keep other conditions the same as in Example 2. Finally, a dark green solid 1p (dr > 20:1, 49.9 mg, 54%) was obtained.

[0185] The detection data of product 1p are as follows:

[0186] mp: 78.9 - 81.2 °C

[0187] 1 1H NMR (400 MHz, CDCl3 ) δ 7.26–7.23 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 6.82 (d, J = 7.1 Hz, 1H), 6.78 (d, J = 7.8 Hz, 2H), 6.65–6.59 (m, 2H), 6.51 (d, J = 8.2 Hz, 1H), 6.47 (s, 1H), 4.92 (d, J = 4.4 Hz, 1H), 3.88–3.86 (m, 1H), 3.82 (s, 3H), 3.72 (s, 3H), 3.64 (s, 3H), 3.53–3.46 (m, 1H), 3.45–3.38 (m, 1H), 2.23 (s, 3H).

[0188] 13 C NMR (101 MHz, CDCl 3 ) δ 149.0, 148.1, 143.3, 135.5, 135.2, 134.4, 128.2, 128.0, 126.8, 126.5, 124.5, 122.8, 120.7, 116.3, 112.0, 111.1, 110.9, 107.0, 68.8, 56.0, 55.9, 39.7, 32.9, 25.5, 21.5.

[0189] HRMS (ESI, Q-TOF) m / z: [M+Na + Calcd for NaC 27 H 27 O 4 NS, 484.1553. Found: 484.1554.

[0190] Example 17:

[0191] Prepare 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound 1q with the following structural formula (Reaction Scheme 17)

[0192]

[0193] Replace 4-(2E)-(3-(3,4,5-trimethoxyphenyl)allyl)-1-methyl-indole in Example 2 with 4-(2E)-(3-(4-dimethylaminophenyl)allyl)-1-methyl-indole, and keep other conditions the same as in Example 2. Finally, obtain dark green solid 1q (dr > 20:1, 28.5 mg, 32%).

[0194] The detection data of product 1q are as follows:

[0195] mp: 184.5 - 185.5 °C

[0196] 1 ¹H NMR (400 MHz, CDCl 3 ) δ 7.26 (d, J = 8.2 Hz, 2H), 7.12–7.07 (m, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 7.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 2H), 6.56 (d, J = 8.5 Hz, 2H), 6.50 (s, 1H), 4.94 (d, J = 3.4 Hz, 1H), 3.75–3.70 (m, 1H), 3.63 (s, 3H), 3.51–3.43 (m, 1H), 3.39–3.31 (m, 1H), 2.89 (s, 6H), 2.22 (s, 3H).

[0197] 13 ¹³C NMR (101 MHz, CDCl 3 ) δ 149.5, 143.1, 135.0, 134.3, 128.8, 128.2, 127.9, 126.9, 126.5, 124.4, 122.6, 116.2, 112.7, 111.8, 106.8, 69.1, 40.8, 38.6, 32.8, 25.1, 21.5.

[0198] HRMS (ESI, Q-TOF) m / z: [M+Na + Calcd for NaC 27 H 28 O 2 N 2 S, 467.1764. Found: 467.1762.

[0199] Example 18:

[0200] Prepare 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound 1r with the following structural formula (Reaction Scheme 18)

[0201]

[0202] Replace 4-(2E)-(3-(3,4,5-trimethoxyphenyl)allyl)-1-methyl-indole in Example 2 with 4-(2E)-(3-(5-benzo[d][1,3]dioxolyl)allyl)-1-methyl-indole, and keep other conditions the same as in Example 2, finally obtaining a dark green solid 1r (dr > 20:1, 55.2 mg, 62%).

[0203] The detection data of product 1r are as follows:

[0204] mp: 151.9 - 152.4 °C

[0205] 1 H NMR (400 MHz, CDCl 3 ) δ 7.27 (d, J = 7.8 Hz, 2H), 7.09 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.84–6.77 (m, 3H), 6.61 (dd, J = 21.0, 7.8 Hz, 2H), 6.49 (s, 1H), 6.43 (s, 1H), 5.86 (d, J = 7.3 Hz, 2H), 4.91 (d, J = 3.3 Hz, 1H), 3.73–3.68 (m, 1H), 3.63 (s, 3H), 3.51–3.44 (m, 1H), 3.40–3.32 (m, 1H), 2.24 (s, 3H).

[0206] 13 C NMR (101 MHz, CDCl 3 ) δ 147.7, 146.4, 143.3, 137.1, 134.9, 134.3, 128.2, 128.0, 126.6, 126.2, 124.4, 122.7, 121.6, 116.3, 111.5, 108.4, 108.1, 106.9, 101.0, 68.8, 39.4, 32.8, 25.2, 21.5.

[0207] HRMS (ESI, Q-TOF) m / z: [M+Na + Calcd for NaC 26 H 23 O 4 NS, 468.1240. Found: 468.1245.

[0208] Anti-tumor activity verification experiment:

[0209] Select the 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]indole compounds prepared in the examples, using human liver cancer cells (SMMC-7721 cells) as receptors, and test their in vitro anti-tumor activity by the CCK-8 method.

[0210] Taking the compound 1a of Example 1 as an example to illustrate the activity test process: (1) Collect cells in the logarithmic phase, adjust the cell suspension concentration, add 100 μL to each well, and plate to make the density of the cells to be tested 5000 cells / well; (2) 5% CO 2, incubate at 37 °C until the cell monolayer covers the bottom of the 96-well flat-bottom plate. Subsequently, add compound 1a at concentration gradients (0.015 μM, 0.045 μM, 0.137 μM, 0.411 μM, 1.234 μM, 3.703 μM, 11.111 μM, 33.333 μM, 100.000 μM), with 3 replicate wells; (3) 5% CO 2 , incubate at 37 °C for 48 hours and observe under an inverted microscope; (4) Add 10 μL of CCK-8 solution to each well and continue culturing for 1 - 4 h; (4) When the color of the solution in the 96-well plate gradually turns orange-red and there is an obvious color change, measure the absorbance of each well at OD450 nm on an automatic microplate reader; (5) At the same time, set up a zero control well (culture medium, CCK-8 solution), a positive control well (cells, cisplatin dissolution medium at the same concentration, culture medium, CCK-8 solution), and a blank control well (without drug, only cells, culture medium, and CCK-8 solution); (6) Plot the cell survival rate (%) against the logarithm-transformed drug concentration (such as log(drug concentration)), and use non-linear regression curve fitting to analyze the data (GraphPad Prism) to obtain the IC50 value of compound 1a; (7) The tumor suppression experiments of the 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds and cisplatin prepared in other examples were operated according to a similar method as above.

[0211] Table 2 shows the inhibitory effects of some compounds in the examples on the proliferation of human liver cancer cells (SMMC-7721 cells).

[0212] Compound Human hepatoma cells (SMMC-7721 cells) [IC50 (μM)] Compound 1a of Example 1 50.35 Compound 1b of Example 2 30.70 Compound 1c of Example 3 27.89 Compound 1d of Example 4 50.61 Compound 1e of Example 5 47.97 Cisplatin 12.36

[0213] As Figure 20 shown, the results indicate that the 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds prepared in the present invention have a certain inhibitory effect on human liver cancer cells.

[0214] The above are only examples of the present invention. Common general knowledge such as specific structures and characteristics in the scheme is not described in detail here. It should be noted that for those skilled in the art, without departing from the structure of the present invention, several modifications and improvements can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the implementation effect of the present invention and the practicality of the patent. The protection scope required by this application should be based on the content of its claims, and the specific implementation manners described in the specification can be used to interpret the content of the claims.

Claims

1. A 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound, characterized in that: Its structural formula is as follows: Ar is 4-methylphenyl, biphenyl, 2-naphthyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-isopropoxyphenyl, 4-butoxyphenyl, 4-phenoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, 3-methyl-4-methoxyphenyl or 2,3-dihydrobenzofuran-5-yl; R is methyl, ethyl, propyl, cyclopropyl, phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-butoxyphenyl, 4-phenoxyphenyl, 4-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, biphenyl, 2-naphthyl, 2-thienyl, 2-furyl or 2-benzofuranyl; R' is hydrogen, methyl or benzyl.

2. The method for preparing the compound according to claim 1, characterized in that: Using β-4'-methylindole arylethylene and alkyl or aryl sulfonyl chloride as raw materials, 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds are obtained through organic photocatalytic synthesis conditions and subsequent purification processes. The reaction formula is as follows:

3. The preparation method according to claim 2, characterized in that: The molar ratio of each substance in the reaction is: β-4'-methylindolyl arylethylene: alkyl or aryl sulfonyl = 1:0.5-5.

4. The preparation method according to claim 3, characterized in that: The solvent is selected from one or more of ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, acetone, 1,2-dichloroethane, toluene, dimethyl sulfoxide, methanol, 1,4-dioxane or N,N-dimethylformamide.

5. The preparation method according to claim 4, characterized in that: The light source is selected from 5-50W purple light, blue light, white light or red light.

6. The preparation method according to claim 5, characterized in that: The temperature used is 0-60°C.

7. The preparation method according to claim 6, characterized in that: The reaction time is 0.5 to 24 hours.

8. The preparation method according to claim 7, characterized in that: The gas atmosphere is selected from air, argon, nitrogen and oxygen.

9. The preparation method according to claim 8, characterized in that: The separation and purification method is selected from column chromatography or recrystallization.

10. Use of the compound according to claim 1 in the preparation of anti-liver cancer drugs.

Images