A method for synthesizing 1-trifluoromethyl indole compounds from 2-alkynyl aryl amines

Abstract

This invention discloses a method for synthesizing 1-trifluoromethylindole compounds from 2-alkynylarylamines, belonging to the field of organic chemistry. The method uses 2-alkynylarylamines and silver trifluoromethyl sulfide as raw materials, with the addition of potassium iodide and silver fluoride. Under the action of a catalyst and ligands, a one-pot synthesis of polysubstituted 1-trifluoromethylindole compounds can be achieved. This method has broad substrate applicability, uses simple and readily available raw materials, and has low economic cost. Furthermore, the method requires only 3-10 hours of reaction time to achieve the synthesis of the target product, yielding a good yield. The target compounds have wide applications in pharmaceuticals, pesticides, and functional materials.

Description

Technical Field

[0001] This invention specifically relates to a method for synthesizing 1-trifluoromethylindole compounds from 2-alkynylarylamines, belonging to the field of organic chemistry. Background Technology

[0002] Trifluoromethyl groups are the smallest and most important perfluoroalkyl functional groups. Introducing trifluoromethyl groups into organic molecules often enhances the physical, chemical, or biological activity of the parent molecule; for example, organic compounds formed by introducing trifluoromethyl groups onto heteroatoms often exhibit better lipophilicity and membrane permeability. Furthermore, indole and its derivatives also exhibit broad-spectrum biological activities in anti-inflammatory, insecticidal, bactericidal, and antitumor effects. However, methods for introducing CF3 onto the nitrogen atom of indole are rarely reported. Therefore, developing a simple and mild N-trifluoromethylation method is of great practical value. In the field of organic synthesis, research on N-trifluoromethylation methods has also attracted widespread attention. Summary of the Invention

[0003] This invention develops a novel method for synthesizing 1-trifluoromethylindole. The method involves the addition cyclization of 1-trifluoromethylindole compounds with 2-alkynyl aromatic amines, silver trifluoromethyl sulfide, potassium iodide, and silver fluoride under catalysis, thus conveniently achieving the synthesis of 1-trifluoromethylindole derivatives.

[0004] The purpose of this invention is to provide a method for synthesizing 1-trifluoromethylindole compounds. The method involves using 2-alkynyl aromatic amine compounds of formula (1) and silver trifluoromethyl sulfide as reactants in an organic solvent, and adding potassium iodide and silver trifluoride. The cyclization reaction is carried out under the catalysis of a catalyst and ligands to synthesize 1-trifluoromethylindole compounds of formula (2).

[0005]

[0006] R1 is selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen (F, Cl, Br), cyano, nitro, C1-C8 alkoxy, acyl and amide and heterocyclic; R2 is selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide and heterocyclic.

[0007] In one embodiment of the present invention, the aryl group includes a substituted or unsubstituted benzene ring or a naphthalene ring; the substitution can be one to three substitutions; the substituted group is selected from halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, ester groups, cyano groups, nitro groups and heterocycles.

[0008] In one embodiment of the present invention, the acyl group is -COR. a R a It is an H, C1-8 alkyl group.

[0009] In one embodiment of the present invention, the amide group is -NHCOR. b R b It is an H, C1-8 alkyl group.

[0010] In one embodiment of the present invention, the heterocycle is a three- to six-membered ring containing 1 to 3 heteroatoms. The heteroatoms include N, O, and S.

[0011] In one embodiment of the present invention, the ester group is -COOR. c R c It is a C1-8 alkyl group.

[0012] In one embodiment of the present invention, the organic solvent includes any one or more of acetonitrile (CH3CN), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO). CH3CN is preferred.

[0013] In one embodiment of the present invention, the catalyst is any one or more of cuprous iodide, cuprous chloride, ruthenium dichloride, copper fluoride, palladium di(triphenylphosphine)chloride, and rhodium tri(triphenylphosphine)chloride. Cuprous iodide is preferred.

[0014] In one embodiment of the invention, the ligand is any one or more of 2,2'-bipyridine, 4,4'-bipyridine, triphenylphosphine, and o-phenanthroline. 2,2'-bipyridine is preferred.

[0015] In one embodiment of the invention, the reaction temperature is 25°C-100°C, preferably 45-55°C.

[0016] In one embodiment of the present invention, the reaction time is 3-10 hours. Specifically, 5 hours may be selected.

[0017] In one embodiment of the present invention, the molar ratio of 2-alkynyl aromatic amine compound, silver trifluoromethyl sulfide, potassium iodide, silver fluoride, catalyst, and ligand is 1:(1.0-2.0):(1.0-2.0):(3.0-6.0):(0.05-0.2):(0.05-0.2). Preferably, it is 1:1.5:1.5:5:0.2:0.2.

[0018] In one embodiment of the present invention, the reaction concentration of the 2-alkynyl aromatic amine compound is 0.05-5 mmol / mL. Specifically, 0.5 mmol / mL is preferred.

[0019] In one embodiment of the present invention, the structure of 2-alkynylaryl isothiocyanate is specifically as follows:

[0020] The definitions of R1 and R2 are the same as above, specifically R 1 Selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen (F, Cl, Br), cyano, nitro, C1-C8 alkoxy, acyl and amide groups, and heterocycles; R 2 It is selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide groups and heterocycles.

[0021] In one embodiment of the invention, the N-trifluoromethylation / cyclization reaction is carried out under an inert atmosphere, such as a nitrogen atmosphere.

[0022] In one embodiment of the present invention, the steps of a novel green and economical synthesis method are as follows:

[0023] Using 2-alkynyl aromatic amines, silver trifluoromethyl sulfide, potassium iodide, and silver fluoride as raw materials, a catalyst and organic ligand were added, and the mixture was stirred at 25℃-50℃ for a period of time to obtain a crude product of polysubstituted-1-trifluoromethylindole compounds. Then, pure polysubstituted-1-trifluoromethylindole compounds were obtained by filtration, washing, vacuum distillation, and column chromatography.

[0024] In one embodiment of the present invention, the separation and purification method is to use rapid column chromatography to obtain the final product, a polysubstituted 1-trifluoromethylindole compound.

[0025] In one embodiment of the present invention, the method is preferably carried out as follows: 2-alkynyl aromatic amine compound, silver trifluoromethyl sulfide, potassium iodide, silver fluoride, catalyst, and organic ligand are added to a reaction vessel containing acetonitrile solvent in a molar ratio of 1:1.5:1.5:5:0.2:0.2, stirred at 25℃-50℃ for 3-10 hours, and then separated and purified to obtain the target product.

[0026] In one embodiment of the present invention, the reaction mechanism is as follows: 2-alkynyl aromatic amines react with silver trifluoromethyl sulfide and potassium iodide to produce 2-alkynyl aryl isothiocyanate. Subsequently, the 2-alkynyl aryl isothiocyanate undergoes desulfurization and fluorination with silver fluoride to form ArN(CF3)Ag units. Under the action of a catalyst, these units undergo nucleophilic addition / cyclization with the alkynyl group adjacent to the aromatic ring to generate polysubstituted -1-trifluoromethylindole compounds.

[0027] The target compound obtained by the method of this invention—a polysubstituted 1-trifluoromethylindole compound—can be used as a synthetic intermediate to prepare many bioactive drug molecules, such as the nicotinic acetylcholine receptor allosteric modulator reported in patent document WO2012131031A1.

[0028] The present invention also provides the application of the above method in the fields of pharmaceuticals, pesticides and functional materials preparation.

[0029] This invention also provides a method for synthesizing an important intermediate of a nicotinic acetylcholine receptor positive allosteric modulator, the structure of which is shown below: The reaction route of the method is as follows:

[0030]

[0031] The definitions of R1 and R2 are the same as above.

[0032] In one embodiment of the present invention, R1 may specifically be H, and R2 may specifically be methyl.

[0033] In one embodiment of the present invention, the method for synthesizing the important intermediate of the nicotinic acetylcholine receptor allosteric modulator includes the following steps:

[0034] (1) In an organic solvent, 2-alkynyl-4-cyanoaromatic amines and silver trifluoromethyl sulfide were used as reactants, and potassium iodide and silver trifluoride were added. The cyclization reaction was carried out under the catalysis of catalyst and ligand to synthesize 1-trifluoromethyl-5-cyanoindole compounds.

[0035] (2) The obtained 1-trifluoromethyl-5-cyanoindole compounds were hydrogenated and reduced to obtain an important intermediate of the nicotinic acetylcholine receptor orthoallosteric regulator.

[0036] In one embodiment of the present invention, the conditions involved in step (1) are the same as those in the above-described synthesis method of 1-trifluoromethylindole compounds.

[0037] In one embodiment of the present invention, the hydrogenation reduction in step (2) involves dissolving a 1-trifluoromethyl-5-cyanoindole compound in MeOH·NH3, then adding Raney-Ni, and reacting at room temperature for a period of time under hydrogen atmosphere.

[0038] In one embodiment of the present invention, the concentration of MeOH·NH3 is 5M.

[0039] In one embodiment of the present invention, the amount of Raney-Ni added relative to the 1-trifluoromethyl-5-cyanoindole compound is 0.2 g / mmol.

[0040] Beneficial effects:

[0041] The method of this invention involves a one-pot reaction in a nitrogen atmosphere using 2-alkynylarylamine, silver trifluoromethyl sulfide, potassium iodide, and silver fluoride as reactants, with the aid of a catalyst and ligands, to construct the 1-trifluoromethylindole skeleton and obtain the target compound.

[0042] The method of this invention uses silver fluoride as the fluorine source, which has wide substrate applicability, simple and readily available raw materials, and low economic cost. In addition, the method of this invention can achieve the synthesis of the target product in good yield with only 3-10 hours of reaction, and the method is fast and efficient.

[0043] The synthesis method of this invention converts readily available 2-alkynylarylamines into corresponding 1-trifluoromethylindole compounds under relatively simple conditions, achieving the synthesis of multi-substituted 1-trifluoromethylindole derivatives in one step. The target compounds have wide applications in the fields of medicine, pesticides, and functional materials. Attached Figure Description

[0044] Figure 1 This is a synthesis route diagram for the method of the present invention. Detailed Implementation

[0045] The following are specific embodiments of the present invention.

[0046] The synthesis route diagram of this invention embodiment is as follows: Figure 1 As shown:

[0047] Using o-alkynylaniline, silver trifluoromethyl sulfide, potassium iodide, and silver fluoride as raw materials, cuprous iodide as a catalyst, 2,2'-bipyridine as a ligand, and acetonitrile as a reaction solvent, the target compound can be obtained by reacting at 25℃-50℃ for 3-10 hours. The reaction formula is as follows: Figure 1 .

[0048] Example 1: Synthesis of 2-phenyl-1-trifluoromethylindole

[0049]

[0050] Under nitrogen protection, p-2-phenylethynylaniline (97 mg, 0.5 mmol), silver trifluoromethyl thiocyanate (157 mg, 0.75 mmol), potassium iodide (125 mg, 0.75 mmol), silver fluoride (317 mg, 2.5 mmol), cuprous iodide (19 mg, 0.1 mmol), 2,2'-bipyridine (16 mg, 0.1 mmol), and acetonitrile (5 mL) were added to a 25 mL reaction tube equipped with a stir bar, and reacted at 50 °C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered with diatomaceous earth, and the filter residue was washed with ethyl acetate. The solvent was removed by vacuum concentration, and the target analyte was purified by column chromatography to obtain 93 mg of product with a fluorine spectrum yield of 88% (71% yield).

[0051] 1H NMR (400MHz, CDCl3) δ7.79-7.69(m,1H),7.69-7.62(m,1H),7.57(dd,J=6.5,2.8Hz,2H),7.52-7.44(m,3H),7.43-7.30(m,2H),6.69-6.61(m,1H). 19 F NMR(376MHz, CDCl3)δ-49.82(s,3F). 13 C NMR(101MHz, CDCl3)δ139.4(s),136.0(s),132.4(s),129.6(s),129.3(s),128.8(s),128.2(s),1 24.4(s),123.0(s),121.1(s),120.7(q,J=263.2Hz),113.2(q,J=4.3Hz),109.8(s).HRMS(ESI)m / z calculated for C 15 H 11 F3N[M+H] + :262.0844,found:262.0838.

[0052] Example 2: Synthesis of 2-p-cyanophenyl-1-trifluoromethylindole

[0053]

[0054] Under nitrogen protection, p-2-cyanophenylethynylaniline (109 mg, 0.5 mmol), silver trifluoromethyl sulfide (157 mg, 0.75 mmol), potassium iodide (125 mg, 0.75 mmol), silver fluoride (317 mg, 2.5 mmol), cuprous iodide (19 mg, 0.1 mmol), 2,2'-bipyridine (16 mg, 0.1 mmol), and acetonitrile (5 mL) were added to a 25 mL reaction tube equipped with a stir bar and reacted at 50 °C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered with diatomaceous earth, and the filter residue was washed with ethyl acetate. The solvent was removed by vacuum concentration, and the target analyte was purified by column chromatography to obtain 109 mg of product with a fluorine spectrum yield of 83% (76% yield).

[0055] 1 H NMR (400MHz, CDCl3) δ7.73 (d, J = 8.5Hz, 2H), 7.69-7.66 (m, 1H), 7.63 (t, J = 7.4Hz, 3H), 7.42-7.37 (m, 1H), 7.35-7.29 (m, 1H), 6.69 (s, 1H). 19F NMR (376MHz, CDCl3) δ-49.90 (s, 3F). 13 C NMR(101MHz, CDCl3)δ137.1(s),136.9(s),136.4(s),132.1(s),130.1-129.8(m),129.0(s),125.3(s),123 .5(s),121.5(s),120.5(q,J=262.1Hz),118.6(s),113.3(q,J=4.2Hz),112.5(s),111.4(s).HRMS(ESI)m / z calcd.for C 16 H 10 F3N2(M+H) + :287.0796; found:287.0791.

[0056] Example 3: Synthesis of 2-Biphenyl-1-trifluoromethylindole

[0057]

[0058] Under nitrogen protection, 2-biphenylethynylaniline (125 mg, 0.5 mmol), silver trifluoromethyl thiocyanate (157 mg, 0.75 mmol), potassium iodide (125 mg, 0.75 mmol), silver fluoride (317 mg, 2.5 mmol), cuprous iodide (19 mg, 0.1 mmol), 2,2'-bipyridine (16 mg, 0.1 mmol), and acetonitrile (5 mL) were added to a 25 mL reaction tube equipped with a stir bar and reacted at 50 °C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered with diatomaceous earth, and the filter residue was washed with ethyl acetate. The solvent was removed by vacuum concentration, and the target analyte was purified by column chromatography to obtain 68 mg of product with a fluorine spectrum yield of 49% (yield 40%).

[0059] 1 H NMR (400MHz, CDCl3) δ7.66(dt,J=5.6,3.5Hz,5H),7.63-7.56(m,3H),7.47(t,J=7.6Hz,2H),7.41-7.26(m,3H),6.64(s,1H). 19 F NMR(376MHz, CDCl3)δ-49.27(s,3F). 13CNMR(101MHz, CDCl3)δ140.94(d,J=108.1Hz),138.98(s),135.99(s),131.14(s),129.85-129.66(m),129.17(s),128.87(s),127.64(s),1 26.94(d,J=36.8Hz),124.27(s),122.93(s),120.97(s),δ120.60(q,J=263.2Hz),113.08(q,J=4.3Hz),109.82(s).HRMS(AP)m / zcalculated for C 21 H 15 F3N[M+H] + :338.1142,found:338.1157.

[0060] Example 4: Synthesis of 1-trifluoromethyl-2-methyl-5-cyano-indole

[0061]

[0062] Under nitrogen protection, 2-propynyl-4-cyanoaniline (0.5 mmol), silver trifluoromethyl sulfide (157 mg, 0.75 mmol), potassium iodide (125 mg, 0.75 mmol), silver fluoride (317 mg, 2.5 mmol), cuprous iodide (19 mg, 0.1 mmol), 2,2'-bipyridine (16 mg, 0.1 mmol), and acetonitrile (5 mL) were added to a 25 mL reaction tube equipped with a stir bar and reacted at 50 °C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered with diatomaceous earth, and the filter residue was washed with ethyl acetate. The solvent was removed by vacuum concentration, and the target analyte was purified by column chromatography to obtain 38 mg of product with a fluorine spectrum yield of 40% (yield 34.2%).

[0063] 1 H NMR (400MHz, CDCl3) δ7.96-7.72(m,1H),7.62(d,J=6.6Hz,1H),7.56-7.43(m,1H),6.45(s,1H),2.54(s,3H). 19 F NMR (376MHz, CDCl3) δ-51.75 (s, 3F). 13C NMR(101MHz, CDCl3)δ137.67(s),137.04(s),129.10(s),126.45(s),δ124.65-115.35(m),125 .07(s),119.53(s),112.99(q,J=4.9Hz),107.27-107.13(m),106.11(s),14.12(q,J=3.6Hz).

[0064] By replacing 2-propynyl-4-cyanoaniline with other substitutions, more corresponding polysubstituted 1-trifluoromethylindole-like compounds were prepared.

[0065] Example 5: Effect of different catalysts on the synthesis of 2-phenyl-1-trifluoromethylindole

[0066] Referring to Example 1, without the addition of ligands, the catalyst was replaced by cuprous chloride, ruthenium dichloride, copper fluoride, palladium di(triphenylphosphine)chloride, and rhodium tri(triphenylphosphine)chloride, respectively. Additionally, an experiment was conducted without any catalyst, with other conditions remaining unchanged, to synthesize 2-phenyl-1-trifluoromethylindole. Specific yield results are shown in Table 1.

[0067] Table 1 Effect of different catalysts on the synthesis of 2-phenyl-1-trifluoromethylindole

[0068]

[0069]

[0070] The results showed that the product yields were worse than those in Example 1 when no catalyst was added or when cuprous chloride, copper acetate, copper chloride, ruthenium dichloride, copper fluoride, palladium di(triphenylphosphine) chloride, or rhodium tri(triphenylphosphine) chloride were used as catalysts.

[0071] Example 6: Effect of different ligands on the synthesis of 2-phenyl-1-trifluoromethylindole

[0072] Referring to Example 1, the catalyst was replaced by 4,4'-bipyridine, triphenylphosphine, and o-phenanthroline, respectively, while other conditions remained unchanged, to synthesize 2-phenyl-1-trifluoromethylindole. Specific yield results are shown in Table 2.

[0073] Table 2. Effects of different ligands on the synthesis of 2-phenyl-1-trifluoromethylindole

[0074] catalyst Fluorine yield (%) 2,2'-Bipyridine 88 4,4'-Bipyridine 24 <![CDATA[PPh3]]> 50 1,10-Phen 40

[0075] The results showed that when 4,4'-bipyridine, triphenylphosphine, and o-phenanthroline were used instead of 2,2'-bipyridine in Example 1 as ligands, the yields of the products obtained were all worse than those in Example 1.

[0076] Example 7: Effect of different solvents on the synthesis of 2-phenyl-1-trifluoromethylindole

[0077] Referring to Example 1, the solvent was replaced by tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and water, respectively, while keeping other conditions unchanged, to synthesize 2-phenyl-1-trifluoromethylindole. Specific yield results are shown in Table 3.

[0078] Table 3 Effect of different solvents on the synthesis of 2-phenyl-1-trifluoromethylindole

[0079] solvent Fluorine yield (%) <![CDATA[CH3CN]]> 88 THF Trace DMF Trace DMSO Trace <![CDATA[H2O]]> 0 o-DCB 0

[0080] The results showed that when tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, water, and 1,2-dichlorobenzene were used instead of acetonitrile as solvents in Example 1, the yields of the products obtained were all worse than those in Example 1.

[0081] Example 8: Synthesis of 2-phenyl-1-trifluoromethylindole at different reaction temperatures

[0082] Referring to Example 1, the reaction temperature was replaced from 50°C to 30°C, 70°C, and 90°C respectively, while other conditions remained unchanged, to synthesize 2-phenyl-1-trifluoromethylindole.

[0083] The specific yield results are shown in Table 3.

[0084] Table 3. Effects of different reaction temperatures on the synthesis of 2-phenyl-1-trifluoromethylindole

[0085]

[0086]

[0087] The results showed that replacing 50°C in Example 2 with 30°C, 70°C, or 90°C did not significantly reduce the product yield compared to Example 1. However, the yield decreased considerably when the temperature reached 90°C.

[0088] Comparative Example 1

[0089] Referring to Example 1, potassium iodide was not added, and everything else remained the same.

[0090] The results showed that without the addition of potassium iodide, the yield dropped to zero.

[0091] Comparative Example 2

[0092] Referring to Example 1, silver fluoride was not added, and everything else remained the same.

[0093] The results showed that without the addition of silver fluoride, the yield dropped to zero.

[0094] Example 9: Synthesis of an important intermediate for a nicotinic acetylcholine receptor allosteric modulator

[0095] An important intermediate of nicotinic acetylcholine receptor orthoallosteric modulators (PAMs) Synthesis method of intermediate M18 (disclosed in China under WO2012131031A1):

[0096]

[0097] 1-Trifluoromethyl-2-methyl-5-cyanoindole (0.5 mmol) was added to Raney-Ni (100 mg) in MeOH·NH3 (10 mL, 5 M) at room temperature. The reaction mixture was stirred under H2 (60 psi) for 2 h. After the reaction was completed, the mixture was filtered, and the filtrate was evaporated to dryness. The crude compound was washed with pentane to give intermediate M18 (70.4 mg, yield 40%).

[0098] 1 H NMR (400MHz, CDCl3) δ7.56-7.37(m,2H),7.17(d,J=8.5Hz,1H),6.32(s,1H),3.87(br s,2H),2.48(s,3H). 19 F NMR(376MHz, CDCl3)δ-52.32(s,3F).

[0099] Furthermore, Further substitutions of R1 and R2 can be made to obtain more analogs, providing corresponding synthetic methods for exploring more small molecules with positive allosteric regulatory activity of nicotinic acetylcholine receptors.

[0100] Furthermore, nicotinic acetylcholine receptor orthoallosteric modulators (PAMs) can be prepared by referring to compounds 83-85 in WO2012131031A1.

Claims

1. A method for synthesizing 1-trifluoromethylindole compounds, wherein the method involves using 2-alkynyl aromatic amine compounds of formula (1) and silver trifluoromethyl sulfide as reactants in an organic solvent, and adding potassium iodide and silver fluoride, and carrying out a cyclization reaction under the catalysis of a catalyst and ligand to synthesize 1-trifluoromethylindole compounds of formula (2); ， wherein R1 is selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, cyano, nitro, C1-C8 alkoxy, acyl and amide and heterocycle; R2 is selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide and heterocycle; The organic solvent is acetonitrile; the catalyst is any one or more of cuprous iodide, cuprous chloride, ruthenium dichloride, palladium di(triphenylphosphine) chloride, and rhodium tri(triphenylphosphine) chloride; the ligand is any one or more of 2,2'-bipyridine, 4,4'-bipyridine, triphenylphosphine, and o-phenanthroline.

2. The method according to claim 1, characterized in that, The reaction temperature is 25 ℃-100 ℃.

3. The method according to claim 1, characterized in that, The molar ratio of 2-alkynyl aromatic amine compounds, silver trifluoromethyl sulfide, potassium iodide, silver fluoride, catalyst, and ligand is 1:(1.0-2.0):(1.0-2.0):(3.0-6.0):(0.05-0.2):(0.05-0.2).

4. The method according to claim 1, characterized in that, The reaction concentration of 2-alkynyl aromatic amines is 0.05-5 mmol / mL.

5. The method according to claim 1, characterized in that, The cyclization reaction is carried out in an inert gas atmosphere.

6. A method for synthesizing an important intermediate of a nicotinic acetylcholine receptor allosteric modulator, characterized in that, The structure of the important intermediate of the nicotinic acetylcholine receptor allosteric regulator is as follows: The reaction route of the method is as follows: ， The definitions of R1 and R2 are the same as in claim 1; Includes the following steps: (1) In an organic solvent, 2-alkynyl-4-cyanoaromatic amines and silver trifluoromethyl sulfide were used as reactants, and potassium iodide and silver fluoride were added. The cyclization reaction was carried out under the catalysis of catalyst and ligand to synthesize 1-trifluoromethyl-5-cyanoindole compounds. (2) The obtained 1-trifluoromethyl-5-cyanoindole compounds were hydrogenated and reduced to obtain an important intermediate of the nicotinic acetylcholine receptor orthoallometric regulator. The organic solvent is acetonitrile; the catalyst is any one or more of cuprous iodide, cuprous chloride, ruthenium dichloride, palladium di(triphenylphosphine) chloride, and rhodium tri(triphenylphosphine) chloride; the ligand is any one or more of 2,2'-bipyridine, 4,4'-bipyridine, triphenylphosphine, and o-phenanthroline.

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