An N-fused-ring indole compound and its preparation method

Abstract

The present invention belongs to the technical field of pharmaceutical synthesis, and specifically relates to an N-fused-ring indole compound and a preparation method thereof. Using an amine derivative and a diazo periodide as raw materials, in a solvent, under the protection of air or argon, reacting at room temperature for 1-3 hours under alkaline conditions, the N-fused-ring indole compound can be obtained in one step, and the yield is 51-70%. The advantages of the present invention are that the substrate has high generality, and various amine substrates, whether phenylpyrrolidine derivatives or 1,2,3,4-tetrahydroisoquinoline derivatives, can be well converted into the target compound; the reaction conditions are mild and only need to be carried out at room temperature; no additives are required, and the post-treatment of the reaction is also very simple. The N-fused-ring indole compound can be obtained by ordinary column chromatography separation.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to an N-fused ring indole compound and a preparation method thereof. Background Art

[0002] Indole compounds are the most widely used nitrogen-containing heterocycles in natural products and medicinal chemistry, and can also be found in vinca alkaloids, fungal metabolites and marine natural products [Fernandes, L.S.; Buchanan, M.S.; Carroll, A.R.; Feng, Y.J.; Quinn, R.J.; Avery, V.M. Org. Lett. 2009, 11, 329]. Indole - as a structural backbone of a chemical drug, has high biological activity and plays a role in drugs in multiple therapeutic fields such as bactericidal and antiviral, anti-tumor, analgesic, and anti-inflammatory. Among them, N-fused ring indole compounds are widely present in natural products and bioactive compounds [Fernandez, L.S.; Buchanan, M.S.; Carroll, A.R.; Feng, Y.J.; Quinn, R.J.; Avery, V.M. Org. Lett. 2009, 11, 329 - 332]. N-fused ring indole compounds are usually prepared by reacting tryptamine or N-methyl-substituted tryptamine with aryl diazonium salts under alkaline conditions [(a) Stephens, D.E.; Larionov, O.V. Eur. J. Org. Chem. 2014, 17, 3662 - 3670; (b) Zhang, G.-Y.; Peng, Y.; Xue, J.; Fan, Y.-H.; Deng, Q.-H., Copper-catalyzed nitrene transfer / cyclization cascade to synthesize

[0003] 3a-Nitrogenous furoindolines and pyrroloindolines[J]. Org. Chem. Front., 2019, 6, 3934 - 3938). This method has problems that raw materials are not easily obtained, ligands and copper bis(triphenylphosphine) borohydride need to be added, and the reaction also needs to be completed at 80 °C, increasing costs and the environmental pollution problem of heavy metals. Ethyl aniline-ethyl hexynoate derivatives can also be used to construct fused-ring indole compounds by intramolecular cyclization under palladium-catalyzed oxidation [Piou T.; Neuville, L.; Zhu, J. Tetrahedron 2013, 69, 4415–4420]. This method has limitations that it requires noble metal catalysis and high-temperature reactions under oxygen conditions. Therefore, it is of great significance to develop a new method for preparing N-fused-ring indole compounds with high efficiency, mildness and easily available substrates. Summary of the Invention

[0004] The present invention provides an N-fused-ring indole compound, and its structural general formula is shown as formula (I):

[0005]

[0006] Wherein, R is hydrogen, methyl, methoxy, tert-butyl, fluorine, chlorine or trifluoromethyl.

[0007] The present invention also provides a preparation method of an N-fused-ring indole compound. The preparation method is as follows: Using an amine derivative and diazomethyl periodide as raw materials, in a solvent, under alkaline conditions, stirred at room temperature for 1 - 3 hours in air or under argon protection to generate an N-fused-ring indole alkaloid.

[0008] Among them, the molar ratio of the aniline derivative to diazomethyl periodide is 1:2 - 1:3.

[0009] The amine derivative is a 1,2,3,4-tetrahydroisoquinoline derivative, and its structure is shown as formula A, wherein X is hydrogen, methyl, methoxy, tert-butyl, fluorine, chlorine or trifluoromethyl; or a phenylpyrrolidine derivative, and its structural formula is shown as formula B, wherein Y is hydrogen, fluorine, methyl or methoxy.

[0010]

[0011] The solvent is one or a combination of two of acetonitrile, dichloromethane, tetrahydrofuran, methanol, ethyl acetate, toluene, and acetone.

[0012] The base used is cesium carbonate, potassium carbonate, sodium bicarbonate or triethylamine.

[0013] The diazomethyl periodide is

[0014] The N-fused ring indole compounds of the present invention are used as intermediates for 5-HT3 receptor drugs or as the parent nucleus of drugs of formula II:

[0015]

[0016] The post-reaction treatment of the present invention is simple and convenient, and only requires a simple column chromatography separation method, and a mixed solvent of petroleum ether and ethyl acetate is used as an eluent to obtain pure N-condensed ring indole compounds.

[0017] Advantages of the present invention: Indole compounds are commonly found in natural products and synthetic drugs and have a wide range of applications in medicine and pharmacology. N-fused-ring indoles are particularly prevalent in natural products and bioactive compounds. This invention, for the first time, utilizes a secondary amine derivative 1 and diazomethylenediamine as starting materials. Under air or argon protection and alkaline conditions, a free radical mechanism is employed to construct N-fused-ring indoles in a single step at room temperature, yielding 48-81%. Compound yields show a high yield of six-membered rings compared to five-membered rings. DETAILED DESCRIPTION

[0018]

[0019] Example 1

[0020] Under nitrogen, a 10 mL Schlenk tube was charged with 2-phenyl-1,2,3,4-tetrahydroisoquinoline (0.3 mmol, 63 mg), diazomethylene periodindole 2a (0.75 mmol, 348 mg), cesium carbonate (10.6 mg), and acetonitrile (2 mL). The reaction was allowed to react at room temperature for 2 hours. After completion of the reaction, monitored by TLC, the reaction solution was concentrated and flash column chromatography (petroleum ether and ethyl acetate as eluents) afforded 3a as a white solid in 78% yield. MP: 117-119°C. 1 H NMR (300MHz, CDCl3) δ8.55-8.52(m,1H),8.22-8.20(m,1H),7.39-7.30(m,5H),7.25-7.23(m,1 H), 4.46 (q, J = 7.1Hz, 2H), 4.22 (t, J = 6.3Hz, 2H), 3.13 (t, J = 6.4Hz, 2H), 1.48 (t, J = 7.1Hz, 3H).

[0021] Example 2

[0022] Under nitrogen protection, in a 10 mL Schlenk tube, add compound 2-p-tolyl-1,2,3,4-tetrahydroisoquinoline (0.3 mmol, 68 mg), diazomethyl periodate 2a (0.75 mmol, 348 mg), cesium carbonate (10.6 mg) and acetonitrile (2 mL). React the mixture at room temperature for 2 hours. After monitoring the completion of the reaction by TLC spotting, concentrate the reaction solution and obtain white solid 3b by flash column chromatography (using petroleum ether and ethyl acetate as eluents) with a yield of 81%. MP: 128 - 130 °C. 1 H NMR (300 MHz, CDCl3) δ 8.44 - 8.40 (m, 1H), 7.92 (s, 1H), 7.30 - 7.15 (m, 4H), 7.02 (dd, J = 8.3, 1.4 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.09 (t, J = 6.3 Hz, 2H), 3.03 (t, J = 6.5 Hz, 2H), 2.42 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H).

[0023] Example 3

[0024] Under nitrogen protection, in a 10 mL Schlenk tube, add compound 2-p-methoxyphenyl-1,2,3,4-tetrahydroisoquinoline (0.3 mmol, 72 mg), diazomethyl periodate 2a (0.75 mmol, 348 mg), cesium carbonate (10.6 mg) and acetonitrile (2 mL). React the mixture at room temperature for 2 hours. After monitoring the completion of the reaction by TLC spotting, concentrate the reaction solution and obtain white solid 3c by flash column chromatography (using petroleum ether and ethyl acetate as eluents) with a yield of 71%. MP: 105 - 106 °C. 1 H NMR (300 MHz, CDCl3) δ 8.50 - 8.47 (m, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.36 - 7.25 (m, 4H), 6.93 (dd, J = 8.8, 2.5 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 4.16 (t, J = 6.3 Hz, 2H), 3.90 (s, 3H), 3.11 (t, J = 6.4 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H).

[0025] Example 4

[0026] Under nitrogen protection, in a 10 mL Schlenk tube, add compound 2-(p-tert-butylphenyl)-1,2,3,4-tetrahydroisoquinoline (0.3 mmol, 80 mg), diazomethyl periodate 2a (0.75 mmol, 348 mg), cesium carbonate (10.6 mg) and acetonitrile (2 mL). React the mixture at room temperature for 3 hours. After monitoring the completion of the reaction by TLC thin-layer chromatography, concentrate the reaction solution, and obtain white solid 3d by flash column chromatography (using petroleum ether and ethyl acetate as eluents), with a yield of 68%. MP: 119 - 121 °C. 1 1H NMR (300 MHz, CDCl3) δ 8.54 - 8.51 (m, 1H), 8.27 (d, J = 1.4 Hz, 1H), 7.42 - 7.28 (m, 5H), 4.45 (q, J = 7.1 Hz, 2H), 4.19 (t, J = 6.3 Hz, 2H), 3.10 (t, J = 6.4 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H), 1.42 (s, 9H).

[0027] Example 5

[0028] Under nitrogen protection, in a 10 mL Schlenk tube, add compound 2-(p-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (0.3 mmol, 80 mg), diazomethyl periodate 2a (0.75 mmol, 348 mg), cesium carbonate (10.6 mg) and acetonitrile (2 mL). React the mixture at room temperature for 3 hours. After monitoring the completion of the reaction by TLC thin-layer chromatography, concentrate the reaction solution, and obtain white solid 3e by flash column chromatography (using petroleum ether and ethyl acetate as eluents), with a yield of 73%. MP: 132 - 134 °C. 1 1H NMR (300 MHz, CDCl3) δ 8.46 - 8.43 (m, 1H), 7.78 (dd, J = 10.3, 2.5 Hz, 1H), 7.31 - 7.27 (m, 1H), <7.24 - 7.20 (m, 3H), 6.91 (dt, J = 8.9, 2.5 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.07 (t, J = 6.3 Hz, 2H), 3.02 (t, J = 6.4 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H).

[0029] Example 6

[0030] Under nitrogen protection, in a 10 mL Schlenk tube, add compound 2-(p-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline (0.3 mmol, 68 mg), diazomethyl periodate 2a (0.75 mmol, 348 mg), cesium carbonate (10.6 mg) and acetonitrile (2 mL). React the mixture at room temperature for 3 hours. After monitoring the completion of the reaction by TLC thin-layer chromatography, concentrate the reaction solution and obtain white solid 3f by flash column chromatography (using petroleum ether and ethyl acetate as eluents), with a yield of 74%. MP: 137 - 139 °C. 1 H NMR(300MHz,CDCl3)δ8.56 - 8.53(m,1H),8.20(d,J=1.7Hz,1H),7.43 - 7.41(m,1H),7.40 - 7.34(m,1H),7.32 - 7.23(m,3H),4.48(q,J=7.1Hz,2H),4.20(t,J=6.3Hz,2H),3.15(t,J=6.5Hz,2H),1.50(t,J=7.1Hz,3H).

[0031] Example 7

[0032] Under nitrogen protection, in a 10 mL Schlenk tube, add compound 2-(p-trifluorophenyl)-1,2,3,4-tetrahydroisoquinoline (0.3 mmol, 84 mg), diazomethyl periodate 2a (0.75 mmol, 348 mg), cesium carbonate (10.6 mg) and acetonitrile (2 mL). React the mixture at room temperature for 3 hours. After monitoring the completion of the reaction by TLC thin-layer chromatography, concentrate the reaction solution and obtain white solid 3g by flash column chromatography (using petroleum ether and ethyl acetate as eluents), with a yield of 65%. MP: 123 - 125 °C. 1 H NMR(300MHz,CDCl3)δ8.55 - 8.53(m,2H),7.50(dd,J=7.1,1.5Hz,1H),7.42 - 7.34(m,3H),7.32 - 7.29(m,1H),4.47(q,J=7.1Hz,2H),4.23(t,J=6.3Hz,2H),3.14(t,J=6.4Hz,2H),1.49(t,J=7.1Hz,3H).

[0033] Example 8

[0034] Under nitrogen protection, 1-phenylpyrrolidine (0.3 mmol, 44 mg), diazomethyl periodide 2a (0.75 mmol, 348 mg), cesium carbonate (10.6 mg) and acetonitrile (2 mL) were added to a 10 mL Schlenk tube. The reaction was carried out at room temperature for 3 hours. After monitoring the completion of the reaction by TLC spotting, the reaction solution was concentrated, and a white solid 3h was obtained by flash column chromatography (petroleum ether and ethyl acetate as eluents), with a yield of 49%. MP: 89 - 91 °C. 1 H NMR (300 MHz, CDCl3) δ 8.04 - 8.02 (m, 1H), 7.18 - 7.13 (m, 3H), 4.28 (q, J = 9.5 Hz, 2H), 4.03 (t, J = 9.5 Hz, 2H), 3.21 (t, J = 7.6 Hz, 2H), 2.63 - 2.52 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H).

[0035] Example 9

[0036] Under nitrogen protection, 1-fluorophenylpyrrolidine (0.3 mmol, 50 mg), diazomethyl periodide 2a (0.75 mmol, 348 mg), cesium carbonate (10.6 mg) and acetonitrile (2 mL) were added to a 10 mL Schlenk tube. The reaction was carried out at room temperature for 3 hours. After monitoring the completion of the reaction by TLC spotting, the reaction solution was concentrated, and a white solid 3i was obtained by flash column chromatography (petroleum ether and ethyl acetate as eluents), with a yield of 60%. MP: 101 - 103 °C. 1 H NMR (400 MHz, CDCl3) δ 7.74 (dd, J = 10.0, 2.5 Hz, 1H), 7.11 (q, J = 4.4 Hz, 1H), 6.88 (dt, J = 9.0, 2.5 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.07 (t, J = 7.1 Hz, 2H), 3.21 (t, J = 7.3 Hz, 2H), 2.67 - 2.60 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H).

[0037] Example 10

[0038] Under nitrogen protection, 1-benzylpyrrolidine (0.3 mmol, 48 mg), diazomethyl periodide 2a (0.75 mmol, 348 mg), cesium carbonate (10.6 mg) and acetonitrile (2 mL) were added to a 10 mL Schlenk tube. The reaction was carried out at room temperature for 3 hours. After monitoring the completion of the reaction by TLC spotting, the reaction solution was concentrated, and a white solid 3j was obtained by flash column chromatography (petroleum ether and ethyl acetate as eluents), with a yield of 51%. MP: 78 - 80 °C. 11H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.93 (dd, J = 8.2, 1.4 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.97 (t, J = 7.1 Hz, 2H), 3.17 (t, J = 7.4 Hz, 2H), 2.57 - 2.49 (m, 2H), 2.39 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H).

[0039] Example 11

[0040] Under nitrogen protection, 1-benzylpyrrolidine (0.3 mmol, 54 mg), diazomethyl periodide 2a (0.75 mmol, 348 mg), cesium carbonate (10.6 mg) and acetonitrile (2 mL) were added to a 10 mL Schlenk tube. The reaction was carried out at room temperature for 3 hours. After monitoring the completion of the reaction by TLC thin-layer chromatography, the reaction solution was concentrated, and white solid 3k was obtained by flash column chromatography (petroleum ether and ethyl acetate as eluents), with a yield of 41%. MP: 113 - 115 °C. 1 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.83 (dd, J = 8.7, 2.5 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.07 (t, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.27 (t, J = 7.5 Hz, 2H), 2.67 - 2.59 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H).

[0041] Example 12

[0042] Under nitrogen protection, 2-phenyl-1,2,3,4-tetrahydroisoquinoline (0.3 mmol, 63 mg), diazomethyl periodide 2a (0.75 mmol, 348 mg), cesium carbonate (10.6 mg) and acetone (2 mL) were added to a 10 mL Schlenk tube. The reaction was carried out at room temperature for 2 hours. After monitoring the completion of the reaction by TLC thin-layer chromatography, the reaction solution was concentrated, and white solid 3a was obtained by flash column chromatography (petroleum ether and ethyl acetate as eluents), with a yield of 43%.

[0043] Example 13

[0044] Under nitrogen protection, in a 10 mL Schlenk tube, add compound 2-phenyl-1,2,3,4-tetrahydroisoquinoline (0.3 mmol, 63 mg), diazomethyl periodide 2a (0.75 mmol, 348 mg), sodium bicarbonate (8.7 mg) and acetonitrile (2 mL). React the mixture at room temperature for 2 hours. After monitoring the completion of the reaction by TLC thin-layer chromatography, concentrate the reaction solution and obtain white solid 3a by flash column chromatography (using petroleum ether and ethyl acetate as eluents), with a yield of 36%.

[0045] Example 14

[0046] In a 10 mL Schlenk tube, add compound 2-phenyl-1,2,3,4-tetrahydroisoquinoline (0.3 mmol, 63 mg), diazomethyl periodide 2a (0.75 mmol, 348 mg), cesium carbonate (10.6 mg) and acetonitrile (2 mL). React the mixture at room temperature for 2 hours. After monitoring the completion of the reaction by TLC thin-layer chromatography, concentrate the reaction solution and obtain white solid 3a by flash column chromatography (using petroleum ether and ethyl acetate as eluents), with a yield of 52%.

[0047] The above examples are the preferred embodiments of the present invention, but the present invention is not limited to the above embodiments. Without departing from the essence of the present invention, any obvious improvements, substitutions or variations that those skilled in the art can make all fall within the protection scope of the present invention.

Claims

1. A method for preparing an N-fused-ring indole compound, characterized in that: The preparation method comprises the following steps: using an amine derivative and diazomethylenediamine as raw materials, reacting them in a solvent under alkaline conditions in air or under argon protection, stirring at room temperature for 1-3 hours to generate an N-fused ring indole compound; The general structural formula of the N-fused ring indole compound is shown in formula (I) or formula (II): Wherein, R 1 is hydrogen, methyl, methoxy, tert-butyl, fluorine, chlorine or trifluoromethyl; in formula II, R 2 is hydrogen, fluorine, methyl or methoxy; The amine derivatives are 1,2,3,4-tetrahydroisoquinoline derivatives, whose structure is shown in Formula A, or phenylpyrrolidine derivatives, whose structure is shown in Formula B. wherein X is hydrogen, methyl, methoxy, tert-butyl, fluorine, chlorine or trifluoromethyl; Y is hydrogen, fluorine, methyl or methoxy; The structural formula of diazomethyl periodindole is:

2. The method for preparing an N-fused-ring indole compound according to claim 1, wherein: The molar ratio of the aniline derivative to the diazomethylene periodate is 1:2-1:

3.

3. The method for preparing an N-fused-ring indole compound according to claim 1, wherein: The solvent is one or a combination of two of acetonitrile, dichloromethane, tetrahydrofuran, methanol, ethyl acetate, toluene and acetone.

4. The method for preparing an N-fused-ring indole compound according to claim 1, wherein: The base is cesium carbonate, potassium carbonate, sodium bicarbonate or triethylamine.

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