Alpha-carboline derivatives and methods for their synthesis

Abstract

The present application mainly relates to a kind of a-karoline derivatives and its synthesis method, under the action of iodine reagent and organic solvent, with indole-3-formaldehyde compound, inorganic ammonium salt, alkyne and other simple and easily obtained raw materials one-step synthesis a-karoline derivatives technical scheme;It overcomes the problems in the prior art a-karoline derivatives synthesis method, such as the need to use expensive metal catalyst, or complex synthesis process, or the need to use high-activity complex reaction substrate etc.It is worth mentioning that the present application can be applied to gram-scale one-step synthesis of a-karoline compound containing antitumor activity.The present application greatly maintains atomic economy;With simple reaction system, high selectivity, low raw material cost and easy to obtain, less reaction equipment, simple experimental operation, high yield, high product utilization value, potential application value in the field of medicine.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of a-quinoline derivatives and its synthesis method, belong to organic synthesis technical field. BACKGROUND

[0002] a-quinoline compounds have various biological activities or pharmacological activities, such as anti-inflammatory, anti-Alzheimer's disease, anxiolytic, antiviral, antitumor, anticancer, anti-HIV, anti-proliferation and other activities, and have wide application value in the field of medicine. However, the existing synthesis method of such compounds has the disadvantages of complex synthesis steps, the need to use multi-step synthesis process, the need to use metal catalyst, the need to use high-activity starting material, and harsh reaction conditions. SUMMARY

[0003] In view of the above, the purpose of the present application is to provide a kind of a-quinoline and its derivatives, which have stable molecular structure, excellent chemical properties, certain biological activity and pharmacological activity, and have wide application value in the field of medicine. At the same time, the present application can also directly synthesize anticancer drug active molecules in one step, and has certain application prospect in the field of medicine.

[0004] Another purpose of the present application is to provide a new method for synthesizing a-quinoline and its derivatives, which is scientific and reasonable, easy to operate, has fewer reaction steps, simple equipment, cheap and easily available raw materials, does not need to use metal catalyst, metal oxidant and acid-base additives, can maintain atomic economy to a large extent, has low investment and high output, and is easy to industrialize and popularize.

[0005] In order to achieve the above purpose, a-quinoline and its derivatives have the general formula I:

[0006]

[0007] Among them

[0008] R 1 selected from hydrogen atom, alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl;

[0009] R 2 selected from hydrogen atom, alkyl, halogen, nitro, cyano, alkoxy, benzyloxy;

[0010] R 3 selected from alkoxy, benzyloxy, substituted or unsubstituted aryl;

[0011] R 4 selected from hydrogen atom, ester group.

[0012] The present application provides a method for synthesizing a-carboline and its derivatives as claimed in claim 1, characterized in that an indole-3-formaldehyde compound, an alkyne compound, an inorganic ammonium salt, a catalyst and an organic solvent are mixed and heated to react, and the product is purified.

[0013] The present application provides a method for synthesizing a-carboline and its derivatives as claimed in claim 1, characterized in that an indole-3-formaldehyde compound, an alkyne compound, an inorganic ammonium salt, a catalyst and an organic solvent are mixed and heated to react, and the product is purified.

[0014]

[0015] wherein

[0016] R 1 selected from a hydrogen atom; an alkyl group; a substituted or unsubstituted phenyl group; a substituted or unsubstituted benzyl group;

[0017] R 2 selected from a hydrogen atom; an alkyl group; a halogen; a nitro group; a cyano group; an alkoxy group; a benzyloxy group.

[0018] The present application provides a method for synthesizing a-carboline and its derivatives as claimed in claim 1, characterized in that an indole-3-formaldehyde compound, an alkyne compound, an inorganic ammonium salt, a catalyst and an organic solvent are mixed and heated to react, and the product is purified.

[0019] The present application provides a method for synthesizing a-carboline and its derivatives as claimed in claim 1, characterized in that an indole-3-formaldehyde compound, an alkyne compound, an inorganic ammonium salt, a catalyst and an organic solvent are mixed and heated to react, and the product is purified.

[0020]

[0021] wherein

[0022] R 3Selected from alkoxy; benzyloxy; substituted or unsubstituted aryl;

[0023] R 4 Selected from hydrogen atoms; ester groups;

[0024] In the synthesis method of the present invention, the alkyne compound is selected from ethyl propargylate; methyl propargylate; tert-butyl propargylate; benzyl propargylate; diethyl 2-butynedioate; 1-phenylprop-2-yn-1-one; 1-(2-bromophenyl)prop-2-yn-1-one; 1-(2-chlorophenyl)prop-2-yn-1-one; 1-(2-methylphenyl)prop-2-yn-1-one; 1-(2-methoxyphenyl)prop-2-yn-1-one; 1-(3-bromophenyl)prop-2-yn-1-one; 1-(3-nitrophenyl)prop-2-yn-1-one; 1-(4-bromophenyl)prop-2-yn-1-one; 1-(4-chlorophenyl)prop-2-yn-1-one; 1-(4-methylphenyl)prop-2-yn-1-one; 1-(4-methoxyphenyl)prop-2-yn-1-one.

[0025] In the synthesis method of this invention, the inorganic ammonium salt is ammonium acetate, ammonium formate, ammonium iodide, ammonium chloride, ammonium bromide, ammonium carbonate, or ammonium phosphate, preferably ammonium acetate; the catalyst is an iodine reagent selected from: trimethyl sulfoxide, ammonium iodide, potassium iodide, sodium iodide, elemental iodine, iodine chloride, iodobenzene, diethyl iodophenyl iodide, N-iodosuccinimide, diiodopentoxide, potassium iodate, sodium periodate, tetrabutylammonium iodide, tetramethylammonium iodide, hydroiodic acid, iodine monobromide, and [bis(trifluoroacetoxy)iodo]benzene, preferably diiodopentoxide; the organic solvent is toluene, xylene, trimethylbenzene, chlorobenzene, o-dichlorobenzene, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, dimethyl sulfoxide, p-xylene, acetone, acetonitrile, and 1,2-dichloroethane, preferably chlorobenzene;

[0026] In the synthesis method of this invention, the molar ratio of the indole-3-carboxaldehyde compound, the inorganic ammonium salt, the alkyne compound, and the catalyst is 1:0.5-10:0.5-10.0:0.01-10.0, preferably 1:3.5:1.5:0.02; the reaction atmosphere is air, oxygen, or argon, preferably argon; the reaction time is 1-36 h, preferably 8 h. Simultaneously, the reaction temperature is 20℃-200℃, preferably 140℃.

[0027] The technical solution of this invention has the following advantages:

[0028] (I) This invention relates to a method for synthesizing α-carboline and its derivatives, which achieves a one-pot reaction of three components—indole-3-carboxaldehyde, inorganic ammonium salt, and alkyne compound—under the action of a catalyst, and obtains α-carboline and its derivatives with high selectivity. This method directly and selectively synthesizes the target product in one step and has the advantages of simple reaction system, short reaction cycle, few required equipment, simple operation, cheap and readily available raw materials, easy application expansion, high product utilization value, and predictable market commercialization prospects. (II) This invention overcomes the shortcomings of existing synthetic methods for α-carboline compounds, such as the need for metal catalysts, the need for relatively highly active starting materials, harsh reaction conditions, and complex reaction steps; it maintains atom economy to the greatest extent. (III) It achieves a technical solution for the highly selective synthesis of α-carboline and its derivatives from three components: indole-3-carboxaldehyde compounds, inorganic ammonium salts, and alkynes. The process is scientific and reasonable, with good group positioning and selectivity, wide availability of raw materials, good atom economy, stable structure, easy experimental operation, significantly shortened reaction steps, and fewer required instruments and equipment. (IV) The α-carboline and its derivatives of this invention have stable molecular structures, excellent chemical properties, and the molecular blocks and compound fragments contain rich biological and pharmacological activities. The products have high utilization value and potential application value in the pharmaceutical field, and are particularly suitable for the scientific research and development of one-pot efficient and selective synthesis of α-carboline compounds.

[0029] The present invention will now be described in further detail with reference to the accompanying drawings and embodiments. Attached Figure Description

[0030] To demonstrate the products of this invention, this invention provides a synthetic route diagram and NMR spectra of some products from embodiments.

[0031] Figure 1 Synthesis route diagram of the present invention.

[0032] Figure 2-1 The hydrogen NMR spectrum of the product in Example 1.

[0033] Figure 2-2 The carbon NMR spectrum of the product in Example 1.

[0034] Figure 3-1 The hydrogen NMR spectrum of the product in Example 22.

[0035] Figure 3-2 The carbon NMR spectrum of the product in Example 22.

[0036] Figure 4-1 The hydrogen NMR spectrum of the product in Example 27.

[0037] Figure 4-2 The carbon NMR spectrum of the product in Example 27.

[0038] Figure 5-1 The hydrogen NMR spectrum of the product in Example 39.

[0039] Figure 5-2 The carbon NMR spectrum of the product in Example 39. Detailed Implementation

[0040] The technical solutions of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention. Furthermore, the technical features involved in the different embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0041] The invention will now be described in further detail with reference to the following reaction formula. The basic structure of the invention is illustrated only by way of illustration, and therefore only shows the components relevant to the invention:

[0042]

[0043] Examples 1-38 include the following steps:

[0044] (1) Add indole-3-carboxaldehyde compounds, inorganic ammonium salts, alkyne compounds, catalysts, and organic solvents to the reaction vessel;

[0045] (2) After the reactants are thoroughly mixed, they are heated under an argon atmosphere;

[0046] (3) The product is obtained by purification after the reaction.

[0047] Referring to the accompanying drawings, Examples 1-39 are as follows:

[0048] Example 1 Synthesis of ethyl 9-methyl-9H-pyrido[2,3-b]indole-3-carboxylate

[0049]

[0050] Take a reaction tube and add 0.04 mmol (13.4 mg) of iodine pentoxide, 0.2 mmol (31.8 mg) of 1-methyl-1H-indole-3-carboxaldehyde, 0.7 mmol (54.0 mg) of ammonium acetate, 0.3 mmol (30 μL) of ethyl propynate, and 0.5 mL of chlorobenzene. Use an oil pump to evacuate the reaction tube to a vacuum state, and then fill it with argon gas. Repeat this process 3-4 times. After sealing the reaction tube, place it in an oil bath at 140 °C and heat it for 8 hours. After conventional treatment, 47.2 mg of pure product was obtained, with a yield of 93%.

[0051] The NMR and mass spectrometry data of the product from Example 1 are as follows:

[0052] 1H NMR(400MHz,Chloroform-d)δ9.15(s,1H),8.87(s,1H),8.07(d,J=7.6Hz,1H),7.55(t,J=7.6Hz,1H),7. 44(d,J=8.0Hz,1H),7.32(t,J=7.6Hz,1H),4.45(q,J=7.2Hz,2H),3.94(s,3H),1.46(t,J=7.0Hz,3H).13C NMR (100MHz, CDCl3) δ166.6,153.6,148.5,140.9,129.5,127.5,121.4,120.9,120.5,117.9,115.3,109.5,61.1,28.0,14.6; HRMS calcd for C 15 H 14 N₂O₂[M+H] + 255.1128, found 255.1139.

[0053] Following the procedure described in Example 1, the following compounds were synthesized in this invention:

[0054]

[0055]

[0056]

[0057]

[0058]

[0059] It is worth mentioning that this invention enables the one-step synthesis of antitumor drug molecules (product of Example 39) on a gram-scale basis. Previous studies have shown that the product of Example 39 exhibits high cytotoxicity against HL-60, COLO205, Hep 3B, and H460 cells, and can serve as a promising pro-apoptotic drug for future development of novel antitumor drugs.

[0060]

[0061] The following are characterization data, including NMR and high-resolution mass spectrometry, of the compounds in some embodiments of the present invention:

[0062] The NMR and mass spectrometry data of the product from Example 2 are as follows:

[0063] 1H NMR(400MHz,Chloroform-d)δ9.18(s,1H),8.93(s,1H),8.13(d,J=7.6Hz,1H),7.57(t,J=7.4Hz,1H),7.50(d,J=8.0Hz ,1H),7.34(t,J=7.4Hz,1H),4.57(q,J=7.2Hz,2H),4.46(q,J=7.2Hz,2H),1.49(t,J=5.2Hz,3H),1.46(t,J=5.2Hz,3H). 13 HRMS calcd for C 16 H 16 N₂O₂[M+H] + 269.1285, found 269.1294.

[0064] The NMR and mass spectrometry data of the product in Example 3 are as follows:

[0065] 1 H NMR(400MHz,Chloroform-d)δ9.17(s,1H),8.91(s,1H),8.10(d,J=8.0Hz,1H),7.55(t,J=7.6Hz,1H),7.47(d,J=8.4Hz,1H),7.32(t,J=7 .6Hz,1H),4.49-4.43(m,4H),1.89(t,J=5.8Hz,2H),1.46(t,J=7.0Hz,3H),1.40-1.34(m,4H),1.27-1.24(m,4H),0.85(t,J=6.8Hz,3H). 13 C NMR (100MHz, CDCl3) δ166.7,153.4,148.5,140.3,129.5,127.4,121.5,120.7,120 .7,117.8,115.3,109.9,61.0,42.0,31.8,29.1,29.0,27.1,22.7,14.6,14.2.HRMS calcd for C 21 H 26 N₂O₂[M+H] + 339.2067, found 339.2077.

[0066] The NMR and mass spectrometry data of the product in Example 4 are as follows:

[0067] 1 H NMR(400MHz,Chloroform-d)δ9.16(s,1H),9.02(s,1H),8.18(d,J=8.0Hz,1H),7.64(d,J=4.4Hz ,4H),7.51(t,J=7.4Hz,3H),7.39(t,J=7.0Hz,1H),4.47(q,J=7.2Hz,2H),1.46(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ166.4,153.7,148.9,140.9,135.7,129.9,129.9,128. 3,127.7,127.4,121.7,121.4,120.9,119.1,115.9,110.9,61.2,14.5.HRMS calcd for C 20 H 16 N₂O₂[M+H] + 317.1285, found 317.1280.

[0068] The NMR and mass spectrometry data of the product in Example 5 are as follows:

[0069] 1 H NMR(400MHz,Chloroform-d)δ9.22(s,1H),8.98(s,1H),8.13(d,J=7.6Hz,1H),7.49(t,J=7.6Hz,1H),7.40(d,J= 8.0Hz,1H),7.33(t,J=7.4Hz,1H),7.29-7.22(m,5H),5.73(s,2H),4.48(q,J=7.1Hz,2H),1.47(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ166.6,153.6,148.7,140.3,136.8,129.8,128.8,127.7, 127.5,127.2,121.5,121.1,120.8,118.4,115.4,110.4,61.1,45.4,14.6.HRMS calcd for C 21 H 18 N₂O₂[M+H] + 331.1441, found 331.1453.

[0070] The NMR and mass spectrometry data of the product in Example 6 are as follows:

[0071] 1 H NMR(400MHz,Chloroform-d)δ9.15(s,1H),8.89(s,1H),7.91(s,1H),7.38(d,J=3 .6Hz,2H),4.45(q,J=7.2Hz,2H),3.96(s,3H),2.55(s,3H),1.46(t,J=7.2Hz,3H). 13 CNMR(100MHz, CDCl3)δ166.7,153.8,148.4,139.2,130.5,129.5,128.8,121.4,120.7,117.7,115.3,109.3,61.1,28.1,21.6,14.6.HRMS calcd for C 16 H 16 N₂O₂[M+H] + 269.1285, found 269.1289.

[0072] The NMR and mass spectrometry data of the product in Example 7 are as follows:

[0073] 1 H NMR(400MHz,Chloroform-d)δ9.13(s,1H),8.86(s,1H),7.57(s,1H),7.36(d,J=8.8Hz,1H),7 .19(d,J=8.8Hz,1H),4.45(q,J=7.1Hz,2H),3.94(s,3H),3.93(s,3H),1.46(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ166.7,155.0,153.7,148.5,135.7,129.6,121.0,117.4,116.6,115.3,110.4,104.3,61.0,56.1,28.0,14.6.HRMS calcd forC 16 H 16 N₂O₃[M+H] + 285.1234, found 285.1234.

[0074] The NMR and mass spectrometry data of the product in Example 8 are as follows:

[0075] 1H NMR(400MHz,Chloroform-d)δ9.14(s,1H),8.86(s,1H),7.58(s,1H),7.37(d,J=8.8Hz,1H),7.20(d,J=8.8Hz ,1H),4.45(q,J=7.1Hz,2H),4.15(q,J=7.0Hz,2H),3.94(s,3H),1.49(t,J=5.6Hz,1H),1.45(t,J=5.6Hz,1H). 13 C NMR (100MHz, CDCl3) δ166.7,154.3,153.8,148.5,135.7,129.6,121.0,117.4,117.2,115.4,110.4,105.2,64.5,61.0,28.1,15.1,14.6.HRMS calcd for C 17 H 18 N₂O₃[M+H] + 299.1390, found 299.1402.

[0076] The NMR and mass spectrometry data of the product in Example 9 are as follows:

[0077] 1 H NMR(400MHz,Chloroform-d)δ9.15(s,1H),8.86(s,1H),7.66(s,1H),7.50(d,J=6.8Hz,2H),7.44-7.34 (m,4H),7.28(d,J=2.4Hz,1H),5.18(s,2H),4.45(q,J=7.2Hz,2H),3.94(s,3H),1.46(t,J=7.2Hz,3H). 13 CNMR (100MHz, CDCl3) δ166.7,154.1,153.8,148.5,137.2,135.9,129.7,128.7,12 8.1,127.6,121.0,117.5,117.4,115.3,110.4,105.9,71.1,61.0,28.1,14.6.HRMS calcd for C 22 H 2O N₂O₃[M+H] + 361.1547, found 361.1556.

[0078] The NMR and mass spectrometry data of the product from Example 10 are as follows:

[0079] 1H NMR(400MHz,Chloroform-d)δ9.09(s,1H),8.74(s,1H),7.65(d,J=8.4Hz,1H) ,7.33-7.20(m,2H),4.42(q,J=7.1Hz,2H),3.88(s,3H),1.44(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ166.3, 159.4, 155.45 (d, J = 314.7Hz), 149.0, 137.1, 129.9, 120.93 (d, J = 9.5Hz), 117. 8,115.24(d,J=25.4Hz),114.82(d,J=4.1Hz),110.26(d,J=9.1Hz),107.28(d,J=24.2Hz),61.1,28.0,14.5. 19 F NMR(376MHz,CDCl3)δ-122.0.HRMS calcd forC 15 H 13 FN2O2[M+H] + 273.1034, found 273.1041.

[0080] The NMR and mass spectrometry data of the product from Example 11 are as follows:

[0081] 1 H NMR(400MHz,Chloroform-d)δ9.17(s,1H),8.85(s,1H),8.04(s,1H),7.51(d,J=8.8Hz ,1H),7.38(d,J=8.8Hz,1H),4.45(q,J=7.2Hz,2H),3.95(s,3H),1.46(t,J=7.2Hz,3H). 13 HRMS calcd for C 15 H 13 ClN2O2[M+H] + 289.0738, found 289.0743.

[0082] The NMR and mass spectrometry data of the product in Example 12 are as follows:

[0083] 1H NMR(400MHz,Chloroform-d)δ9.18(s,1H),8.86(s,1H),8.21(s,1H),7.65(d,J=8.4Hz ,1H),7.35(d,J=8.8Hz,1H),4.46(q,J=7.1Hz,2H),3.96(s,3H),1.46(t,J=7.2Hz,3H). 13 HRMS calcd for C 15 H 13 BrN2O2[M+H] + 333.0233, found 333.0232.

[0084] The NMR and mass spectrometry data of the product in Example 13 are as follows:

[0085] 1 H NMR(400MHz,Chloroform-d)δ9.23(s,1H),9.00(s,1H),8.97(s,1H),8.47(d,J=9.2Hz ,1H),7.53(d,J=8.8Hz,1H),4.47(q,J=7.2Hz,2H),4.04(s,3H),1.47(t,J=7.2Hz,3H). 13 HRMS calcd for C 15 H 13 N3O4[M+Na] + 322.0798, found 322.0801.

[0086] The NMR and mass spectrometry data of the product in Example 14 are as follows:

[0087] 1H NMR(400MHz,Chloroform-d)δ9.23(s,1H),8.94(s,1H),8.41(s,1H),7.82(d,J=8.4Hz ,1H),7.55(d,J=8.8Hz,1H),4.47(q,J=7.1Hz,2H),4.02(s,3H),1.47(t,J=7.2Hz,3H). 13 HRMS calcd for C 16 H 13 N3O2[M+Na] + 302.0900, found 302.0906.

[0088] The NMR and mass spectrometry data of the product in Example 15 are as follows:

[0089] 1 H NMR(400MHz,Chloroform-d)δ9.12(s,1H),8.84(s,1H),7.96(d,J=8.0Hz,1H),7.25(s,1H),7 .15(d,J=8.0Hz,1H),4.46(t,J=7.1Hz,2H),3.93(s,3H),2.58(s,3H),1.45(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ166.8,153.8,147.9,141.4,138.0,129.0,122.4,121.1,118.2,117.8,115.5,109.8,61.0,27.9,22.5,14.6.HRMS calcd forC 16 H 16 N₂O₂[M+H] + 269.1285, found 269.1293.

[0090] The NMR and mass spectrometry data of the product in Example 16 are as follows:

[0091] 1H NMR(400MHz,Chloroform-d)δ9.07(s,1H),8.77(s,1H),7.95(d,J=8.4Hz,1H),6.94- 6.88(m,2H),4.44(q,J=7.1Hz,2H),3.95(s,3H),3.92(s,3H),1.45(t,J=7.2Hz,3H). 13 HRMS calcd for C 16 H 16 N₂O₃[M+H] + 285.1234, found 285.1243.

[0092] The NMR and mass spectrometry data of the product in Example 17 are as follows:

[0093] 1 H NMR(400MHz,Chloroform-d)δ9.14(s,1H),8.86(s,1H),8.05-8.01(m,1H),7.15(d,J=9.2 Hz,1H),7.07(t,J=9.0Hz,1H),4.46(q,J=7.1Hz,2H),3.95(s,3H),1.46(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ166.5,162.90(d,J=245.8Hz),154.2,148.0,141.9,129.2,122.73(d,J =10.6Hz),118.5,116.9,115.2,109.13(d,J=24.4Hz),96.89(d,J=27.1Hz),61.2,28.2,14.6. 19 F NMR(376MHz,CDCl3)δ-111.5.HRMS calcd forC 15 H 13 FN2O2[M+H] + 273.1034, found 273.1044.

[0094] The NMR and mass spectrometry data of the product in Example 18 are as follows:

[0095] 1H NMR(400MHz,Chloroform-d)δ9.13(s,1H),8.81(d,J=6.4Hz,1H),7.97-7.92(m,1H),7.42(d ,J=5.2Hz,1H),7.30-7.26(m,1H),4.45(q,J=7.1Hz,2H),3.90(s,3H),1.45(t,J=7.0Hz,3H). 13 HRMS calcd for C 15 H 13 ClN2O2[M+H] + 289.0738, found 289.0747.

[0096] The NMR and mass spectrometry data of the product in Example 19 are as follows:

[0097] 1 H NMR(400MHz,Chloroform-d)δ9.17(s,1H),8.87(s,1H),7.94(d,J=8.4Hz,1H),7.62(s ,1H),7.45(d,J=8.4Hz,1H),4.45(q,J=7.1Hz,2H),3.94(s,3H),1.46(t,J=7.0Hz,3H). 13 HRMS calcd for C 15 H 13 BrN2O2[M+Na] + 355.0053, found 355.0047.

[0098] The NMR and mass spectrometry data of the product from Example 20 are as follows:

[0099] 1H NMR(400MHz,Chloroform-d)δ9.16(s,1H),8.87(s,1H),7.94(d,J=7.6Hz,1H),7.26(d,J=6.8Hz,1 H),7.20(t,J=7.6Hz,1H),4.45(q,J=7.1Hz,2H),4.26(s,3H),2.87(s,3H),1.46(t,J=7.2Hz,3H). 13 HRMScalcd for C 16 H 16 N₂O₂[M+H] + 269.1285, found 269.1295.

[0100] The NMR and mass spectrometry data of the product from Example 21 are as follows:

[0101] 1 H NMR(400MHz,Chloroform-d)δ9.30(s,1H),9.10(s,1H),7.39(t,J=4.2Hz,1H),7 .32(d,J=4.4Hz,2H),4.45(q,J=7.1Hz,2H),3.89(s,3H),1.46(t,J=7.2Hz,3H). 13 CNMR(100MHz, CDCl3)δ166.4,153.1,148.9,141.7,131.5,127.8,124.6,119.5,118.1,117.6,114.9,108.4,61.1,28.1,14.6.HRMS calcd for C 15 H 13 BrN2O2[M+Na] + 355.0053, found 355.0049.

[0102] The NMR and mass spectrometry data of the product from Example 22 are as follows:

[0103] 1H NMR (400MHz, DMSO-d6) δ12.29(s,1H),9.05(s,1H),9.00(s,1H),8.32(d,J=8.0Hz,1H),7.56(d,J=7. 6Hz,1H),7.52(t,J=7.6Hz,1H),7.29(t,J=7.2Hz,1H),4.38(q,J=7.1Hz,2H),1.37(t,J=7.0Hz,3H). 13 C NMR (100MHz, DMSO) δ165.7,153.8,147.9,139.5,129.6,127.5,121.9,120.5,120.4,117.2,114.9,111.7,60.6,14.3.HRMS calcd forC 14 H 12 N₂O₂[M+H] + 241.0972, found 241.0980.

[0104] The NMR and mass spectrometry data of the product in Example 23 are as follows:

[0105] 1 H NMR(400MHz,Chloroform-d)δ9.12(s,1H),8.85(s,1H),8.05(d,J=7.6Hz,1H),7.54(t ,J=7.6Hz,1H),7.42(d,J=8.4Hz,1H),7.32(t,J=7.4Hz,1H),3.98(s,3H),3.92(s,3H). 13 HRMS calcd for C 14 H 12 N₂O₂[M+H] + 241.0792, found 241.0983.

[0106] The NMR and mass spectrometry data of the product in Example 24 are as follows:

[0107] 1H NMR(400MHz,Chloroform-d)δ9.13(s,1H),8.87(s,1H),8.11(d,J=8.0Hz,1H),7.57(t ,J=7.6Hz,1H),7.48(d,J=8.4Hz,1H),7.34(t,J=7.6Hz,1H),3.98(s,3H),1.66(s,9H). 13 HRMS calcd for C 17 H 18 N₂O₂[M+H] + 283.1441, found 283.1454.

[0108] The NMR and mass spectrometry data of the product from Example 25 are as follows:

[0109] 1 H NMR (400MHz, CDCl3) δ9.16 (s, 1H), 9.02 (s, 1H), 8.18 (d, J = 8.0Hz, 1H), 7.64 (d, J = 4.4Hz, 4H) ,7.51(t,J=7.4Hz,3H),7.39(t,J=7.0Hz,1H),4.47(q,J=7.2Hz,2H),1.46(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ166.4,153.7,148.9,140.9,135.7,129.9,129.9,128.3, 127.7,127.4,121.7,121.4,120.9,119.1,115.9,110.9,61.2,14.5.HRMScalcd for C 20 H 16 N₂O₂[M+H] + 317.1285, found 317.1280.

[0110] The NMR and mass spectrometry data of the product in Example 26 are as follows:

[0111] 1H NMR(400MHz,Chloroform-d)δ8.90(s,1H),8.14(d,J=7.6Hz,1H),7.61(t,J=7.6Hz,1H),7.50(d,J=8.4Hz ,1H),7.38(t,J=7.6Hz,1H),4.52(t,J=7.1Hz,2H),4.44(t,J=7.1Hz,2H),4.00(s,3H),1.47-1.42(m,6H). 13 C HRMS calcd for C 19 H 20 N₂O₄[M+Na] + 349.1159, found 349.1154.

[0112] The NMR and mass spectrometry data of the product in Example 27 are as follows:

[0113] 1 H NMR(400MHz,Chloroform-d)δ8.97(s,1H),8.83(s,1H),8.11(d,J=7.6Hz,1H),7.85(d,J=7.2Hz,2H) ,7.63(t,J=6.8Hz,1H),7.59(d,J=8.0Hz,1H),7.55-7.49(m,3H),7.36(t,J=7.4Hz,1H),4.01(s,3H). 13 CNMR(100MHz, CDCl3)δ195.5,153.5,149.7,141.2,138.4,132.4,130.2,130.0,128.5,127.8,125.3,121.6,121.2,120.7,115.7,109.7,28.1.HRMS calcd for C 19 H 14 N₂O[M+Na] + 309.0998, found 309.1012.

[0114] The NMR and mass spectrometry data of the product in Example 28 are as follows:

[0115] 1H NMR(400MHz,Chloroform-d)δ8.87(s,1H),8.82(s,1H),8.09(d,J=8.0Hz,1H),7.59(t,J=7.6Hz ,1H),7.49(d,J=8.0Hz,1H),7.45-7.35(m,4H),7.30(t,J=7.4Hz,1H),3.99(s,3H),2.37(s,3H). 13 C NMR (100MHz, CDCl3) δ197.5,153.7,150.2,141.2,139.0,136.5,131.2,130.3,129. 7,128.4,127.8,125.6,125.5,121.6,121.2,120.8,115.9,109.7,28.1,20.1.HRMS calcd for C 20 H 16 N₂O[M+Na] + 323.1155, found 323.1169.

[0116] The NMR and mass spectrometry data of the product in Example 29 are as follows:

[0117] 1 H NMR(400MHz,Chloroform-d)δ8.87(s,1H),8.85(s,1H),8.10(d,J=7.6Hz,1H),7.58(t,J=7.8Hz,1H),7.50(t,J=7.1Hz,2 H),7.46(d,J=7.6Hz,1H),7.35(t,J=7.4Hz,1H),7.10(t,J=7.4Hz,1H),7.03(d,J=8.4Hz,1H),3.99(s,3H),3.74(s,3H). 13 CNMR (100MHz, CDCl3) δ195.2,157.3,153.7,150.3,141.1,132.1,129.8,129.5,129 .1,127.6,125.9,121.6,121.1,120.9,120.9,115.8,111.5,109.7,55.7,28.1.HRMS calcdfor C 20 H 16 N₂O₂[M+Na] + 339.1104, found 339.1119.

[0118] The NMR and mass spectrometry data of the product in Example 30 are as follows:

[0119] 1 H NMR(400MHz,Chloroform-d)δ8.84(s,1H),8.82(s,1H),8.09(d,J=8.0Hz,1H),7.58(t,J= 7.6Hz,1H),7.51-7.45(m,4H),7.42(t,J=7.0Hz,1H),7.35(t,J=7.4Hz,1H),3.97(s,3H). 13 C NMR (100MHz, CDCl3) δ194.1,153.9,150.3,141.2,138.8,131.4,131.3,130.3,1 29.5,129.2,127.9,127.0,124.6,121.6,121.4,120.7,116.1,109.8,28.1.HRMS calcd for C 19 H 13 ClN2O[M+Na] + 343.0609, found 343.0630.

[0120] The NMR and mass spectrometry data of the product from Example 31 are as follows:

[0121] 1 H NMR(400MHz,Chloroform-d)δ8.83(s,2H),8.11(d,J=7.6Hz,1H),7.69(d,J=8.0Hz ,1H),7.59(t,J=7.6Hz,1H),7.52-7.40(m,4H),7.36(t,J=7.2Hz,1H),3.99(s,3H). 13 C NMR (100MHz, CDCl3) δ194.7,153.9,150.5,141.2,140.9,133.4,131.4,129.6,1 29.1,127.9,127.5,124.3,121.7,121.4,120.8,119.7,116.2,109.8,28.1.HRMS calcd forC 19 H 13 BrN2O[M+H] + 365.0284, found 365.0300.

[0122] The NMR and mass spectrometry data of the product from Example 32 are as follows:

[0123] 1H NMR(400MHz,Chloroform-d)δ8.92(s,1H),8.84(s,1H),8.68(s,1H),8.48(d,J=8.0Hz,1H),8.17(d,J=8.0Hz,1H),8.13( d,J=7.6Hz,1H),7.75(t,J=7.8Hz,1H),7.63(t,J=7.6Hz,1H),7.53(d,J=8.0Hz,1H),7.39(t,J=7.4Hz,1H),4.03(s,3H). 13 C NMR (100MHz, CDCl3) δ193.0,153.8,149.5,148.3,141.3,139.9,135.4,129.9,1 29.8,128.1,126.7,124.7,124.1,121.7,121.5,120.6,116.2,109.9,28.2.HRMS calcd for C 19 H 13 N3O3[M+Na] + 354.0849, found 354.0863.

[0124] The NMR and mass spectrometry data of the product of Example 33 are as follows:

[0125] 1 H NMR(400MHz,Chloroform-d)δ8.93(s,1H),8.82(s,1H),8.12(d,J=7.6Hz,1H),7.98(s,1H),7.7 5(d,J=7.6Hz,2H),7.61(t,J=7.6Hz,1H),7.51(d,J=8.0Hz,1H),7.43-7.35(m,2H),4.01(s,3H). 13 C NMR (100MHz, CDCl3) δ193.9,153.6,149.6,141.2,140.2,135.2,132.8,130.1,1 30.0,128.5,127.9,124.7,122.9,121.7,121.3,120.6,115.9,109.8,28.1.HRMS calcd for C 19 H 13 BrN2O[M+Na] + 387.0103, found 387.0117.

[0126] The NMR and mass spectrometry data of the product in Example 34 are as follows:

[0127] 1 H NMR(400MHz,Chloroform-d)δ8.96(s,1H),8.81(s,1H),8.10(d,J=7.6Hz,1H),7.77(d,J=8.0Hz ,2H),7.59(t,J=7.6Hz,1H),7.49(d,J=8.4Hz,1H),7.37-7.30(m,3H),4.00(s,3H),2.47(s,3H). 13 C NMR (100MHz, CDCl3) δ195.2,153.4,149.4,143.2,141.1,135.6,130.3,130. 1,129.2,127.7,125.5,121.6,121.1,120.7,115.6,109.7,28.1,21.8.HRMS calcd for C 20 H 16 N₂O[M+Na] + 323.1155, found 323.1176.

[0128] The NMR and mass spectrometry data of the product in Example 35 are as follows:

[0129] 1 H NMR(400MHz,Chloroform-d)δ8.94(s,1H),8.78(s,1H),8.10(d,J=7.6Hz,1H),7.87(d,J=8.4Hz,2H),7.58(t ,J=7.6Hz,1H),7.49(d,J=8.0Hz,1H),7.34(t,J=7.4Hz,1H),7.01(d,J=8.8Hz,2H),4.00(s,3H),3.90(s,3H). 13 C NMR (100MHz, CDCl3) δ194.2,163.2,153.3,149.1,141.1,132.5,130.8,130. 1,127.6,125.8,121.6,121.0,120.7,115.6,113.8,109.6,55.6,28.0.HRMS calcd for C 20 H 16 N₂O₂[M+Na] + 339.1104, found 339.1125.

[0130] The NMR and mass spectrometry data of the product in Example 36 are as follows:

[0131] 1H NMR(400MHz,Chloroform-d)δ8.93(s,1H),8.80(s,1H),8.11(d,J=7.6Hz,1H),7.80(d,J=8 .4Hz,2H),7.61(t,J=8.0Hz,1H),7.51(d,J=8.4Hz,3H),7.37(t,J=7.6Hz,1H),4.01(s,3H). 13 C HRMScalcd for C 19 H 13 ClN2O[M+Na] + 343.0609, found 343.0626.

[0132] The NMR and mass spectrometry data of the product in Example 37 are as follows:

[0133] 1 H NMR(400MHz,Chloroform-d)δ8.92(s,1H),8.78(s,1H),8.10(d,J=7.6Hz,1H),7.72(d,J=8.4Hz,2H),7 .66(d,J=8.4Hz,2H),7.60(t,J=7.8Hz,1H),7.50(d,J=8.4Hz,1H),7.36(t,J=7.6Hz,1H),4.00(s,3H). 13 C NMR (100MHz, CDCl3) δ194.3,153.5,149.4,141.2,137.1,131.8,131.5,130.0,127.8,127.4,124.8,121.6,121.2,120.6,115.8,109.7,28.1.HRMS calcd for C 19 H 13 BrN2O[M+Na] + 387.0103, found 387.0117.

[0134] The NMR and mass spectrometry data of the product in Example 38 are as follows:

[0135] 1H NMR(400MHz,Chloroform-d)δ9.20(s,1H),8.97(s,1H),8.12(d,J=7.6Hz,1H),7.49(t,J=7.6Hz ,1H),7.40(d,J=8.0Hz,1H),7.33(t,J=7.6Hz,1H),7.28-7.23(m,5H),5.73(s,2H),4.01(s,3H). 13 C NMR (100MHz, CDCl3) δ167.1,153.7,148.7,140.3,136.8,129.8,128.9,127. 7,127.6,127.2,121.5,121.2,120.8,118.1,115.5,110.5,52.2,45.4.HRMS calcd for C 20 H 16 N₂O₂[M+H] + 317.1285, found 317.1305.

[0136] The NMR and mass spectrometry data of the product of Example 39 are as follows:

[0137] 1 H NMR(400MHz,Chloroform-d)δ9.19(s,1H),8.96(s,1H),8.12(d,J=7.6Hz,1H),7.51(t,J=7.6Hz,1H),7.44 (d,J=8.0Hz,1H),7.34(t,J=7.4Hz,1H),6.51(s,2H),5.63(s,2H),4.00(s,3H),3.77(s,3H),3.71(s,6H). 13 C NMR (100MHz, CDCl3) δ167.0,153.6,153.5,148.6,140.3,137.5,132.5,129.9,127 .6,121.5,121.3,120.8,118.2,115.5,110.4,104.3,60.9,56.1,52.3,45.7.HRMS calcd for C 23 H 22 N2O5 HRMS calcd for C 23 H 22 N₂O₅[M+H] + 407.1601, found 407.1608.

[0138] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for synthesizing α-carboline and its derivatives, characterized in that, The catalyst, inorganic ammonium salt, indole-3-carboxaldehyde, alkynes and their derivatives and organic solvents were mixed and heated under a reaction atmosphere to carry out the reaction, and finally purified to obtain the product. The inorganic ammonium salt is one or more of the following: ammonium acetate, ammonium formate, ammonium iodide, ammonium chloride, ammonium bromide, ammonium carbonate, and ammonium phosphate. The catalyst is an iodine reagent selected from one or more of the following: trimethyl sulfoxide, ammonium iodide, potassium iodide, sodium iodide, elemental iodine, iodine chloride, iodobenzene, iodophenyl diacetic acid, N-iodosuccinimide, diiodine pentoxide, potassium iodate, sodium periodate, tetrabutylammonium iodide, tetramethylammonium iodide, hydroiodic acid, iodine monobromide, and [bis(trifluoroacetoxy)iodo]benzene; The organic solvent is one or more of the following: toluene, xylene, trimethylbenzene, chlorobenzene, o-dichlorobenzene, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, dimethyl sulfoxide, p-xylene, acetone, acetonitrile, 1,2-dichloroethane, etc. The molar ratio of indole-3-carboxaldehyde compounds, inorganic ammonium salts, alkynes, and catalysts is 1:0.5-10:0.5-10.0:0.01-10.0; the reaction atmosphere is air, oxygen, or argon; the reaction time is 1-36 h; and the reaction temperature is 20℃-200℃. The indole-3-carboxaldehyde compounds are selected from: 4-bromo-1-methyl-1H-indole-3-carboxaldehyde; 5-methyl-1-methyl-1H-indole-3-carboxaldehyde; 5-methoxy-1-methyl-1H-indole-3-carboxaldehyde; 5-ethoxy-1-methyl-1H-indole-3-carboxaldehyde; 5-benzyloxy-1-methyl-1H-indole-3-carboxaldehyde; 5-fluoro-1-methyl-1H-indole-3-carboxaldehyde; 5-chloro-1-methyl-1H-indole-3-carboxaldehyde; 5-bromo-1-methyl-1H-indole-3-carboxaldehyde; 5-nitro-1-methyl-1H-indole-3-carboxaldehyde; 5-cyano-1-methyl-1H-indole -3-Carbaldehyde; 6-Fluoro-1-methyl-1H-indole-3-carbaldehyde; 6-Chloro-1-methyl-1H-indole-3-carbaldehyde; 6-Methyl-1-methyl-1H-indole-3-carbaldehyde; 6-Bromo-1-methyl-1H-indole-3-carbaldehyde; 6-Methoxy-1-methyl-1H-indole-3-carbaldehyde; 7-Methyl-1-methyl-1H-indole-3-carbaldehyde; 1H-indole-3-carbaldehyde; 1-Ethyl-1H-indole-3-carbaldehyde; 1-Heptyl-1H-indole-3-carbaldehyde; 1-Phenyl-1H-indole-3-carbaldehyde; 1-Benzyl-1H-indole-3-carbaldehyde; 1-(3,4,5-Trimethoxybenzyl)-1H-indole-3-carbaldehyde; The alkyne compounds are selected from ethyl propargyl acid; methyl propargyl acid; tert-butyl propargyl ester; benzyl propargyl acid; diethyl 2-butynedioate; 1-phenylprop-2-yn-1-one; 1-(2-bromophenyl)prop-2-yn-1-one; 1-(2-chlorophenyl)prop-2-yn-1-one; 1-(2-methylphenyl)prop-2-yn-1-one; 1-(2-methoxyphenyl)prop-2-yn-1-one; 1-(3-bromophenyl)prop-2-yn-1-one; 1-(3-nitrophenyl)prop-2-yn-1-one; 1-(4-bromophenyl)prop-2-yn-1-one; 1-(4-chlorophenyl)prop-2-yn-1-one; 1-(4-methylphenyl)prop-2-yn-1-one; 1-(4-methoxyphenyl)prop-2-yn-1-one; The structural formulas of α-carboline and its derivatives are: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

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