Preparation method of tetrahydro-gamma-carboline

Abstract

The invention discloses a preparation method of tetrahydro-gamma-carboline, and belongs to the field of organic synthesis. According to the method, 3-iodo-indole with indole N-H protected by p-toluenesulfonyl, aziridine and olefin are used as initial raw materials and stirred to react in an organic solvent at the temperature of 80-110 DEG C under the action of a palladium catalyst, norbornene, a phosphine ligand and alkali, and the 4-substituted tetrahydro-gamma-carboline derivative can be obtained. The raw materials used in the method are cheap and easy to obtain, the reaction process is mild, the substrate universality is good, the 4-substituted tetrahydro-gamma-carboline derivative can be obtained through one-step reaction, the method has high step economy and practicability, and a convenient and feasible path is opened up for synthesis of the 4-substituted tetrahydro-gamma-carboline derivative.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and specifically relates to a method for preparing tetrahydro-γ-carboline, and is embodied as a method for preparing 4-substituted tetrahydro-γ-carboline derivatives. Background Art

[0002] Tetrahydro-γ-carboline skeletons, as a key class of indole alkaloid heterocyclic compounds, are widely present in many active drug molecules, and their unique molecular structure fragments are regarded as an ideal platform for the development of new drug lead molecules. This type of compound exhibits a variety of pharmacological activities, including but not limited to anti-allergic, antiviral, and anti-tumor effects. In recent years, drug research and development based on the tetrahydro-γ-carboline skeleton has made significant progress, and some drugs have successfully entered the clinical application stage, such as methionine, a specific antagonist of histamine H1 receptors, which has shown good efficacy in the treatment of various allergic diseases. This achievement highlights the potential value and application prospects of functionalization research around tetrahydro-γ-carboline skeletons.

[0003] There are several methods for constructing achiral tetrahydro-γ-carboline skeletons:

[0004] (1) Fischer indole synthesis method, which is obtained by heating various substituted phenylhydrazines and N-alkyl substituted piperidones under acidic conditions (such as hydrochloric acid, sulfuric acid, etc.) (J. Med. Chem. 1980, 23, 635). Subsequently, many researchers have synthesized active molecules based on the tetrahydro-γ-carboline skeleton based on this method (CN115197206, CN115197207). The disadvantages of this method are that its raw material substituted phenylhydrazines are difficult to obtain, have high toxicity and high commercial price, and various N-alkyl substituted-4-piperidones are not common and easy to obtain.

[0005] (2) The nitrogen ylide and the corresponding aldehyde undergo aza-Wittig reaction to obtain an imine, which is then subjected to an intramolecular cyclization reaction under Lewis acid (such as SnCl4) or strong base (such as KHMDS) conditions to prepare a tetrahydro-γ-carboline skeleton (Tetrahedron 1996, 52, 5833.). A major limitation of this method is that the raw materials required, various substituted-(2-aminoethyl) compounds, are not widely available. At the same time, the strong acid or strong base environment also limits the practical application of this method.

[0006] (3) Using 2-fluorophenylimine as a raw material, in the presence of a strong base (such as lithium diisopropylamide), an intramolecular substitution reaction occurs to generate tetrahydro-γ-carboline compounds (Synthesis 2003, 11, 1661.). The disadvantage of this method is that it strongly depends on the ortho-fluorine substituent in the substrate, which limits the scope of application of this method.

[0007] (4) Starting from aniline, N-aryl enamine is obtained, followed by oxidative coupling under palladium catalysis, and then the amide six-membered ring is constructed by intramolecular aminolysis, and finally the carbonyl group is reduced to obtain tetrahydro-γ-carboline derivatives (CN103130802). The disadvantage of this method is that it has many steps and uses a strong reducing agent, lithium aluminum hydride, which limits its substrate range.

[0008] So far, there is no convenient way to synthesize 4-substituted tetrahydro-γ-carboline derivatives. Summary of the invention

[0009] In order to solve the problems existing in the prior art, the object of the present invention is to provide a method for preparing tetrahydro-γ-carboline.

[0010] To achieve the above purpose, the technical solution provided by the present invention is as follows:

[0011] Under the protection of inert gas, 3-iodo-1-toluenesulfonyl-1H-indole derivative A, aziridine B and olefin derivative C are used as starting materials, under the action of palladium catalyst D, norbornene derivative E, phosphine ligand F and base G, the reaction is stirred in an organic solvent H under heating conditions of 80-110° C. until the reaction is completed, and the reaction mixture is filtered, concentrated and purified by column chromatography to obtain a 4-substituted tetrahydro-γ-carboline derivative I as shown in the reaction formula. The reaction formula of the reaction is shown as follows:

[0012]

[0013] Where n represents R 1 The number of, 0≤n≤4; m represents R 2 The number of, 0≤m≤5; R 1 is C1-C2 alkyl, C1-C2 alkoxy, ester, cyano, nitro, sulfonyl or halogen; when n≥2, each R 1 Same or different;

[0014] R 2 is C1-C2 alkyl, C1-C2 alkoxy, ester, cyano, nitro, sulfonyl or halogen; when m≥2, each R 2 Same or different;

[0015] R 3is hydrogen, ester group, aryl group, cyano group, nitro group;

[0016] Furthermore, the molar ratio of the indole derivative A, aziridine B, olefin derivative C, palladium catalyst D, norbornene derivative E, phosphine ligand F, and base G is (1-2): (1-3): (3-5): (0.05-0.5): (3-5): (0.2-1): (3-5).

[0017] Further, the palladium catalyst D is one of palladium acetate, bis(cyanobenzene)palladium dichloride, bis(acetylacetone)palladium, palladium chloride, tris(dibenzylideneacetone)dipalladium, palladium trifluoroacetate, bis(acetonitrile)palladium chloride, bistriphenylphosphinepalladium dichloride, and tetrakis(triphenylphosphine)palladium, among which palladium acetate is preferred.

[0018] Furthermore, the norbornene derivative E is one of: 2-cyano-5-norbornene, 5-norbornene-2-carboxylic acid, 5-norbornene-2-ol, 5-norbornene-2-yl acetate, 5-norbornene-2-carboxylic acid methyl ester, and norbornene, among which 2-cyano-5-norbornene is preferred.

[0019] Further, the phosphine ligand F is: 1,2-bis(diphenylphosphino)ethane, 2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, 4 -(di-tert-butylphosphino)-N,N-dimethylaniline, tri(2-furanyl)phosphine, tri(2-methoxyphenyl)phosphine, tri(3-methoxyphenyl)phosphine, tri(3-chlorophenyl)phosphine, tri(4-fluorophenyl)phosphine, tri(4-methoxyphenyl)phosphine, tri(4-chlorophenyl)phosphine, tri(o-methylphenyl)phosphine, tri(pentafluorophenyl)phosphine, triphenylphosphine, among which tri(2-furanyl)phosphine is preferred.

[0020] Furthermore, the base G is one of cesium acetate, sodium acetate, cesium carbonate, potassium carbonate, potassium acetate, sodium acetate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium bicarbonate, and sodium bicarbonate, among which potassium carbonate is preferred.

[0021] Furthermore, the solvent H is one of 1,4-dioxane, ethylene glycol dimethyl ether, acetonitrile, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, among which 1,4-dioxane is preferred.

[0022] Furthermore, in the preparation method, the heating process can use an oil bath, which can be silicone oil or paraffin oil; the filtration process uses a sand core funnel and filters under reduced pressure; the concentration process can use atmospheric distillation or reduced pressure distillation, preferably using a rotary evaporator to concentrate under reduced pressure; the purification process is to obtain a pure product through column chromatography.

[0023] The method of the present invention can efficiently prepare 4-substituted-tetrahydro-γ-carboline. Compared with the prior art, the present invention has the following advantages:

[0024] 1. The main raw materials involved in the present invention are iodoindole, aziridine and olefin, which can be commercial reagents without special treatment, and are low in price and in a wide variety;

[0025] 2. The reaction conditions involved in the method of the present invention do not require an acidic environment, which is more environmentally friendly than the strongly acidic environment required by most previous reactions;

[0026] 3. The reaction involved in the method of the present invention has good tolerance and universality to functional groups, and the substituents can be alkyl, alkoxy, cyano, ester, aldehyde, nitro, halogen atoms (F, Cl, Br), etc.

[0027] 4. The method of the present invention can be used for large-scale (gram-level) preparation, laying a good foundation for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 Compound I-3 1 H-NMR (400MHz, CDCl3) chart;

[0029] Figure 2 Compound I-3 13 C-NMR (100 MHz, CDCl3) chart. DETAILED DESCRIPTION

[0030] The following are specific embodiments of the present invention, which further describe the technical solutions of the present invention, but the present invention is not limited to these embodiments.

[0031] Example 1: Preparation of Compound I-1

[0032]

[0033] To a Schlenk tube (10 mL) pre-equipped with a magnetic stirrer and thoroughly dried, palladium acetate (2.3 mg, 0.01 mmol, 10 mol%), tri(2-furyl)phosphine (5.6 mg, 0.024 mmol, 24 mol%), potassium carbonate (41.5 mg, 0.3 mmol, 3.0 equiv), 3-iodo-5-methoxy-1-toluenesulfonyl-1H-indole (59.7 mg, 0.1 mmol) and 1H-dole (50.7 mg, 0.1 mmol) were added in sequence. l, 1.0equiv) and 1-(4-toluenesulfonyl)aziridine (39.4mg, 0.2mmol, 2.0equiv), the air was replaced by a double-row tube connected to argon, and then ethyl acrylate (32.6μL, 0.3mmol, 3.0equiv) and 2-cyano-5-norbornene (35.8μL, 0.3mmol, 3.0equiv) were added in sequence through a syringe, and then 1,4-dioxane (1mL) was added. The above reaction solution was placed in an oil bath at 100°C and heated with stirring for 24 hours. After TLC monitoring, the reaction was completed, cooled to room temperature, filtered, extracted with ethyl acetate and water, the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain a crude product. The target product I-1 (47.8mg, yield 84%) was obtained by rapid column chromatography separation and purification (petroleum ether: ethyl acetate = 5:1, V:V). 1 H NMR(400MHz, CDCl3)δ7.94(dd,J=8.7,0.9Hz,1H),7.73–7.60(m,2H),7.57–7.49(m,2 H),7.16(dd,J=18.8,8.1Hz,4H),6.89–6.85(m,2H),5.61(dd,J=9.1,3.9Hz,1H),4.15 –4.03(m,3H),3.84(s,3H),3.50–3.33(m,1H),3.01(dd,J=17.9,4.5Hz,1H),2.92–2. 76(m,2H),2.66(dd,J=14.9,9.1Hz,1H),2.36(d,J=5.1Hz,6H),1.23(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ170.34,156.83,145.03,143.66,137.62,135.79,133.69,130.61,130.09,129.70,128.14, 127.28,126.48,117.99,115.50,113.24,101.43,61.24,55.89,49.51,40.50,38.82,23.80,21.73,21.65,14.24.

[0034] Example 2: Preparation of Compound I-2

[0035]

[0036] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 3-iodo-4-methyl-1-toluenesulfonyl-1H-indole (0.1 mmol, 41.1 mg), to obtain compound I-2 (white solid, 50.1 mg, yield 88%). 1 H NMR (400MHz, CDCl3) δ7.92(d,J=8.4Hz,1H),7.62(d,J=8.0Hz,2H),7.55(d,J=8.1Hz,2H), 7.22–7.12(m,3H),7.08(d,J=8.0Hz,2H),7.00(d,J=7.4Hz,1H),5.94(dd,J=11.2,2.7Hz, 1H),4.10(dq,J=18.4,6.8Hz,3H),3.49(ddd,J=15.9,11.4,5.6Hz,1H),3.08–2.87(m,2H) ,2.80(dd,J=15.2,2.8Hz,1H),2.66(s,4H),2.34(d,J=8.4Hz,6H),1.26(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ169.71,145.05,143.63,137.40,136.24,135.88,132.43,130.09,129.67,129.52,127.33, 126.53,125.98,125.94,124.61,118.43,112.17,61.21,50.41,41.58,37.51,23.43,21.71,21.59,20.11,14.23.

[0037] Example 3: Preparation of Compound I-3

[0038]

[0039] The operation steps and conditions are the same as those of Example 1, except that the indole substrate used is 3-iodo-5-methyl-1-toluenesulfonyl-1H-indole (0.1 mmol, 41.1 mg), and compound I-3 (brown oil, 42.7 mg, yield 75%) is obtained. 1H NMR(400MHz, CDCl3)δ7.92(d,J=8.5Hz,1H),7.67–7.58(m,2H),7.58–7.50(m,2H),7.18( d,J=8.3Hz,3H),7.11(dd,J=10.5,8.2Hz,3H),5.61(dd,J=9.4,3.7Hz,1H),4.21–4.05(m, 3H),3.41(ddd,J=15.0,11.8,4.8Hz,1H),3.00(dd,J=17.8,4.5Hz,1H),2.91–2.77(m,2H) ,2.66(dd,J=14.7,9.3Hz,1H),2.41(s,3H),2.35(d,J=4.2Hz,6H),1.25(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ170.30,144.99,143.60,137.69,135.89,134.29,133.57,133.02,130.07,129.67,127.35, 127.25,126.49,126.16,118.35,117.62,114.25,61.23,49.66,40.58,38.81,23.68,21.72,21.64,21.43,14.25.

[0040] Example 4: Preparation of Compound I-4

[0041]

[0042] The operation steps and conditions are the same as those of Example 1, except that the indole substrate used is 3-iodo-6-methyl-1-toluenesulfonyl-1H-indole (0.1 mmol, 41.1 mg), to obtain compound I-4 (light yellow solid, 44.9 mg, yield 79%). 1H NMR (400MHz, CDCl3) δ7.87 (s, 1H), 7.65–7.60 (m, 2H), 7.57–7.50 (m, 2H), 7.30 (d, J = 8.0Hz, 1H), 7. 20(d,J=8.1Hz,2H),7.12(d,J=8.1Hz,2H),7.07(dd,J=8.0,1.4Hz,1H),5.62(dd,J=9.2,3.8Hz,1H ),4.20–4.04(m,3H),3.40(ddd,J=15.0,11.7,4.7Hz,1H),2.98(dd,J=17.8,4.5Hz,1H),2.88–2.7 4(m,2H),2.66(dd,J=14.8,9.1Hz,1H),2.47(s,3H),2.36(d,J=2.5Hz,6H),1.24(t,J=7.2Hz,3H). 13 CNMR(101MHz, CDCl3)δ170.30,145.01,143.58,137.70,136.53,136.02,135.03,132.21,130.10,129.68,127.23, 126.47,125.21,124.86,118.00,117.70,114.74,61.22,49.66,40.67,38.87,23.65,22.12,21.73,21.64,14.24.

[0043] Example 5: Preparation of Compound I-5

[0044]

[0045] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 3-iodo-7-methyl-1-toluenesulfonyl-1H-indole (0.1 mmol, 41.1 mg), and compound I-5 (yellow oil, 49.1 mg, yield 87%) is obtained. 1 H NMR (400MHz, CDCl3) δ7.69–7.61(m,2H),7.21(d,J=8.4Hz,2H),7.18–7.13(m,4H),7.12–7.03(m,3H),5.56–5.48(m,1H),4.07(s,2H),4.04–3.95( m,1H),3.27(ddd,J=14.7,9.9,6.2Hz,1H),3.02–2.84(m,2H),2.67–2.58 (m,4H),2.52–2.42(m,1H),2.34(d,J=12.3Hz,6H),1.25(t,J=7.2Hz,3H).13 C NMR (101MHz, CDCl3) δ170.24,144.69,143.68,138.36,137.47,136.56,134.71,130.66,129.68,129.49,129.22, 128.64,127.39,126.25,125.16,122.44,116.03,61.24,49.40,40.16,39.28,25.15,22.23,21.68,21.62,14.28.

[0046] Example 6: Preparation of Compound I-6

[0047]

[0048] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 5-fluoro-3-iodo-1-toluenesulfonyl-1H-indole (0.1 mmol, 41.5 mg), to obtain compound I-6 (brown solid, 50.2 mg, yield 88%). 1 H NMR(400MHz, CDCl3)δ8.01(dd,J=9.1,4.4Hz,1H),7.68–7.61(m,2H),7.57–7.52(m,2H),7.21(d,J=8. 2Hz, 2H), 7.15 (d, J=8.2Hz, 2H), 7.09 (dd, J=8.5, 2.5Hz, 1H), 7.00 (td, J=9.0, 2.6Hz, 1H), 5.58 (dd, J= 8.9,4.1Hz,1H),4.19–4.03(m,3H),3.39(ddd,J=15.0,11.6,4.8Hz,1H),3.10–2.99(m,1H),2.99–2.8 5(m,1H),2.76(dd,J=14.9,4.1Hz,1H),2.66(dd,J=14.9,8.7Hz,1H),2.36(s,6H),1.31–1.17(m,3H). 13 C NMR (101MHz, CDCl3) δ170.11,161.08,145.37,143.75,137.45,135.59,134.91,132.30,130.21,129.73,128.20,127.32,12 6.52,117.78,115.70,112.57(d,J=25.3Hz),104.42(d,J=24.6Hz),61.31,49.29,40.50,38.79,23.92,21.74,21.64,14.22. 19F NMR (376MHz,CDCl3)δ-118.51.

[0049] Example 7: Preparation of Compound I-7

[0050]

[0051] The operation steps and conditions are the same as those of Example 1, except that the indole substrate used is 6-fluoro-3-iodo-1-toluenesulfonyl-1H-indole (0.1 mmol, 41.5 mg), and compound I-7 (yellow oil, 46.1 mg, yield 81%) is obtained. 1 H NMR(400MHz, CDCl3) δ7.81(dd,J=10.1,2.3Hz,1H),7.66–7.60(m,2H),7.57(d,J=8.4Hz,2H),7.35( dd,J=8.6,5.2Hz,1H),7.25–7.20(m,2H),7.17–7.09(m,2H),7.00(td,J=8.8,2.3Hz,1H),5.61(dd, J=8.9,4.1Hz,1H),4.19–4.02(m,3H),3.39(ddd,J=14.9,11.6,4.8Hz,1H),3.01(dd,J=17.8,4.6Hz ,1H),2.94–2.73(m,2H),2.67(dd,J=14.9,8.8Hz,1H),2.37(d,J=5.3Hz,6H),1.22(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ170.05, 160.86 (d, J = 241.9Hz), 145.30, 143.58, 137.3 5,136.16(d,J=12.4Hz),135.46,133.15(d,J=3.6Hz),130.12,129.55,127. 12,126.44,123.28,118.97(d,J=9.7Hz),117.35,111.90(d,J=24.3Hz),102 .10(d,J=29.1Hz),61.13,49.23,40.53,38.62,23.57,21.61,21.49,14.08. 19 F NMR (376MHz,CDCl3)δ-115.92.

[0052] Example 8: Preparation of Compound I-8

[0053]

[0054] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 5-chloro-3-iodo-1-toluenesulfonyl-1H-indole (0.1 mmol, 43.2 mg), and compound I-8 (yellow solid, 42.3 mg, yield 72%) is obtained. 1 H NMR(400MHz, CDCl3) δ7.99(d,J=8.8Hz,1H),7.68–7.61(m,2H),7.57–7.52(m,2H),7.39(d,J=2.1Hz,1 H),7.26–7.19(m,3H),7.15(d,J=8.1Hz,2H),5.58(dd,J=8.9,4.1Hz,1H),4.11(qd,J=7.1,3.0Hz,3H), 3.39(ddd,J=14.9,11.6,4.8Hz,1H),3.04(dd,J=18.0,4.6Hz,1H),2.91(dddd,J=18.0,11.6,6.3,1.6H z,1H),2.77(dd,J=14.8,4.2Hz,1H),2.66(dd,J=14.9,8.8Hz,1H),2.36(s,6H),1.24(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ170.03,145.47,143.76,137.43,135.54,134.65,134.39,130.24,129.75,129.72,128. 35,127.30,126.53,124.99,118.17,117.26,115.58,61.33,49.25,40.57,38.72,23.81,21.75,21.64,14.22.

[0055] Example 9: Preparation of Compound I-9

[0056]

[0057] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 5,6-dichloro-3-iodo-1-toluenesulfonyl-1H-indole (0.1mmol, 46.6mg), and compound I-9 (yellow solid, 49.6mg, yield 80%) is obtained. 1H NMR (400MHz, CDCl3) δ8.21(s,1H),7.63(d,J=8.0Hz,2H),7.57(d,J=8.3Hz,2H),7.49 (s,1H),7.25(d,J=8.2Hz,2H),7.15(d,J=8.0Hz,2H),5.56(dd,J=8.7,4.4Hz,1H),4. 17–4.04(m,3H),3.37(ddd,J=15.4,11.6,4.8Hz,1H),3.10–2.96(m,1H),2.95–2.82( m,1H),2.70(qd,J=15.0,6.6Hz,2H),2.38(s,3H),2.36(s,3H),1.23(t,J=7.2Hz,3H). 13 CNMR (101MHz, CDCl3) δ169.96,145.79,143.86,137.32,135.31,135.14,134.66,130.40,129.75,128.98,128. 27,127.29,126.67,126.59,119.49,116.95,116.23,61.38,49.05,40.59,38.62,23.79,21.79,21.64,14.22.

[0058] Example 10: Preparation of Compound I-10

[0059]

[0060] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 6-bromo-3-iodo-1-toluenesulfonyl-1H-indole (0.1mmol, 47.6mg), and compound I-10 (light yellow solid, 55.1mg, yield 87%) is obtained. 1H NMR (400MHz, CDCl3) δ8.26(d,J=1.7Hz,1H),7.62(d,J=8.4Hz,2H),7.57(d,J=8.5Hz,2H),7.37(dd ,J=8.3,1.7Hz,1H),7.29(d,J=8.4Hz,1H),7.24(d,J=8.2Hz,2H),7.13(d,J=8.1Hz,2H),5.61(dd,J =8.9,4.1Hz,1H),4.19–4.02(m,3H),3.38(ddd,J=14.9,11.7,4.8Hz,1H),3.00(dd,J=17.9,4.6Hz, 1H),2.91–2.72(m,2H),2.66(dd,J=14.9,8.8Hz,1H),2.37(d,J=8.7Hz,6H),1.22(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ170.13,145.54,143.77,137.45,136.70,135.60,133.64,130.32,129.72,127.25,127. 12,126.59,125.93,119.51,118.56,117.62,117.51,61.30,49.30,40.66,38.73,23.65,21.78,21.65,14.23.

[0061] Example 11: Preparation of Compound I-11

[0062]

[0063] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 3-iodo-1-toluenesulfonyl-1H-indole-5-carboxylic acid ethyl ester (0.1mmol, 46.9mg), to obtain compound I-11 (yellow oil, 50.2mg, yield 80%). 1H NMR (400MHz, CDCl3) δ8.10(d,J=9.1Hz,2H),7.99(dd,J=8.8,1.6Hz,1H),7.64(d,J=8.0Hz,2H),7.58(d,J=8.1Hz,2H), 7.21(d,J=8.1Hz,2H),7.13(d,J=8.0Hz,2H),5.69(dd,J=9.3,4.1Hz,1H),4.40(qq,J=7.5,3.7Hz,2H),4.12(qd,J=7.1 ,4.8Hz,3H),3.42(ddd,J=15.4,11.5,4.8Hz,1H),3.04(dd,J=17.9,4.8Hz,1H),2.93(td,J=11.5,5.8Hz,1H),2.85(dd ,J=14.8,4.2Hz,1H),2.69(dd,J=14.8,9.2Hz,1H),2.36(d,J=2.3Hz,6H),1.42(t,J=7.1Hz,3H),1.24(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ169.91,166.61,145.56,143.76,138.55,137.46,135.57,134.55,130.27,129.69,127.32,126.96, 126.58,126.30,126.11,120.32,118.04,114.16,61.28,49.31,40.70,38.71,23.71,21.75,21.63,14.54,14.23,14.20.

[0064] Example 12: Preparation of Compound I-12

[0065]

[0066] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 5-cyano-3-iodo-1-toluenesulfonyl-1H-indole (0.1mmol, 42.2mg), and compound I-12 (light yellow solid, 52.8mg, yield 91%) is obtained. 1HNMR (400MHz, CDCl3) δ8.18(d,J=8.7Hz,1H),7.77(d,J=1.6Hz,1H),7.66(d,J=8.3Hz,2H),7 .60(d,J=8.1Hz,2H),7.55(dd,J=8.7,1.6Hz,1H),7.27(s,1H),7.25(s,1H),7.17(d,J=8.0Hz ,2H),5.63(dd,J=8.8,4.4Hz,1H),4.18–4.04(m,3H),3.39(ddd,J=15.4,11.3,4.8Hz,1H),3 .14–2.92(m,2H),2.71(qd,J=15.0,6.4Hz,2H),2.38(d,J=5.9Hz,6H),1.23(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ169.89,146.03,143.94,137.80,137.22,135.82,135.33,130.47,129.78,127.92,127.39,1 27.20,126.66,123.18,119.15,117.36,115.26,107.51,61.45,48.95,40.66,38.72,23.88,21.81,21.66,14.23.

[0067] Example 13: Preparation of Compound I-13

[0068]

[0069] The operation steps and conditions are the same as those of Example 1, except that the indole substrate used is 3-iodo-7-nitro-1-toluenesulfonyl-1H-indole (0.1mmol, 44.2mg), and compound I-13 (yellow oil, 51.9mg, yield 87%) is obtained. 1HNMR(400MHz, CDCl3)δ7.72–7.65(m,2H),7.59(dd,J=11.7,8.1Hz,4H),7.40(t,J=7.9 Hz,1H),7.35–7.29(m,1H),7.27(s,1H),7.14(d,J=8.0Hz,2H),5.63(dd,J=8.7,4.3Hz ,1H),4.10(pt,J=11.1,5.5Hz,3H),3.30(dt,J=15.4,8.3Hz,1H),2.77(dd,J=8.4,3.7 Hz,2H),2.66(dd,J=13.8,6.4Hz,2H),2.42(s,3H),2.35(s,3H),1.25(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ169.97,145.74,144.12,140.79,137.84,137.12,135.14,131.69,129.97,129.78,128. 20,127.22,126.94,124.68,122.98,121.03,120.53,61.43,49.15,40.54,38.76,23.88,21.81,21.63,14.26.

[0070] Example 14: Preparation of Compound I-14

[0071]

[0072] The operation steps and conditions were the same as those in Example 1, except that the olefin substrate used was tert-butyl acrylate (0.3 mmol, 43.9 μL), and compound I-14 (yellow oil, 43.8 mg, yield 74%) was obtained. 1H NMR (400MHz, CDCl3) δ8.05(d,J=8.0Hz,1H),7.64(d,J=8.1Hz,2H),7.56(d,J=8.1Hz,2H),7.47–7.40(m,1H),7.3 2–7.27(m,1H),7.24(dd,J=7.4,1.3Hz,1H),7.20(s,2H),7.10(d,J=8.0Hz,2H),5.66(dd,J=9.0,3.6Hz,1H),4.0 7(dd,J=15.0,6.3Hz,1H),3.42(ddd,J=15.0,11.7,4.8Hz,1H),2.97(dd,J=17.9,4.6Hz,1H),2.83(ddd,J=18.0, 9.0,5.3Hz,1H),2.75(dd,J=15.1,3.7Hz,1H),2.61(dd,J=15.1,8.9Hz,1H),2.35(d,J=2.7Hz,6H),1.44(s,9H). 13 C NMR (101MHz, CDCl3) δ169.53,145.09,143.60,137.61,136.03,135.91,132.78,130.11,129.64,127.31,127. 22,126.54,124.79,123.77,118.55,118.02,114.47,81.59,49.46,41.93,38.86,28.14,23.48,21.72,21.63.

[0073] Example 15: Preparation of Compound I-15

[0074]

[0075] The operation steps and conditions were the same as those in Example 1, except that the olefin substrate used was methyl acrylate (0.3 mmol, 27.0 μL), and compound I-15 (light yellow oil, 46.6 mg, yield 78%) was obtained. 1H NMR (400MHz, CDCl3) δ8.10–8.03(m,1H),7.64(d,J=8.4Hz,2H),7.56(d,J=8.4Hz,2H),7.4 5–7.38(m,1H),7.32–7.22(m,2H),7.19(d,J=8.2Hz,2H),7.13(d,J=8.0Hz,2H),5.64(dd, J=9.5,3.7Hz,1H),4.17–4.07(m,1H),3.67(s,3H),3.41(ddd,J=15.0,11.7,4.7Hz,1H),3 .04(dd,J=17.8,4.5Hz,1H),2.95–2.80(m,2H),2.69(dd,J=14.7,9.4Hz,1H),2.35(s,6H). 13 C NMR (101MHz, CDCl3) δ170.62,145.14,143.66,137.60,136.08,135.87,133.07,130.13,129.70,127.26,1 27.06,126.54,124.87,123.85,118.33,117.62,114.58,52.19,49.64,40.37,38.84,23.72,21.72,21.64.

[0076] Example 16: Preparation of Compound I-16

[0077]

[0078] The operation steps and conditions are the same as those in Example 1, except that the olefin substrate used is acrylonitrile (0.3 mmol, 19.7 μL), and compound I-16 (light yellow solid, 41.9 mg, yield 81%) is obtained. 1 H NMR (400MHz, CDCl3) δ8.13–8.06(m,1H),7.75–7.67(m,2H),7.61–7.53(m,2H),7.37–7.27(m,3H),7.22(dd,J=11.0,8.1Hz,4H),5.49– 5.41(m,1H),4.12–4.03(m,1H),3.70(ddd,J=15.2,11.3,4.5Hz,1H),3.23–3.03(m,2H),2.98–2.82(m,2H),2.40(s,3H),2.34(s,3H). 13C NMR (101MHz, CDCl3) δ145.39,144.35,136.79,136.34,135.64,134.56,130.25,130.11,127.31,126.5 6,126.47,125.24,124.09,117.91,117.06,114.95,114.84,48.45,39.64,24.85,23.62,21.73,21.71.

[0079] Example 17: Preparation of Compound I-17

[0080]

[0081] The operation steps and conditions are the same as those in Example 1, except that the aziridine substrate used is 1-(3-fluorophenylsulfonyl)aziridine (0.2 mmol, 40.2 mg), to obtain compound I-17 (light yellow solid, 42.1 mg, yield 74%). 1 H NMR(400MHz, CDCl3)δ8.13–8.06(m,1H),7.58–7.52(m,3H),7.50–7.42(m,2H),7.35–7.2 6(m,3H),7.20(d,J=8.2Hz,2H),7.15(ddd,J=8.2,2.6,1.0Hz,1H),5.66(dd,J=9.4,3.6H z,1H),4.13(qd,J=7.1,2.0Hz,3H),3.45(ddd,J=15.0,11.8,4.6Hz,1H),3.18–3.06(m,1 H),2.91–2.77(m,2H),2.69(dd,J=15.0,9.3Hz,1H),2.37(s,3H),1.24(t,J=7.1Hz,3H). 13 CNMR (101MHz, CDCl3) δ170.14, 162.37 (d, J = 251.6Hz), 145.24, 142.77 (d, J = 6. 5Hz),135.98(d,J=32.6Hz),132.72,130.82(d,J=7.7Hz),130.16,126.88,126 .50,125.03,123.92,122.95(d,J=3.3Hz),119.92(d,J=21.3Hz),118.34,117. 50,114.71,114.63,114.46,61.32,49.85,40.51,39.00,23.70,21.73,14.23. 19 FNMR (376MHz,CDCl3)δ-109.45.

[0082] Example 18: Preparation of Compound I-18

[0083]

[0084] The operation steps and conditions are the same as those in Example 1, except that the aziridine substrate used is 1-(4-chlorobenzenesulfonyl)aziridine (0.2 mmol, 43.5 mg), to obtain compound I-18 (yellow oil, 48.4 mg, yield 82%). 1 H NMR(400MHz,CDCl3)1H NMR (400MHz, CDCl3) δ8.12–8.05(m,1H),7.78–7.65(m,2H),7.58–7.49(m,2H),7.43(dd ,J=7.3,1.5Hz,1H),7.33–7.26(m,4H),7.22(d,J=8.1Hz,2H),5.63(dd,J=9.3,3.6Hz,1 H),4.21–4.05(m,3H),3.45(ddd,J=15.0,11.8,4.6Hz,1H),3.13(dd,J=17.8,4.4Hz,1H ),2.91–2.77(m,2H),2.69(dd,J=14.9,9.3Hz,1H),2.37(s,3H),1.25(d,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ170.18,145.32,139.37,139.24,136.10,135.76,132.75,130.19,129.36,128.63,1 26.88,126.51,125.03,123.90,118.35,117.49,114.64,61.33,49.83,40.56,38.94,23.68,21.75,14.24.

[0085] Example 19: Preparation of Compound I-19

[0086]

[0087] The operation steps and conditions are the same as those in Example 1, except that the aziridine substrate used is 1-(4-methoxyphenylsulfonyl)aziridine (0.2 mmol, 42.6 mg), to obtain compound I-19 (yellow oil, 52.8 mg, yield 91%). 1HNMR(400MHz, CDCl3)δ8.08–8.01(m,1H),7.72–7.63(m,2H),7.60–7.49(m,2H),7.48–7.40(m,1H) ),7.27(s,1H),7.25(d,J=1.3Hz,1H),7.19(d,J=8.1Hz,2H),6.82–6.74(m,2H),5.64(dd,J=9.4,3 .7Hz,1H),4.23–4.06(m,3H),3.81(s,3H),3.42(ddd,J=15.1,11.8,4.7Hz,1H),3.04(dd,J=17.8 ,4.5Hz,1H),2.90–2.76(m,2H),2.68(dd,J=14.7,9.3Hz,1H),2.35(s,3H),1.26(d,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ170.29,163.03,145.18,136.04,135.80,133.01,132.23,130.12,129.34,127.11,126. 54,124.84,123.81,118.42,117.67,114.54,114.27,61.26,55.70,49.64,40.68,38.78,23.53,21.72,14.26.

[0088] Example 20: Preparation of Compound I-20

[0089]

[0090] The operation steps and conditions are the same as those in Example 1, except that the aziridine substrate used is 1-benzenesulfonylaziridine (0.2 mmol, 36.6 mg), to obtain compound I-20 (light yellow solid, 43.9 mg, yield 79%). 1 H NMR (400MHz, CDCl3) δ8.10–8.03(m,1H),7.79–7.69(m,2H),7.59–7.49(m,2H), 7.49–7.40(m,2H),7.33–7.27(m,3H),7.25(d,J=1.4Hz,1H),7.22–7.17(m,2H), 5.68(dd,J=9.4,3.7Hz,1H),4.21–4.04(m,3H),3.44(ddd,J=15.0,11.8,4.7Hz ,1H),3.14–3.00(m,1H),2.90–2.63(m,3H),2.36(s,3H),1.24(t,J=7.2Hz,3H).13 C NMR (101MHz, CDCl3) δ170.20,145.13,140.72,136.08,135.87,132.87,132.71,130.15,129.05,127.13,1 27.00,126.54,124.91,123.85,118.38,117.59,114.56,61.27,49.77,40.65,38.87,23.53,21.73,14.24.

[0091] Example 21: Preparation of Compound I-21

[0092]

[0093] The operation steps and conditions are the same as those of Example 1, except that the aziridine substrate used is 1-(4-bromobenzenesulfonyl)aziridine (0.2 mmol, 52.4 mg), to obtain compound I-21 (light yellow oil, 45.4 mg, yield 72%). 1 HNMR(400MHz, CDCl3)δ8.12–8.05(m,1H),7.67–7.60(m,2H),7.58–7.51(m,2H),7.50– 7.39(m,3H),7.33–7.25(m,2H),7.24–7.19(m,2H),5.63(dd,J=9.4,3.6Hz,1H),4.12(q q,J=6.9,3.7Hz,3H),3.45(ddd,J=14.9,11.8,4.6Hz,1H),3.14(dd,J=17.7,4.5Hz,1H ),2.93–2.79(m,2H),2.69(dd,J=14.9,9.2Hz,1H),2.37(s,3H),1.24(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ170.19,145.32,139.89,136.11,135.76,132.78,132.36,130.21,128.74,127.74,1 26.89,126.52,125.03,123.91,118.36,117.52,114.66,61.34,49.82,40.54,38.96,23.76,21.77,14.25.

[0094] The specific embodiments described herein are merely examples of the spirit of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the appended claims.

Claims

1. A method for preparing tetrahydro-γ-carboline, characterized in that: The preparation method is as follows: under the protection of inert gas, 3-iodo-1-toluenesulfonyl-1H-indole derivative A, aziridine B and olefin derivative C are used as starting materials, and under the action of palladium catalyst D, norbornene derivative E, phosphine ligand F and base G, the mixture is stirred in an organic solvent H under heating conditions of 80-110° C. until the reaction is completed, and the reaction mixture is filtered, concentrated and purified by column chromatography to obtain a 4-substituted tetrahydro-γ-carboline derivative I as shown in the reaction formula; the reaction formula of the reaction is shown as follows: Where n represents R 1 The number of, 0≤n≤4; m represents R 2 The number of , 0≤m≤5; R 1 is C1-C2 alkyl, C1-C2 alkoxy, ester, cyano, nitro, sulfonyl or halogen; when n≥2, each R 1 Same or different; R 2 is C1-C2 alkyl, C1-C2 alkoxy, ester, cyano, nitro, sulfonyl or halogen; when m≥2, each R 2 Same or different; R 3 It is hydrogen, ester group, aromatic group, cyano group and nitro group.

2. The method for preparing tetrahydro-γ-carboline according to claim 1, characterized in that: The molar ratio of the indole derivative A, aziridine B, olefin derivative C, palladium catalyst D, norbornene derivative E, phosphine ligand F, and base G is (1-2): (1-3): (3-5): (0.05-0.5): (3-5): (0.2-1): (3-5).

3. The method for preparing tetrahydro-γ-carboline according to claim 1, characterized in that: The palladium catalyst D is one of palladium acetate, di(cyanobenzene)palladium dichloride, di(acetylacetone)palladium, palladium chloride, tri(dibenzylideneacetone)dipalladium, palladium trifluoroacetate, bis(acetonitrile)palladium chloride, bistriphenylphosphinepalladium dichloride and tetrakis(triphenylphosphine)palladium.

4. The method for preparing tetrahydro-γ-carboline according to claim 1, characterized in that: The norbornene derivative E is one of 2-cyano-5-norbornene, 5-norbornene-2-carboxylic acid, 5-norbornene-2-ol, 5-norbornene-2-yl acetate, 5-norbornene-2-carboxylic acid methyl ester and norbornene.

5. The method for preparing tetrahydro-γ-carboline according to claim 1, characterized in that: The phosphine ligand F is one of 1,2-bis(diphenylphosphino)ethane, 2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, 4-(di-tert-butylphosphino)-N,N-dimethylaniline, tri(2-furanyl)phosphine, tri(2-methoxyphenyl)phosphine, tri(3-methoxyphenyl)phosphine, tri(3-chlorophenyl)phosphine, tri(4-fluorophenyl)phosphine, tri(4-methoxyphenyl)phosphine, tri(4-chlorophenyl)phosphine, tri(o-methylphenyl)phosphine, tri(pentafluorophenyl)phosphine, and triphenylphosphine.

6. The method for preparing tetrahydro-γ-carboline according to claim 1, characterized in that: The base G is one of cesium acetate, sodium acetate, cesium carbonate, potassium carbonate, potassium acetate, sodium acetate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium bicarbonate, and sodium bicarbonate.

7. The method for preparing tetrahydro-γ-carboline according to claim 1, characterized in that: The solvent H is one of 1,4-dioxane, ethylene glycol dimethyl ether, acetonitrile, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.

8. The method for preparing tetrahydro-γ-carboline according to claim 1, characterized in that: In the preparation method, the heating process can adopt an oil bath, which is silicone oil or paraffin oil; the filtration process uses a sand core funnel and filters under reduced pressure; the concentration process can adopt atmospheric distillation or reduced pressure distillation; the purification process is to obtain a pure product through column chromatography.

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