C-3 benzylated indole compounds, methods of making and uses thereof

Abstract

The application discloses a C-3 benzylated indole compound in the technical field of organic chemical synthesis, and a structural formula is as follows: when preparing the C-3 benzylated indole compound, unsaturated alcohol, an acid catalyst and an indole compound are sequentially mixed with an organic solvent, and the C-3 benzylated indole compound is obtained through room temperature reaction and subsequent treatment and purification. The raw materials and catalysts used in the application are cheap and easy to obtain, the operation method is simple, the reaction condition is mild, and the application is green and efficient, so that an efficient preparation method is provided for synthesis of the C-3 benzylated indole compound.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic chemical synthesis, in particular to a C-3 benzylated indole compound, a preparation method and application thereof. BACKGROUND

[0002] C-3 benzylated indole is an important chemical skeleton structure, and is an important intermediate for synthesizing therapeutic compounds, drug active molecules and natural products. Among the synthesis methods of C-3 benzylated indole, the direct intermolecular hydrogen arylation reaction of olefin and indole is a relatively efficient strategy. At present, most of the relatively complete hydrogen arylation reaction systems need a large amount of metal catalysts, such as palladium catalyst (J. Am. Che. Soc. 2018, 140, 3542) or copper catalyst (J. Am. Chem. Soc. 2019, 141, 3901.) and the like, and since strong acid can weaken the nucleophilicity of indole, even lead to the dimerization of olefin (Tetrahedron. 2021, 85, 132037), therefore, the example of using strong acid to catalyze the hydrogen arylation reaction of olefin and indole is relatively rare.

[0003] Literature research shows that although there are a few reports on proton acid catalyzed olefin hydrogen arylation reaction (Adv. Synth. Catal. 2024, 366, 2705; J. Org. Chem. 2022, 87, 1086; Org. Biomol. Chem. 2023, 21, 9534), but these methods usually have certain limitations: need to use expensive HFIP as solvent, or rely on higher reaction temperature, or only suitable for specific types of olefin substrates, resulting in narrow substrate application range. At the same time, since olefin compounds are prone to intramolecular cyclization reaction under strong acid conditions (Org. Lett. 2017, 19, 2062), therefore, there is no related research report on the hydrogen arylation reaction of olefin compounds catalyzed by Bronsted acid. SUMMARY

[0004] The present application is designed for the deficiencies of the prior art, and a hydrogen arylation reaction of olefin compounds catalyzed by Bronsted acid.

[0005] One of the purposes of the present application is to provide a series of C-3 benzylated indole compounds, the structural formula of which is as follows:

[0006]

[0007] wherein: Ar is 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-iso- propoxyphenyl, 3,4-dimethoxyphenyl, 4-n-butoxyphenyl, 4-phenoxyphenyl, 4- methylthiophenyl, 3-methyl-4-methoxyphenyl, 3-methyl-4-ethoxyphenyl, 3-methyl- 4-propoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, 3,4,5-trimethoxyphenyl, or 2- furanyl;

[0008] Ar' is naphthyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-iso- propoxyphenyl, 3,4-dimethoxyphenyl, 4-n-butoxyphenyl, 4-phenoxyphenyl, 3- methyl-4-methoxyphenyl, 3-methyl-4-ethoxyphenyl, 3-methyl-4-propoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, or 3,4,5-trimethoxyphenyl;

[0009] R 1 is hydrogen, methyl, or phenyl;

[0010] R 2 is 4-methyl, 5-methyl, 6-methyl, 7-methyl, 5-methoxy, 6-fluoro, 5-bromo, 6-bromo, 7-bromo, 5-cyano, or 5-iodo.

[0011] Further, the structure of the C-3 benzylated indole compound is shown as follows:

[0012]

[0013] The second object of the present application is to provide a preparation method of the C-3 benzylated indole compound. Specifically, unsaturated alcohol, acid catalyst, and indole compound are sequentially added into an organic solvent, and then the C-3 benzylated indole compound is prepared after stirring and reaction, and purification treatment. The reaction formula is as follows:

[0014]

[0015] Further, the molar ratio of the substances in the reaction is: unsaturated alcohol: acid catalyst: indole compound = 1:0.05-1.0:1.0-2.0. Preferably, unsaturated alcohol: acid catalyst: indole compound = 1:0.1:1.2.

[0016] Further, the organic solvent is selected from acetonitrile, methanol, tetrahydrofuran, or 1,4-dioxane. Preferably, acetonitrile.

[0017] Further, the reaction temperature is 0-100°C. Preferably, room temperature; the reaction time is 1-48 hours. Preferably, 24 hours. The reaction starts after stirring, and 24 hours is the best reaction time considering the cost.

[0018] Furthermore, the acid catalyst used is selected from hydrochloric acid, hydroiodic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid or trimethylchlorosilane, preferably hydroiodic acid.

[0019] Furthermore, the reaction is carried out under a gas atmosphere selected from oxygen, air or argon, preferably air.

[0020] A third object of the present invention is to provide a use of a C-3 benzylated indole compound in the preparation of an anti-gastric adenocarcinoma drug. The C-3 benzylated indole compound has been shown to have anti-gastric adenocarcinoma SGC-7901 cell activity.

[0021] This project creatively uses a catalytic amount of hydroiodic acid to complete the hydroarylation reaction of enol compounds at room temperature to prepare C-3 benzylated indole. The raw materials are simple and easy to obtain, and the reaction is green and efficient, opening up a new path for the hydroarylation reaction of alkenes. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Compound 1a prepared in Example 1 1 H NMR spectrum;

[0023] Figure 2 Compound 1a prepared in Example 1 13 C NMR spectrum;

[0024] Figure 3 Compound 1b prepared in Example 2 1 H NMR spectrum;

[0025] Figure 4 Compound 1b prepared in Example 2 13 C NMR spectrum;

[0026] Figure 5 Compound 1c prepared in Example 3 1 H NMR spectrum;

[0027] Figure 6 Compound 1c prepared in Example 3 13 C NMR spectrum;

[0028] Figure 7 Compound 1d prepared in Example 4 1 H NMR spectrum;

[0029] Figure 8 Compound 1d prepared in Example 4 13 C NMR spectrum;

[0030] Figure 9 Compound 1e prepared in Example 51 H NMR spectrum;

[0031] Figure 10 For Example 5, compound 1e was prepared 13 C NMR spectrum;

[0032] Figure 11 Compound 1f prepared in Example 6 1 H NMR spectrum;

[0033] Figure 12 Compound 1f prepared in Example 6 13 C NMR spectrum;

[0034] Figure 13 1g of compound prepared in Example 7 1 H NMR spectrum;

[0035] Figure 14 1g of compound prepared in Example 7 13 C NMR spectrum;

[0036] Figure 15 Compound 1h prepared in Example 8 1 H NMR spectrum;

[0037] Figure 16 Compound 1h prepared in Example 8 13 C NMR spectrum;

[0038] Figure 17 Compound 1i prepared in Example 9 1 H NMR spectrum;

[0039] Figure 18 Compound 1i prepared in Example 9 13 C NMR spectrum;

[0040] Figure 19 Compound 1j prepared in Example 10 1 H NMR spectrum;

[0041] Figure 20 Compound 1j prepared in Example 10 13 C NMR spectrum;

[0042] Figure 21 Schematic diagram of the inhibitory effect of some compounds on the proliferation of human gastric adenocarcinoma cells (SGC-7901 cells). DETAILED DESCRIPTION

[0043] The following is further described in detail through specific implementation methods:

[0044] Example 1

[0045] Taking the preparation of C-3 benzylated indole compound 1a with the following structural formula as an example, the raw materials and preparation method used are as follows:

[0046] Acetonitrile (2 mL) was added to a 5 mL reaction vial. (3E)-4-(4-propoxyphenyl)-3-buten-1-ol (41.3 mg, 0.2 mmol), aqueous hydroiodic acid (57 wt.%, 2.6 uL, 0.02 mmol), and 7-bromo-1H-indole (47.1 mg, 0.24 mmol) were added sequentially to the acetonitrile and stirred at room temperature. The yield was 20% in 1 hour, 31% in 2 hours, 43% in 5 hours, 65% in 12 hours, 74% in 24 hours, and 76% in 36 hours (the product was completely consumed, but some raw materials were converted to byproducts and separation losses resulted in no significant further improvement in yield). Taking all factors into consideration, 24 hours was the optimal reaction time. After 24 hours, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to yield 1a (59.8 mg, 74% yield) as a brown oil.

[0047] The test data of product 1a are as follows:

[0048] 1 H NMR (400MHz, CDCl3) δ8.30 (s, 1H), 7.36 (d, J = 7.9Hz, 1H), 7.30 (d, J = 7.6Hz, 1H) , 7.17 (d, J=8.6Hz, 2H), 7.07 (s, 1H), 6.89 (t, J=7.8Hz, 1H), 6.81 (d, J=8.6Hz, 2H ), 4.08(t, 1H), 3.87(t, J=6.6Hz, 2H), 3.66(t, J=6.5Hz, 2H), 2.27–2.19(m, 1H), 2.07–1.97(m, 1H), 1.82–1.75(m, 2H), 1.64–1.54(m, 2H), 1.02(t, J=7.4Hz, 3H).

[0049] 13 C NMR (101MHz, CDCl3) δ157.6, 136.7, 135.3, 128.8, 128.3, 124.4, 121.9, 12 1.6, 120.5, 118.9, 114.4, 104.8, 69.5, 63.0, 42.1, 32.4, 31.3, 22.7, 10.7.

[0050] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 21H 25 O2BrN + , 402.1063; Found: 402.1060.

[0051] Example 2

[0052] Prepare C-3 benzylated indole compound 1b with the following structural formula:

[0053] The (3E)-4-(4-propoxyphenyl)-3-butene-1-ol in Example 1 was replaced by 4-(1-methyl-1H-indol-5-yl)-4-penten-1-ol, and 7-bromo-1H-indole was replaced by N-methylindole. Other conditions were the same as in Example 1, and a brown oily liquid 1b (30.7 mg, 44% yield) was finally obtained.

[0054] The test data of product 1b are as follows:

[0055] 1 H NMR (400MHz, CDCl3) δ7.68 (s, 1H), 7.27 (d, J=5.3Hz, 1H), 7.17–7.08 (m, 3H), 7.04–6.97 (m, 3H), 6.79 (t, J=7.5Hz, 1H), 6.43 (d, J=2 .9Hz, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 3.56 (t, J=6.6Hz, 2H), 2.39–2.31 (m, 1H), 2.29–2.21 (m, 1H), 1.78 (s, 3H), 1.45–1.38 (m, 2H).

[0056] 13 C NMR (101MHz, CDCl3) δ139.8, 137.7, 135.1, 128.7, 128.1, 126.7, 126.2, 124.1, 121.9, 12 1.7, 121.1, 118.4, 118.3, 109.0, 108.8, 101.0, 63.8, 41.9, 38.0, 32.9, 32.8, 28.4, 28.3.

[0057] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 23 H 27 ON2 + , 347.2118; Found: 347.2116.

[0058] Example 3

[0059] Prepare C-3 benzylated indole compound 1c with the following structural formula:

[0060] The (3E)-4-(4-propoxyphenyl)-3-butene-1-ol in Example 1 was replaced by (5E)-6-(4-butoxyphenyl)-5-hexen-1-ol, and 7-bromo-1H-indole was replaced by N-methylindole. Other conditions were the same as in Example 1, and finally a brown oily liquid 1c (51.2 mg, 67% yield) was obtained.

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

[0062] 1 H NMR (400MHz, CDCl3) δ7.49 (d, J=7.9Hz, 1H), 7.29 (d, J=8.2Hz, 1H), 7.26–7.16 (m, 3H) , 7.05(t, J=7.4Hz, 1H), 6.86(d, J=3.9Hz, 2H), 6.83(s, 1H), 4.16–4.11(m, 1H), 3.95( t, J=6.5Hz, 2H), 3.75 (s, 3H), 3.61 (t, J=6.5Hz, 2H), 2.23–2.16 (m, 1H), 2.04–1.96 (m , 1H), 1.82–1.73 (m, 2H), 1.59–1.47 (m, 5H), 1.46–1.38 (m, 3H), 1.00 (t, J=7.4Hz, 3H).

[0063] 13 C NMR (101MHz, CDCl3) δ157.3, 137.5, 137.2, 128.8, 127.4, 125.8, 121.5, 119.6, 119. 5, 118.6, 114.2, 109.2, 67.6, 63.0, 42.0, 36.5, 32.7, 31.5, 28.0, 25.9, 19.4, 14.0.

[0064] HRMS (ESI, Q-TOF) m / z: [M+Na + ]Calcd for C 25 H 33 O2NNa + , 402.2404; Found: 402.2401.

[0065] Example 4

[0066] Prepare C-3 benzylated indole compound 1d with the following structural formula:

[0067] The (3E)-4-(4-propoxyphenyl)-3-butene-1-ol in Example 1 was replaced with (3E)-4-(4-phenoxyphenyl)-3-butene-1-ol, hydroiodic acid (2.6 uL, 0.02 mmol) was replaced with hydroiodic acid (8 uL, 0.06 mmol), 7-bromo-1H-indole was replaced with N-methylindole, and the 25 ° C condition was replaced by heating to 70 ° C. The other conditions were the same as in Example 1, and a brown oily liquid 1d (54.5 mg, 73% yield) was finally obtained.

[0068] The test data of product 1d are as follows:

[0069] 1 H NMR (400MHz, CDCl3) δ7.46 (d, J=7.9Hz, 1H), 7.31 (d, J=8.3Hz, 2H), 7.29–7.26 ( m, 3H), 7.19 (t, J=7.4Hz, 1H), 7.08 (d, J=7.3Hz, 1H), 7.03 (t, 1H), 6.97 (d, J=7.7 Hz, 2H), 6.92 (d, J=5.2Hz, 2H), 6.90 (s, 1H), 4.16 (t, J=7.6Hz, 1H), 3.76 (s, 3H), 3.68(t, J=6.5Hz, 2H), 2.29–2.21(m, 1H), 2.10–2.02(m, 1H), 1.65–1.58(m, 2H).

[0070] 13 C NMR (101MHz, CDCl3) δ157.6, 155.2, 140.5, 137.3, 129.8, 129.1, 127.4, 125.9, 123. 0, 121.7, 119.6, 119.0, 118.80, 118.76, 118.7, 109.3, 63.1, 42.1, 32.9, 32.6, 31.5.

[0071] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 25 H 26 O2N + , 372.1958; Found: 372.1957.

[0072] Example 5

[0073] Prepare C-3 benzylated indole compound 1e with the following structural formula:

[0074] The (3E)-4-(4-propoxyphenyl)-3-butene-1-ol in Example 1 was replaced by 5-(4-tert-butoxyphenyl)-5-hexene-1-ol, and 7-bromo-1H-indole was replaced by N-methylindole. Other conditions were the same as in Example 1, and finally a brown oily liquid 1e (35.1 mg, 54% yield) was obtained.

[0075] The test data of product 1e are as follows:

[0076] 1 H NMR (400MHz, CDCl3) δ7.28–7.23 (m, 1H), 7.17–7.09 (m, 3H), 7.02 (d, J=8.0Hz, 1H), 6.91 (s, 1H), 6.85 (t, J=7.9Hz, 1H), 6.68 (d, J=8.7 Hz, 2H), 3.75 (s, 3H), 3.55 (t, J=6.6Hz, 2H), 2.25–2.16 (m, 1H), 2.11–2.03 (m, 1H), 1.65 (s, 3H), 1.55–1.47 (m, 2H), 1.21–1.10 (m, 2H).

[0077] 13 C NMR (101MHz, CDCl3) δ153.6, 141.2, 137.8, 128.2, 126.5, 126.3, 123.6, 12 1.5, 121.2, 118.4, 114.8, 109.2, 63.0, 41.8, 41.6, 33.4, 32.8, 27.9, 20.9.

[0078] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 21 H 26 O2N + , 324.1958; Found: 324.1956.

[0079] Example 6

[0080] Prepare C-3 benzylated indole compound 1f with the following structural formula:

[0081] The 7-bromo-1H-indole in Example 1 was replaced by 5-iodo-1H-indole, and other conditions were the same as in Example 1, to finally obtain brown oily liquid 1f (68.6 mg, 76% yield).

[0082] The test data of product 1f are as follows:

[0083] 1H NMR (400MHz, CDCl3) δ8.23 (s, 1H), 7.76 (s, 1H), 7.36 (d, J=7.1Hz, 1H), 7.14 (d, J=8.6Hz, 2H), 7.04 (d, J=8.5Hz, 1H), 6.91 (s, 1H), 6.80 (d, J=8.6Hz, 2H), 4.02 (t , J=7.6Hz, 1H), 3.87(t, J=6.6Hz, 2H), 3.64(t, J=6.5Hz, 2H), 2.21–2.12(m, 1H), 2.03–1.94(m, 1H), 1.81–1.75(m, 3H), 1.60–1.51(m, 2H), 1.03(t, J=7.4Hz, 3H).

[0084] 13 C NMR (101MHz, CDCl3) δ157.5, 136.7, 135.6, 130.3, 129.6, 128.7, 128.3, 12 1.8, 120.0, 114.5, 113.2, 82.8, 69.6, 63.0, 41.7, 32.6, 31.3, 22.7, 10.7.

[0085] HRMS (ESI, Q-TOF) m / z: [M+Na + ]Calcd for C 21 H 24 O2INNa + , 472.0744; Found: 472.0740.

[0086] Example 7

[0087] Taking the preparation of 1g of C-3 benzylated indole compound with the following structural formula as an example, the raw materials and preparation method used are as follows:

[0088] The (3E)-4-(4-propoxyphenyl)-3-butene-1-ol in Example 1 was replaced by (3E)-4-(4-methoxyphenyl)-3-butene-1-ol, and 7-bromo-1H-indole was replaced by N-methylindole. Other conditions were the same as in Example 1, and 1 g (52.6 mg, 85% yield) of a brown oily liquid was finally obtained.

[0089] The test data of 1g of product are as follows:

[0090] 1H NMR (400MHz, CDCl3) δ7.45 (d, J=7.9Hz, 1H), 7.27 (d, J=7.5Hz, 1H), 7.23 (d, J=8.6Hz, 2H), 7.18 (t, J=7.2Hz, 1H), 7.02 (t, J=7.0Hz, 1H), 6.88 (s, 1 H), 6.82(d, J=8.6Hz, 2H), 4.13(t, 1H), 3.77(s, 3H), 3.75(s, 3H), 3.66(t , J=6.6Hz, 2H), 2.30–2.21(m, 1H), 2.08–2.00(m, 1H), 1.65–1.56(m, 2H).

[0091] 13 C NMR (101MHz, CDCl3) δ157.8, 137.5, 137.3, 128.8, 127.4, 125.9, 121.6, 119.7, 119.1, 118.7, 113.8, 109.2, 63.1, 55.3, 41.9, 32.8, 32.6, 31.5.

[0092] HRMS (ESI, Q-TOF) m / z: [M+Na + ]Calcd for C 20 H 23 O2NNa + , 332.1621; Found: 332.1621.

[0093] Example 8

[0094] Prepare C-3 benzylated indole compound 1h with the following structural formula:

[0095] The (3E)-4-(4-propoxyphenyl)-3-butene-1-ol in Example 1 was replaced by (3E)-4-(3,4-dimethoxyphenyl)-3-butene-1-ol, and 7-bromo-1H-indole was replaced by N-methylindole. Other conditions were the same as in Example 1, and a purple oily liquid 1h (62.4 mg, 92% yield) was finally obtained.

[0096] The product 1h detection data are as follows:

[0097] 1H NMR (400 MHz, CDC13) δ 7.48 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.90 - 6.86 (m, 2H), 6.84 (s, 1H), 6.79 (d, J = 8.2 Hz, 1H), 4.12 (t, J = 7.0 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.74 (s, 3H), 3.66 (t, J = 6.5 Hz, 2H), 2.30 - 2.22 (m, 1H), 2.05 - 1.99 (m, 1H), 1.66 - 1.56 (m, 2H).

[0098] 13 C NMR (101 MHz, CDC13) δ 148.8, 147.2, 138.1, 137.3, 127.4, 125.9, 121.6, 119.8, 119.6, 119.0, 118.7, 111.3, 111.1, 109.2, 76.8, 63.0, 55.9, 42.4, 32.7, 32.5, 31.4.

[0099] HRMS (ESI, Q-TOF) m / z: [M+H + ] Calcd for C 21 H 26 O3N + , 340.1907; Found: 340.1905.

[0100] Example 9

[0101] To prepare the C-3 benzylated indole compound 1i of the following structure:

[0102] Replace 7-bromo-1H-indole in Example 1 with N-methylindole, and follow the same procedure as Example 1 to give the yellow oily liquid 1i (62.7 mg, 93% yield).

[0103] The product 1i was detected as follows:

[0104] 1H NMR (400MHz, CDCl3) δ7.46 (d, J=8.0Hz, 1H), 7.26 (t, J=5.7Hz, 1H), 7.22 (d, J=8.7Hz, 2H ), 7.18 (d, J=7.5Hz, 1H), 7.03 (t, J=7.4Hz, 1H), 6.88 (s, 1H), 6.83 (d, J=8.6Hz, 2H), 4.13 (t, J=7.8Hz, 1H), 3.89 (t, J=6.6Hz, 2H), 3.74 (s, 3H), 3.65 (t, J=6.6Hz, 2H), 2.29–2.20 (m, 1H), 2.07–2.00 (m, 1H), 1.83–1.76 (m, 2H), 1.65–1.58 (m, 2H), 1.03 (t, J=7.4Hz, 3H).

[0105] 13 C NMR (101MHz, CDCl3) δ157.4, 137.32, 137.27, 128.8, 127.4, 125.9, 121.6, 119. 7, 119.2, 118.7, 114.4, 109.2, 69.5, 63.1, 41.9, 32.7, 32.6, 31.4, 22.7, 10.7.

[0106] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 22 H 28 O2N + , 338.2115; Found: 338.2115.

[0107] Example 10

[0108] Prepare C-3 benzylated indole compound 1j with the following structural formula:

[0109] The (3E)-4-(4-methoxyphenyl)-3-butene-1-ol in Example 1 was replaced by 4-(4-methoxyphenyl)-4-pentene-1-ol, and 7-bromo-1H-indole was replaced by N-methylindole. Other conditions were the same as in Example 1, and finally a yellow oily liquid 1i (57.3 mg, 89% yield) was obtained.

[0110] The test data of product 1j are as follows:

[0111] 1H NMR (400MHz, CDCl3) δ7.28 (d, J=8.3Hz, 1H), 7.24 (d, J=8.8Hz, 2H), 7.14 (t, J=7.3Hz, 1H), 7.02 (d, J=8.0Hz, 1H), 6.97 (s, 1H), 6.87 (t, J=7.5Hz, 1H), 6.79 (d, J=8.8Hz, 2H), 3.78 (d, J=1.6Hz, 6H), 3.56 (t, J=6.6Hz, 2H) , 2.32–2.23(m, 1H), 2.20–2.11(m, 1H), 1.70(s, 3H), 1.43–1.35(m, 2H).

[0112] 13 C NMR (101MHz, CDCl3) δ157.4, 141.1, 137.8, 128.0, 126.5, 126.3, 123.3, 12 1.5, 121.2, 118.4, 113.3, 109.2, 63.6, 55.2, 41.5, 37.7, 32.8, 28.3, 28.0.

[0113] HRMS (ESI, Q-TOF) m / z: [M+Na + ]Calcd for C 21 H 25 O2NNa + , 346.1778; Found: 346.1778.

[0114] Example 11

[0115] Prepare C-3 benzylated indole compound 1k with the following structural formula:

[0116] The (3E)-4-(4-methoxyphenyl)-3-butene-1-ol in Example 1 was replaced by 4-(4-phenoxyphenyl)-4-pentene-1-ol, and 7-bromo-1H-indole was replaced by N-methylindole. Other conditions were the same as in Example 1, and finally a brown oily liquid 1k (58.1 mg, 75% yield) was obtained.

[0117] The product 1k test data is as follows:

[0118] 1H NMR (400 MHz, CDC13) δ 7.37 - 7.27 (m, 5H), 7.18 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 7.3 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 7.04 - 7.00 (m, 3H), 6.95 - 6.89 (m, 3H), 3.79 (s, 3H), 3.59 (t, J = 6.4 Hz, 2H), 2.36 - 2.26 (m, 1H), 2.24 - 2.14 (m, 1H), 1.74 (s, 3H), 1.49 - 1.39 (m, 2H).

[0119] 13 C NMR (101 MHz, CDC13) δ 157.6, 154.8, 144.1, 137.8, 129.7, 128.4, 126.42, 126.37, 12.0, 121.4, 121.3, 118.6, 118.5, 118.4, 109.2, 63.6, 41.7, 37.7, 32.8, 28.3, 27.9.

[0120] HRMS (ESI, Q-TOF) m / z: [M+H + ] Calcd for C 26 H 28 O2N + , 386.2115; Found: 386.2113.

[0121] Anti-tumor activity verification

[0122] The C-3 alkylated indole compounds prepared in the examples were selected, and human gastric adenocarcinoma cells (SGC-7901 cells) were used as receptors to test their in vitro anti-tumor activity by CCK-8 method.

[0123] The activity test process was illustrated by taking the compound 1b of Example 2 as an example: (1) Collecting cells in the logarithmic phase, adjusting the concentration of the cell suspension, adding 100 uL per well, and plating to adjust the density of the test cells to 5000 cells per well.

[0124] (2) Incubating at 37°C in 5% CO2 until the cell monolayer covers the bottom of the well (96-well flat-bottom plate), adding drugs with a concentration gradient, and setting 3 replicate wells.

[0125] (3) Incubating at 37°C in 5% CO2 for 48 hours, and observing under an inverted microscope.

[0126] (4) Adding 10 uL of CCK-8 solution per well, and continuing to culture for 1-4 h.

[0127] (5) When the color of the solution in the 96-well plate gradually changes into orange red, the obvious color change occurs, and the absorbance of each well is measured at OD 450 nm by an automatic microplate reader.

[0128] (6) The zero hole (culture medium, CCK-8 solution) and the control hole (cells, same concentration of drug dissolving medium, culture solution, CCK-8 solution) are set at the same time.

[0129] (7) Cell survival rate = (A cell drug group-A drug group blank plate) / (A cell blank group-A blank group blank plate) x 100%.

[0130] (8) The cell survival rate (%) is plotted with the logarithmic transformed drug concentration (such as log (drug concentration)), and the IC 50 value of the compound 1b is obtained by using nonlinear regression curve fitting data (GraphPad Prism); (9) The tumor inhibition experiment of the C-3 alkylated indole compound and cisplatin prepared in other embodiments is operated according to the similar method.

[0131] The following table is the inhibition effect of part of the compounds of the examples on the proliferation of human gastric adenocarcinoma cells (SGC-7901 cells).

[0132]

[0133]

[0134] As Figure 21 shown, the results show that the C-3 alkylated indole compound prepared by the application has a certain inhibitory effect on human gastric adenocarcinoma cells, especially example 2, the effect of inhibiting gastric adenocarcinoma cells is equivalent to cisplatin.

[0135] The above is only an embodiment of the application, and the specific structure and characteristics of the known scheme are not described in detail. It should be pointed out that for those skilled in the art, without departing from the structure of the application, a number of modifications and improvements can be made, which should be regarded as the protection scope of the application, and these will not affect the effect and practicality of the application. The protection scope claimed in this application should be subject to the content of its claims, and the specific implementation mode and the like recorded in the specification can be used to explain the content of the claims.

Claims

1. C-3 benzylated indole compounds, characterized in that: Its structural formula is as follows: ， Wherein: Ar is 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-isopropoxyphenyl, 3,4-dimethoxyphenyl, 4-n-butoxyphenyl, 4-phenoxyphenyl, 4-methylthiophenyl, 3-methyl-4-methoxyphenyl, 3-methyl-4-ethoxyphenyl, 3-methyl-4-propoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, 3,4,5-trimethoxyphenyl or 2-furyl; Ar′ is naphthyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-isopropoxyphenyl, 3,4-dimethoxyphenyl, 4-n-butoxyphenyl, 4-phenoxyphenyl, 3-methyl-4-methoxyphenyl, 3-methyl-4-ethoxyphenyl, 3-methyl-4-propoxyphenyl, 3,5-dimethyl-4-methoxyphenyl or 3,4,5-trimethoxyphenyl; R 1 is hydrogen, methyl or phenyl; R 2 is 4-methyl, 5-methyl, 6-methyl, 7-methyl, 5-methoxy, 6-fluoro, 5-bromo, 6-bromo, 7-bromo, 5-cyano or 5-iodo.

2. A C-3 benzylated indole compound, characterized in that: Selected from the compounds shown below, 。 3. The method for preparing the compound according to claim 1, wherein: An unsaturated alcohol, an acid catalyst, and an indole compound are sequentially added to an organic solvent, stirred for reaction, and then purified to obtain a C-3 benzylated indole compound. The reaction formula is as follows: 。 4. The preparation method according to claim 3, wherein: The molar ratio of each substance in the reaction is: unsaturated alcohol: acid catalyst: indole compound = 1:0.05~1.0:1.0~2.

0.

5. The preparation method according to claim 4, characterized in that: The organic solvent is selected from acetonitrile, methanol, tetrahydrofuran or 1,4-dioxane.

6. The preparation method according to claim 5, wherein: The reaction temperature is 0 ℃ ~ 100 ℃.

7. The preparation method according to claim 6, characterized in that: The acid catalyst used is selected from hydrochloric acid, hydroiodic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid or trimethylsilyl chloride.

8. The preparation method according to claim 7, characterized in that: The reaction is carried out under a gas atmosphere selected from oxygen, air or argon.

9. Use of the compound according to claim 1 or 2 in the preparation of anti-gastric adenocarcinoma drugs.

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