Indole alkaloid and preparation method thereof

Abstract

The invention discloses a method for preparing indole compounds through an efficient synthesis route by taking a simple and easily prepared brominated substrate as a starting raw material. Compared with the prior art, the route provided by the invention has the following remarkable advantages: 1, high-activity iodide used in a traditional method is avoided, and the raw material preparation difficulty is reduced; 2, the reaction condition is mild, the operation is simple and convenient, and a complex process harmful to the environment is avoided; 3, the catalyst is small in dosage, cheap and easy to obtain, and the production cost is reduced; and 4, the yield of the derivative is high, the atom economy is good, and the method is suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to a class of indole alkaloids and a preparation method thereof. Background Art

[0002] Fungal natural products and their effects have been known to humans for many years. Throughout the Middle Ages, toxic alkaloids produced by filamentous fungi growing on rye posed a threat to thousands of people and livestock. However, with the continuous development of science, their use in medicine, and the subsequent discovery of antibiotics and other fungal-derived drugs, have changed the negative reputation of fungi as "toxins" in history. For example, the indole alkaloid Nb-acetyltryptamine, isolated from the fungus Gracilaria verrucosa, which grows on the surface of marine red algae, has strong anticancer activity. IndiacenA, a fungus-derived compound first synthesized by Maringanti's group, also has strong antibacterial activity. These findings demonstrate that most fungal indole alkaloids possess excellent biological activity and possess significant medicinal value. Examples include reserpine, an indole alkaloid used to treat hypertension and mental illness; vincristine, a protein-interfering anticancer drug extracted from the Apocynaceae plant Catharanthus roseus; strychnine, used to treat paresis or amblyopia; and 10-hydroxycamptothecin, used to treat liver and head and neck cancers. TMC-205, a recently discovered indole alkaloid, can activate the SV40 promoter to promote anti-cancer gene expression and inhibit the proliferation of human tumor cells. Its trifluoroacetyl analog is more potent and stable in anticancer activity. Furthermore, compounds containing 1,1-dimethylallyl alcohol are often active compounds, demonstrating potential biological activity. 3-Trifluoroacetyl-6-isoprenylindole is a typical example. This type of indole derivative has attracted the interest of many researchers due to its rich pharmacological activity to synthesize various compounds containing indole structures, hoping to use indole and various heterocycles to design various compounds for the treatment of various diseases.

[0003] Synthetic chemists have been conducting research on a range of strategies for introducing isoprenyl and enol groups, and have made some progress. These strategies primarily focus on Suzuki coupling, Still coupling, Hiyama coupling, dehydration of 1,1-dimethylallyl alcohol, and reduction / dehydration of 1,1-dimethylpropargyl alcohol.

[0004] For the synthesis of isoprene compounds, a more practical approach is to introduce them through the palladium-catalyzed Suzuki cross-coupling of iodides and isoprenyl borate. In 2015, when Lei Xiaoguang's research group synthesized kuwanon, they needed to prepare isoprene compound 3 to complete the DA reaction (Org. Lett., 2016, 18(3):360-363.; https: / / doi.org / 10.1021 / acs.orglett.5b03285). Diene 3 was prepared by Suzuki coupling of iodide 1 and isoprenyl borate 2. Suzuki coupling has good substrate adaptability and functional group tolerance. After the crude coupling reaction mixture is further protected by acetyl group, the yield can reach 89%. This strategy cleverly utilizes the electron-withdrawing protecting group (acetyl group) and the highly active carbon-iodine bond to ensure the reaction efficiency of polyphenol bromides with low palladium-catalyzed coupling activity. However, this method is not atom-economical, and the preparation of isoprenylboronate 2 requires the use of excessive and expensive isopropenyl acetylene 4 and highly flammable and equally expensive pinacol borane.

[0005]

[0006] In 2007, the Hiyamak group (J. Organomet. Chem., 2007, 692:585-603; https: / / doi.org / 10.1016 / j.jorganchem.2006.04.046) used tetrahydropyranyl ether (THP)-protected [2-(hydroxymethyl)phenyl]dimethylsilane to synthesize stable prenylsilanes through stereo- and regioselective hydrosilylation of alkynes in the presence of platinum or ruthenium catalysts. These silanes then cross-couple with various aryl and alkenyl iodides to prepare conjugated arylene and diene compounds. While this strategy cleverly combines multiple synthetic transformations and offers excellent substrate adaptability and yields, it is somewhat cumbersome, exhibits low atom economy, and requires demanding and complex experimental procedures.

[0007]

[0008] In 1990, the Reid group (Liebigs Annalen der Chemie, 1990, 209-210; 10.1002 / jlac.199019900137) completed the total synthesis of the natural product Gleinadiene. To introduce isoprene, they first prepared allyl alcohol via the Heck reaction, using iodocoumarin and 1,1-dimethylallyl alcohol. p-TsCl was then used as a sulfonation reagent to convert the tertiary alcohol into a sulfonate ester, which was then eliminated. Although this method leveraged the strong leaving ability of the -OTs group to successfully eliminate the hydroxyl group in a hot pyridine environment to obtain the isoprene structure, the dehydration yield of the allyl alcohol was relatively low, perhaps due to the harsh conditions. Furthermore, this reaction strategy still suffers from the drawbacks of harsh conditions, environmental issues, and low atom economy. Furthermore, this strategy is not very versatile when the substrate contains reactive groups such as -OH and -NH2 and lacks protecting groups.

[0009]

[0010] In 2014, Lei Xiaoguang's group (Angew. Chem., 2015, 53(35):9257-9261.; 10.1002 / anie.201404499) used isoprene intermediate 19 in the synthesis of mixed terpenes Kuwanon I and Kuwanon J. Their preparation first involved photooxidation of isopentenyl chalcone 16 with Rose bengal as a photosensitizer, followed by PPh3 reduction to 1,1-dimethylallyl alcohol 18, and finally dehydration to the isoprene structure via SOCl2 / DBU. This strategy used a common isopentenyl group to prepare its homologue isoprene through a series of transformations. However, the photooxidation and reduction strategy for preparing 1,1-dimethylallyl alcohol 18 yielded low yields, and the difficult-to-separate allyl alcohol isomer 17 was present. Furthermore, the dehydration reaction required ultra-low temperatures, making the reaction conditions less than mild. The use of highly active SOCl2 and DBU also affects the greenness and atom economy of this strategy.

[0011]

[0012] In 2013, Cuik's group (Synth. Commun., 2013, 43(17): 2380-2384.; 10.1080 / 00397911.2012.711881) reported a one-pot method for preparing (E)-dienes from propargyl alcohol using LiAlH4 / AlCl3 as the reduction / dehydration reagent. This strategy is highly applicable to a variety of aromatic propargyl alcohol substrates, and the 1,3-dienes obtained using this method have good stereoselectivity and yield. However, the preparation of the propargyl alcohol substrate requires the use of a strong base, n-butyl lithium, and is carried out at ultra-low temperatures. The reduction and dehydration steps of the alkynol use the strong reducing agent LiAlH4 and the strong Lewis acid AlCl3, respectively. The reaction conditions are relatively harsh, which affects the substrate compatibility of this strategy.

[0013] Summary of the Invention

[0014] The present invention provides a method for preparing indole compounds through an efficient synthetic route using a simple and easy-to-prepare bromosubstrate as a starting material. The method obtains the target product in a relatively high yield. Specifically, the method couples different bromine-substituted compounds with 2-methyl-3-butene-2-ol via a palladium-catalyzed Heck reaction to obtain the target indole compound in a medium to high yield. Compared with the prior art, the route of the present invention has the following significant advantages: 1. It avoids the highly active iodide used in traditional methods, reducing the difficulty of raw material preparation; 2. The reaction conditions are mild and the operation is simple, avoiding complex and environmentally harmful processes; 3. The catalyst is used in a small amount and is inexpensive and readily available, reducing production costs; 4. The derivative yield is relatively high, the atom economy is good, and it is suitable for large-scale production. In addition, the indole compounds synthesized by this method have potential physiological activity, providing an important material basis for related drug development and biological activity research.

[0015] The technical problems to be solved by the present invention are:

[0016] 1. Avoid the use of highly active iodides that are difficult to prepare; use electron-rich, sterically hindered deactivated bromo compounds as intermediates to synthesize indole compounds in high yield via the Heck reaction in the presence of trialkylamines; 2. Solve the problems of low purity, complex operation, low yield, and inability to mass produce in existing technologies; 3. Improve the atom economy of the reaction; 4. Provide a method for preparing indole compounds with stable process, simple operation, and high synthesis efficiency.

[0017] The present invention provides a method for preparing indole alkaloids, the reaction formula of which is:

[0018]

[0019] in,

[0020] Said X is a halogen;

[0021] R1 is H or C1-C6 alkyl;

[0022] The R2 is selected from When R2 is The preparation conditions are:

[0023] Under a nitrogen environment, a sufficient amount of ultra-dry solvent (water content ≤50 ppm), an alkaline reagent, and substrate B are added to substrate A, a palladium catalyst, and BHT (2,6-di-tert-butyl-4-methylphenol), and the mixed system is placed in an oil bath at 90-95° C. for reaction for 1-11 hours. After the reaction is completed, the reaction mixture is cooled to room temperature and an alkaline solution is added and stirred; then filtered through a silica gel column, the filtrate is extracted with ethyl acetate, washed with water, and then washed with brine, and the aqueous phase is stripped with ethyl acetate. The organic phases are combined, dried, and concentrated in vacuo to obtain a crude product, which is purified to obtain the final product.

[0024] The molar ratio of substrate A, palladium catalyst, BHT, alkaline reagent and substrate B is: 1:0.05-0.1:0.08-0.15:1.5:4-5; when R2 is The preparation conditions are:

[0025] Under a nitrogen environment, a sufficient amount of ultra-dry solvent (water content ≤50 ppm), an alkaline reagent, and substrate B are added to substrate A, a palladium catalyst, and BHT (2,6-di-tert-butyl-4-methylphenol), and the mixed system is placed in an oil bath at 110-115° C. for reaction for 8-20 hours. After the reaction is completed, the reaction mixture is cooled to room temperature and an alkaline solution is added and stirred; the mixture is then filtered through a silica gel column, the filtrate is extracted with ethyl acetate, washed with water, and then washed with brine, and the aqueous phase is stripped with ethyl acetate. The organic phases are combined, dried, and concentrated in vacuo to obtain a crude product, which is purified to obtain the final product.

[0026] The molar ratio of the substrate A, palladium catalyst, BHT, alkaline reagent and substrate B is: 1:0.05-0.1:0.08-0.15:1:4-5. In some embodiments, the palladium catalyst is selected from one or more of di(tri-tert-butylphosphine)palladium, palladium chloride, tris(dibenzylideneacetone)dipalladium, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium-chloroform adduct, palladium acetate, palladium carbon, tetrakistriphenylphosphine palladium chloride, palladium trifluoroacetate, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II), preferably di(tri-tert-butylphosphine)palladium; in some embodiments, the ultra-dry solvent is selected from one or more of ultra-dry N,N-dimethylacetamide, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, benzene, xylene, 1,4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, 1,2-dichloroethane, polyethylene glycol, acetonitrile, chlorobenzene, and dimethyl sulfoxide, preferably dry N,N-dimethylacetamide;

[0027] In some embodiments, the alkaline reagent is selected from one or more of tri-n-propylamine, triethylamine, N,N-diisopropylethylamine, N,N-diethylaniline, tri-n-octylamine, N,N-cyclohexylmethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, tetrabutylammonium chloride, tetrabutylammonium bromide, triethylenediamine, N-methyldicyclohexylamine, tetrabutylammonium hydroxide, potassium acetate, sodium acetate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, sodium carbonate, potassium carbonate, ammonium carbonate, calcium carbonate, cesium carbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, sodium phosphate, and calcium phosphate, preferably tri-n-propylamine.

[0028] In some embodiments, the alkaline solution is selected from one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, sodium phosphate, and calcium phosphate solutions, preferably sodium bicarbonate solution.

[0029] In some embodiments, wherein X is Br.

[0030] In some embodiments, wherein R1 is H.

[0031] In some embodiments, wherein R1 is methyl.

[0032] In some embodiments, when R2 is The molar ratio of substrate A, Pd(t-Bu3P)2, BHT, (n-C3H7)3N, and substrate B is: 1:0.08:0.1:1.5:4.5;

[0033] In some embodiments, when R2 is The molar ratio of the substrate A, Pd(t-Bu3P)2, BHT, (n-C3H7)3N, and substrate B is: 1:0.08:0.1:1:4.5.

[0034] In some embodiments, when R2 is The reaction temperature of the mixed system is 90°C.

[0035] In some embodiments, when R2 is The reaction temperature of the mixed system is 115°C.

[0036] In some embodiments, the structure of Compound C is selected from one of the following structures:

[0037] DETAILED DESCRIPTION

[0038] The following examples are intended to enable those skilled in the art to more fully understand the technical solutions and implementation effects of the present invention, but the scope of protection of the present invention is not limited thereto. This section further describes the present invention in detail in conjunction with specific implementation cases, and its technical features and advantages will be clearly reflected in the description. It should be pointed out that the embodiments are only exemplary descriptions and are not intended to limit the scope of the claims of the present invention. Any detailed adjustments, equivalent replacements, or adaptive improvements based on the core principles of the present invention fall within the substantive protection scope of the present invention.

[0039] Example 1: Preparation of (E)-2,2,2-trifluoro-1-(4-(3-hydroxy-3-methylbut-1-en-1-yl)-1H-indol-3-yl)ethan-1-one:

[0040]

[0041] Under nitrogen, a two-necked flask with a condenser was charged with a magnetron, substrate 24a (50.0 mg, 0.172 mmol, 1.0 eq.), Pd(t-Bu3P)2 (7.0 mg, 0.01376 mmol, 0.08 eq.), and BHT (3.8 mg, 0.0172 mmol, 0.1 eq.). The flask was sealed and ventilated three times with an oil pump to completely replace the air inside with nitrogen. Ultra-dry DMA (1.1 mL), (n-C3H7)3N (47.3 μL, 0.258 mmol, 1.5 eq.), and 15 (80.8 μL, 0.774 mmol, 4.5 eq.) were then added. The flask was then sealed and placed in an oil bath at 90°C for 1.5 h. After completion of the reaction, the reaction mixture was cooled to room temperature and stirred for 2 min after the addition of 1 mL of saturated aqueous NaHCO3. The crude reaction product was then filtered through a short silica gel column. The filtrate was diluted with EA (100 mL) and washed with water (2 × 10 mL) and brine (1 × 10 mL). Another 50 mL of EA was used to sequentially extract the aqueous phase. The organic phases were combined, dried over anhydrous Na2SO4, and then concentrated in vacuo to obtain the crude product. Dry loading: The crude product was dissolved in acetone, silica gel was added, and the solvent was dried by spin drying. The powdered solid produced by mixing the crude product with silica gel was transferred to a chromatographic column. Purification by column chromatography (PE:EA = 5:1 to 1:1) afforded the target compound 25a (47.4 mg, 93%).

[0042] Structural characterization data of compound (E)-2,2,2-trifluoro-1-(4-(3-hydroxy-3-methylbut-1-en-1-yl)-1H-indol-3-yl)ethan-1-one:

[0043] 1 H NMR (400MHz, Acetone-d6) δ8.49(q,J=2.1Hz,1H),8.01(d,J=16.0Hz,1H),7.55–7.47(m,2H),7.33(t,J=7.8Hz,1H),6.30(d,J=16.0Hz,1H),1.46(s,6H). 13C NMR (101MHz, Acetone-d6)173.59,139.42,138.69,138.11,133.13,126.96,124.80,123.43,120.88,111.48,110.79,70.01,29.74,29 .31.IR(KBr):3229.51,2974.26,1636.19,1525.62,1496.75,1426.11,1393.38,1266.33,1184.00,1088.13,895.18,731.35,664.56cm -1 ;HRMS(ESI-APPI)m / z calcd for C 15 H 13 NO2F3[MH] - 296.0903,found 296.0904.

[0044] Example 2: Preparation of (E)-2,2,2-trifluoro-1-(4-(3-methylbut-1,3-dien-1-yl)-1H-indol-3-yl)ethan-1-one:

[0045]

[0046] Under nitrogen, a magnet, substrate 24a (50.0 mg, 0.172 mmol, 1.0 eq.), Pd(t-Bu3P)2 (7.0 mg, 0.01376 mmol, 0.08 eq.), and BHT (3.8 mg, 0.0172 mmol, 0.1 eq.) were added to a two-necked flask with a condenser. The flask was sealed and evacuated three times with an oil pump to completely replace the air inside with nitrogen. Ultra-dry DMA (1.1 mL), (n-C3H7)3N (31.5 μL, 0.172 mmol, 1.0 eq.), and 15 (80.8 μL, 0.774 mmol, 4.5 eq.) were then added. The flask was then sealed and placed in an oil bath at 115°C for 8 h. After the reaction is complete, the reaction mixture is cooled to room temperature, followed by the addition of 1 mL of saturated aqueous NaHCO₃ and stirring for 2 minutes until the reaction solution becomes turbid. The reaction solution is then filtered through a short silica gel column. The filtrate is diluted with EA (100 mL) and washed with water (2 × 10 mL) and brine (1 × 10 mL). Another 50 mL of EA is then used to strip the aqueous phase. The organic phases are combined, dried over anhydrous Na₂SO₄, and then concentrated in vacuo to yield the crude product. Dry loading: The crude product is dissolved in acetone, silica gel is added, and the solvent is evaporated. The resulting powdery solid, which is mixed with silica gel, is transferred to a chromatographic column. Purification by column chromatography (PE:EA = 5:1 to 3:1) afforded the target compound 25b (45.6 mg, 95%).

[0047] Structural characterization data of compound (E)-2,2,2-trifluoro-1-(4-(3-methylbut-1,3-dien-1-yl)-1H-indol-3-yl)ethan-1-one:

[0048] 1 H NMR (400MHz, Acetone-d6) δ11.80(s,1H),8.60–8.48(m,1H),8.22(d,J=16.0Hz,1H),7.62(d,J=7.6Hz,1H),7.55 (dd,J=8.1,0.9Hz,1H),7.36(t,J=7.8Hz,1H),6.89(d,J=15.9Hz,1H),5.20–4.99(m,2H),2.11(t,J=1.0Hz,3H). 13C NMR (101MHz, Acetone-d6)173.82,143.25,139.10,138.26,132.69,131.88,130.23,124.88,123.70,120.44,119.39,116.01,111.8 8,110.85,18.27;IR(KBr):3228.72,1636.77,1525.84,1481.11,1443.43,1293.95,1266.42,1185.83,1038.14,1020.56,846.01cm -1 ;HRMS(ESI-APPI)m / z calcd for C 15 H 11 NOF3[MH] - 278.0797,found 278.1198.

[0049] Example 3: Preparation of (E)-2,2,2-trifluoro-1-(5-(3-hydroxy-3-methylbut-1-en-1-yl)-1H-indol-3-yl)ethan-1-one:

[0050]

[0051] Under nitrogen, a two-necked flask with a condenser was charged with a magnetron, substrate 24b (50.0 mg, 0.172 mmol, 1.0 eq.), Pd(t-Bu3P)2 (7.0 mg, 0.01376 mmol, 0.08 eq.), and BHT (3.8 mg, 0.0172 mmol, 0.1 eq.). The flask was sealed and ventilated three times with an oil pump to completely replace the air inside with nitrogen. Ultra-dry DMA (1.1 mL), (n-C3H7)3N (47.3 μL, 0.258 mmol, 1.5 eq.), and 15 (80.8 μL, 0.774 mmol, 4.5 eq.) were then added. The flask was then sealed and placed in an oil bath at 90°C for 6 h. After completion of the reaction, the reaction mixture was cooled to room temperature and stirred for 2 min with the addition of 1 mL of saturated aqueous NaHCO3. The crude reaction product was then filtered through a short silica gel column. The filtrate was diluted with EA (100 mL) and washed with water (2×10 mL) and brine (1×10 mL). Another 50 mL of EA was taken to strip the aqueous phase in sequence. The organic phases were combined, dried over anhydrous Na2SO4, and then concentrated in vacuo to obtain the crude product. Dry loading: The crude product was dissolved in acetone, silica gel was added, and the solvent was dried by spin drying. The powdered solid produced by mixing the crude product with silica gel was transferred to a chromatographic column. Purification by column chromatography (PE:EA = 5:1 to 1:1) afforded the target compound 25c (16:46.4 mg, 91%).

[0052] Structural characterization data of compound (E)-2,2,2-trifluoro-1-(5-(3-hydroxy-3-methylbut-1-en-1-yl)-1H-indol-3-yl)ethan-1-one:

[0053] 1 H NMR (400MHz, Acetone-d6) δ8.40(t,J=2.3Hz,1H),8.34(dt,J=1.7,0.9Hz,1H),7.63–7.56(m,1H),7.50( dd,J=8.5,1.7Hz,1H),6.78(dd,J=16.2,1.2Hz,1H),6.50(dd,J=16.0,1.0Hz,1H),1.40(t,J=1.3Hz,6H). 13C NMR (101MHz, Acetone-d6)174.43,138.01,136.76,136.16,133.47,126.65,125.93,123.07,119.38,112.76,109.83,69.80,29.61 .IR(KBr):3229.51,2974.26,1636.19,1525.62,1496.75,1426.24,1393.30,1266.33,1184.97,1038.13,872.18,731.35,669.56cm -1 ;HRMS(ESI-APPI)m / z calcd forC 15 H 13 NO2F3[MH]-296.0903,found 296.0954.

[0054] Example 4: Preparation of (E)-2,2,2-trifluoro-1-(5-(3-methylbut-1,3-dien-1-yl)-1H-indol-3-yl)ethan-1-one:

[0055]

[0056] Under nitrogen, a magnet, substrate 24b (50.0 mg, 0.172 mmol, 1.0 eq.), Pd(t-Bu3P)2 (7.0 mg, 0.01376 mmol, 0.08 eq.), and BHT (3.8 mg, 0.0172 mmol, 0.1 eq.) were added to a two-necked flask with a condenser. The flask was sealed and evacuated three times with an oil pump to completely replace the air inside with nitrogen. Ultra-dry DMA (1.1 mL), (n-C3H7)3N (31.5 μL, 0.172 mmol, 1.0 eq.), and 15 (80.8 μL, 0.774 mmol, 4.5 eq.) were then added. The flask was then sealed and placed in an oil bath at 115°C for 9 h. After the reaction is complete, the reaction mixture is cooled to room temperature, followed by the addition of 1 mL of saturated aqueous NaHCO₃ and stirring for 2 minutes until the reaction solution becomes turbid. The reaction solution is then filtered through a short silica gel column. The filtrate is diluted with EA (100 mL) and washed with water (2 × 10 mL) and brine (1 × 10 mL). Another 50 mL of EA is then used to strip the aqueous phase. The organic phases are combined, dried over anhydrous Na₂SO₄, and then concentrated in vacuo to obtain the crude product. Dry loading: The crude product is dissolved in acetone, silica gel is added, and the solvent is dried by spin drying. The powdered solid produced by mixing the crude product with silica gel is transferred to a chromatographic column. Purification by column chromatography (PE:EA = 5:1 to 3:1) afforded the target compound 25d (42.7 mg, 89%).

[0057] Structural characterization data of compound (E)-2,2,2-trifluoro-1-(5-(3-methylbut-1,3-dien-1-yl)-1H-indol-3-yl)ethan-1-one:

[0058] 1 H NMR (400MHz, Acetone-d6) δ11.69 (s, 1H), 8.45–8.36 (m, 2H), 7.60 (d, J = 1.2Hz, 2H), 7. 04(d,J=16.2Hz,1H),6.81(d,J=16.2Hz,1H),5.33–4.95(m,2H),2.02(t,J=1.0Hz,3H). 13 C NMR (101MHz, Acetone-d6) δ174.45,142.32,136.39,133.30,130.66,129.40,126.71,122.97,119.98,118.63,116.44,112.93,1 09.88,17.92.IR(KBr):3028.72,1736.77,1525.84,1501.53,1413.43,1321.95,1266.42,1190.83,1138.14,1001.51,896.33cm -1 ;HRMS(ESI-APPI)m / z calcd for C 15 H 11 NOF3[MH]-278.0797,found278.0738.

[0059] Example 5: Preparation of (E)-2,2,2-trifluoro-1-(6-(3-hydroxy-3-methylbut-1-en-1-yl)-1H-indol-3-yl)ethan-1-one:

[0060]

[0061] Under nitrogen, a two-necked flask with a condenser was charged with a magnetron, substrate 24c (50.0 mg, 0.172 mmol, 1.0 eq.), Pd(t-Bu3P)2 (7.0 mg, 0.01376 mmol, 0.08 eq.), and BHT (3.8 mg, 0.0172 mmol, 0.1 eq.). The flask was sealed and ventilated three times with an oil pump to completely replace the air inside with nitrogen. Ultra-dry DMA (1.1 mL), (n-C3H7)3N (47.3 μL, 0.258 mmol, 1.5 eq.), and 15 (80.8 μL, 0.774 mmol, 4.5 eq.) were then added. The flask was then sealed and placed in an oil bath at 90°C for 8.5 h. After completion of the reaction, the reaction mixture was cooled to room temperature and stirred for 2 min with the addition of 1 mL of saturated aqueous NaHCO3. The crude reaction product was then filtered through a short silica gel column. The filtrate was diluted with EA (100 mL) and washed with water (2×10 mL) and brine (1×10 mL). Another 50 mL of EA was taken to extract the aqueous phase in sequence. The organic phases were combined, dried over anhydrous Na2SO4, and then concentrated in vacuo to obtain the crude product. Dry loading: The crude product was dissolved in acetone, silica gel was added, and the solvent was dried. The powdered solid produced by mixing the crude product with silica gel was transferred to a chromatographic column. Purification by column chromatography (PE:EA = 5:1 to 1:1) gave the target compound 25e (48.5 mg, 95%).

[0062] Structural characterization data of compound (E)-2,2,2-trifluoro-1-(6-(3-hydroxy-3-methylbut-1-en-1-yl)-1H-indol-3-yl)ethan-1-one:

[0063] 1 H NMR(400MHz, Methanol-d4)8.15(m,1H),8.11(d,J=8.3Hz,1H),7.45(s,1H),7 .36(d,J=8.4,1H),6.63(d,J=16.0Hz,1H),6.38(d,J=16.0,1H),1.34(s,6H); 13C NMR (101MHz, Methanol-d4)176.61,138.71,138.45,135.59,127.56,123.09,122.70,120.02,117.32,111.28,111.21,71.52,49.43,29 .98; IR(KBr):3229.51,2974.26,1636.19,1525.62,1496.75,1426.24,1363.30,1266.13,1184.97,1088.13,895.18,731.35,633.56cm -1 ;HRMS(ESI-APPI)m / z calcd for C 15 H 13 NO2F3[MH]-296.0903, found 296.0924.

[0064] Example 6: Preparation of (E)-2,2,2-trifluoro-1-(6-(3-methyl-1,3-butadien-1-yl)-1H-indol-3-yl)ethan-1-one:

[0065]

[0066] Under nitrogen, a round-bottom flask was charged with a magnetron, substrate 24c (1.0 g, 3.44 mmol, 1.0 eq.), Pd(t-Bu3P)2 (140.6 mg, 0.2752 mmol, 0.08 eq.), and BHT (75.8 mg, 0.344 mmol, 0.1 eq.). The round-bottom flask and condenser were sealed and evacuated three times with an oil pump to completely replace the air inside the round-bottom flask and condenser with nitrogen. Ultra-dry DMA (22.0 mL), (n-C3H7)3N (630.0 μL, 3.44 mmol, 1.0 eq.), and 15 (1616.0 μL, 15.48 mmol, 4.5 eq.) were then added. The round-bottom flask with condenser was then placed in an oil bath at 115°C for 16 h. After the reaction is completed, the sealed tube is cooled and returned to room temperature. Saturated aqueous NaHCO3 solution (2 mL) is added and stirred for 3 minutes. The reaction solution is then filtered through a short silica gel column. The filtrate is diluted with EA (300 mL) and washed with water (2×20 mL) and brine (1×20 mL). Another 100 mL of EA is taken to strip the aqueous phase in sequence. The organic phases are combined, dried over anhydrous Na2SO4, and then concentrated in vacuo to obtain the crude product. Dry loading: The crude product is dissolved in acetone, silica gel is added, and the solvent is dried by spin drying. The powdered solid produced by mixing the crude product with silica gel is transferred to a chromatographic column. Purification by column chromatography (PE:EA = 5:1 to 3:1) afforded the target compound 25f (916.8 mg, 95.5%).

[0067] Structural characterization data of compound (E)-2,2,2-trifluoro-1-(6-(3-methyl-1,3-butadien-1-yl)-1H-indol-3-yl)ethan-1-one:

[0068] 1 H NMR(400MHz, Acetone-d6)11.70(s,1H),8.41(d,J=1.9Hz,1H),8.24(d,J=8.4Hz,1H),7.72(s,1H),7.58 (dd,J=8.3,1.5Hz,1H),7.05(d,J=16.1Hz,1H),6.75(d,J=16.1Hz,1H),5.20–5.07(m,2H),1.98(s,3H). 13C NMR (101MHz, Acetone-d6)175.08,143.05,138.27,135.21,132.05,129.90,126.56,122.94,122.49,119.50,117.64,116.61,111.5 9,110.83,18.72;IR(KBr):3228.72,1636.77,1525.84,1501.53,1443.43,1393.95,1266.42,1185.83,1138.14,1090.56,896.01cm -1 ;HRMS(ESI-APPI)m / z calcd for C 15 H 11 NOF3[MH]-278.0797,found 278.0798.

[0069] Example 7: Preparation of (E)-2,2,2-trifluoro-1-(7-(3-hydroxy-3-methylbut-1-en-1-yl)-1H-indol-3-yl)ethan-1-one:

[0070]

[0071] Under nitrogen, a two-necked flask with a condenser was charged with a magnetron, substrate 24d (50.0 mg, 0.172 mmol, 1.0 eq.), Pd(t-Bu3P)2 (7.0 mg, 0.01376 mmol, 0.08 eq.), and BHT (3.8 mg, 0.0172 mmol, 0.1 eq.). The flask was sealed and ventilated three times with an oil pump to completely replace the air inside with nitrogen. Ultra-dry DMA (1.1 mL), (n-C3H7)3N (47.3 μL, 0.258 mmol, 1.5 eq.), and 15 (80.8 μL, 0.774 mmol, 4.5 eq.) were then added. The flask was then sealed and placed in an oil bath at 90°C for 1 h. After completion of the reaction, the reaction mixture was cooled to room temperature and stirred for 2 min after the addition of 1 mL of saturated aqueous NaHCO3. The crude reaction product was then filtered through a short silica gel column. The filtrate was diluted with EA (100 mL) and washed with water (2×10 mL) and brine (1×10 mL). Another 50 mL of EA was taken to extract the aqueous phase in sequence. The organic phases were combined, dried over anhydrous Na2SO4, and then concentrated in vacuo to obtain the crude product. Dry loading: The crude product was dissolved in acetone, silica gel was added, and the solvent was dried. The powdered solid produced by mixing the crude product with silica gel was transferred to a chromatographic column. Purification was performed by column chromatography (PE:EA=5:1 to 1:1) to obtain 25g (47.4 mg, 93%) of the target compound.

[0072] Structural characterization data of compound (E)-2,2,2-trifluoro-1-(7-(3-hydroxy-3-methylbut-1-en-1-yl)-1H-indol-3-yl)ethan-1-one:

[0073] 1 HNMR (400MHz, Acetone-d6) δ12.02(s,1H),8.40(q,J=1.9Hz,1H),8.21(dd,J=7.9,1.0Hz,1H),7.55(dt ,J=7.5,0.8Hz,1H),7.35(t,J=7.7Hz,1H),7.11(d,J=15.9Hz,1H),6.64(d,J=15.9Hz,1H),1.41(s,6H). 13 C NMR (101MHz, Acetone-d6)174.35,141.32,134.65,126.68,123.86,123.10,120.87,120.36,119.63,118.63,115.75,110.02,70.05,29 .54.IR(KBr):3229.51,2974.26,1636.19,1525.62,1496.75,1426.24,1393.30,1266.33,1184.97,1088.13,895.18,731.35,664.56cm -1 ;HRMS(ESI-APPI)m / z calcd forC 15 H 13 NO2F3[MH]-296.0903,found 296.0904.

[0074] Example 8: Preparation of (E)-2,2,2-trifluoro-1-(5-(3-methylbut-1,3-dien-1-yl)-1H-indol-3-yl)ethan-1-one:

[0075]

[0076] Under nitrogen, a magnet, substrate 24d (50.0 mg, 0.172 mmol, 1.0 eq.), Pd(t-Bu3P)2 (7.0 mg, 0.01376 mmol, 0.08 eq.), and BHT (3.8 mg, 0.0172 mmol, 0.1 eq.) were added to a two-necked flask with a condenser. The flask was sealed and evacuated three times with an oil pump to completely replace the air inside with nitrogen. Ultra-dry DMA (1.1 mL), (n-C3H7)3N (31.5 μL, 0.172 mmol, 1.0 eq.), and 15 (80.8 μL, 0.774 mmol, 4.5 eq.) were then added. The flask was then sealed and placed in an oil bath at 115°C for 12.5 h. After the reaction is complete, the reaction mixture is cooled to room temperature, followed by the addition of 1 mL of saturated aqueous NaHCO₃ and stirring for 2 minutes until the reaction solution becomes turbid. The reaction solution is then filtered through a short silica gel column. The filtrate is diluted with EA (100 mL) and washed with water (2×10 mL) and brine (1×10 mL). Another 50 mL of EA is then used to strip the aqueous phase. The organic phases are combined, dried over anhydrous Na₂SO₄, and then concentrated in vacuo to obtain the crude product. Dry loading: The crude product is dissolved in acetone, silica gel is added, and the solvent is dried by spin drying. The powdered solid produced by mixing the crude product with silica gel is transferred to a chromatographic column. Purification by column chromatography (PE:EA = 5:1 to 3:1) afforded the target compound 25h (43.2 mg, 90%).

[0077] Structural characterization data of compound (E)-2,2,2-trifluoro-1-(5-(3-methylbut-1,3-dien-1-yl)-1H-indol-3-yl)ethan-1-one:

[0078] 1 H NMR (400MHz, Acetone-d6) δ12.03(s,1H),8.41(s,1H),8.23(dd,J=7.9,1.0Hz,1H),7.67(d,J= 7.5Hz,1H),7.37(t,J=7.7Hz,1H),7.17(d,J=1.9Hz,2H),5.28–5.12(m,2H),2.04–2.01(m,3H). 13C NMR (101MHz, Acetone-d6) δ174.53,142.29,134.80,133.61,126.77,123.93,122.97,122.57,120.80,120.62,118.60,117.83,115. 71,110.07,17.83; IR(KBr):3208.72,1536.77,1555.84,1531.53,1443.43,1393.95,1246.42,1185.83,1138.14,1020.56,896.01cm -1 ;HRMS(ESI-APPI)m / z calcd for C 15 H 11 NOF3[MH]-278.0797, found 278.0748.

[0079] Example 9: Preparation of (E)-2,2,2-trifluoro-1-(5-(3-hydroxy-3-methylbut-1-en-1-yl)-1-methyl-1H-indol-3-yl)ethan-1-one:

[0080]

[0081] Under nitrogen, a two-necked flask with a condenser was charged with a magnetron, substrate 24e (50.0 mg, 0.164 mmol, 1.0 eq.), Pd(t-Bu3P)2 (6.7 mg, 0.01312 mmol, 0.08 eq.), and BHT (3.6 mg, 0.0164 mmol, 0.1 eq.). The flask was sealed and ventilated three times with an oil pump to completely replace the air inside with nitrogen. Ultra-dry DMA (1.1 mL), (n-C3H7)3N (45 μL, 0.246 mmol, 1.5 eq.), and 15 (77 μL, 0.738 mmol, 4.5 eq.) were then added. The flask was then sealed and placed in an oil bath at 90°C for 3.5 h. After completion of the reaction, the reaction mixture was cooled to room temperature and stirred for 2 min with the addition of 1 mL of saturated aqueous NaHCO3. The crude reaction product was then filtered through a short silica gel column. The filtrate was diluted with EA (100 mL) and washed with water (2×10 mL) and brine (1×10 mL). Another 50 mL of EA was taken to extract the aqueous phase in sequence. The organic phases were combined, dried over anhydrous Na2SO4, and then concentrated in vacuo to obtain the crude product. Dry loading: The crude product was dissolved in acetone, silica gel was added, and the solvent was dried. The powdered solid produced by mixing the crude product with silica gel was transferred to a chromatographic column. Purification by column chromatography (PE:EA=5:1 to 1:1) gave the target compound 25i (47.4 mg, 93%).

[0082] Structural characterization data of compound (E)-2,2,2-trifluoro-1-(5-(3-hydroxy-3-methylbut-1-en-1-yl)-1-methyl-1H-indol-3-yl)ethan-1-one:

[0083] 1 H NMR (400MHz, Acetone-d6) δ8.50–8.21(m,2H),7.70–7.43(m,2H),6.78(d,J=16.0Hz,1H),6.51(d,J=16.0Hz,1H),4.05(s,3H),1.40(s,6H). 13 C NMR (101MHz, Acetone-d6)173.77,141.02,138.28,137.12,133.74,127.25,125.75,122.94,119.45,111.15,108.52,69.73,69. 62,33.44,29.60.IR(KBr):3477.79,3136.92,2968.93,1677.44,1532.80,1459.59,1376.12,1132.42,969.60,814.05,728.60cm -1 .

[0084] Example 10: Preparation of (E)-2,2,2-trifluoro-1-(1-methyl-5-(3-methylbut-1,3-dien-1-yl)-1H-indol-3-yl)ethan-1-one:

[0085]

[0086] Under nitrogen, a two-necked flask with a condenser was charged with a magnetron, substrate 24e (50.0 mg, 0.164 mmol, 1.0 eq.), Pd(t-Bu3P)2 (6.7 mg, 0.01312 mmol, 0.08 eq.), and BHT (3.6 mg, 0.0164 mmol, 0.1 eq.). The flask was sealed and ventilated three times with an oil pump to completely replace the air inside with nitrogen. Ultra-dry DMA (1.1 mL), (n-C3H7)3N (30.03 μL, 0.164 mmol, 1.0 eq.), and 15 (77 μL, 0.738 mmol, 4.5 eq.) were then added. The flask was then sealed and placed in an oil bath at 115°C for 10.5 h. After completion of the reaction, the reaction mixture was cooled to room temperature and stirred for 2 min with the addition of 1 mL of saturated aqueous NaHCO3. The crude reaction product was then filtered through a short silica gel column. The filtrate was diluted with EA (100 mL) and washed with water (2×10 mL) and brine (1×10 mL). Another 50 mL of EA was taken to strip the aqueous phase in sequence. The organic phases were combined, dried over anhydrous Na2SO4, and then concentrated in vacuo to obtain the crude product. Dry loading: The crude product was dissolved in acetone, silica gel was added, and the solvent was dried. The powdered solid produced by mixing the crude product with silica gel was transferred to a chromatographic column. Purification by column chromatography (PE:EA=5:1 to 3:1) gave the target compound 25j (41.8 mg, 87%).

[0087] Structural characterization data of compound (E)-2,2,2-trifluoro-1-(1-methyl-5-(3-methylbut-1,3-dien-1-yl)-1H-indol-3-yl)ethan-1-one:

[0088] 1 H NMR (400MHz, Acetone-d6) δ8.44–8.29(m,2H),7.68–7.51(m,2H),7.05(d,J=16.1H z,1H),6.81(d,J=16.2Hz,1H),5.28–5.02(m,2H),4.05(s,3H),2.04–1.99(m,3H). 13CNMR(101MHz,Acetone-d6)δ173.62,142.29,140.17,140.12,137.33,133.5 2,130.85,129.25,127.30,122.81,120.06,116.58,111.33,108.59,33.45,1 7.91.IR(KBr):3124.17,3006.73,2970.03,1654.49,1527.50,1468.40,1315 .18,1288.17,1125.47,1081.97,1033.77,957.97,863.78,814.61,725.38cm -1 ;HRMS(ESI-APPI)m / z calcd forC 16 H 14 NOF3Na[M+Na] + 316.0921,found 316.0920.

[0089] Example 11: Preparation of (E)-2,2,2-trifluoro-1-(6-(3-hydroxy-3-methylbut-1-en-1-yl)-1-methyl-1H-indol-3-yl)ethan-1-one:

[0090]

[0091] Under nitrogen, a two-necked flask with a condenser was charged with a magnetron, substrate 24f (50.0 mg, 0.164 mmol, 1.0 eq.), Pd(t-Bu3P)2 (6.7 mg, 0.01312 mmol, 0.08 eq.), and BHT (3.6 mg, 0.0164 mmol, 0.1 eq.). The flask was sealed and ventilated three times with an oil pump to completely replace the air inside with nitrogen. Ultra-dry DMA (1.1 mL), (n-C3H7)3N (45 μL, 0.246 mmol, 1.5 eq.), and 15 (77 μL, 0.738 mmol, 4.5 eq.) were then added. The flask was then sealed and placed in an oil bath at 90°C for 11 h. After completion of the reaction, the reaction mixture was cooled to room temperature and 1 mL of saturated aqueous NaHCO3 was added and stirred for 2 min. The crude product was then filtered through a short silica gel column. The filtrate was diluted with EA (100 mL) and washed with water (2 × 10 mL) and brine (1 × 10 mL). Another 50 mL of EA was then used to sequentially extract the aqueous phase. The organic phases were combined, dried over anhydrous Na₂SO₄, and then concentrated in vacuo to yield the crude product. Dry loading: The crude product was dissolved in acetone, silica gel was added, and the solvent was evaporated. The resulting powdered solid was transferred to a chromatographic column. Purification by column chromatography (PE:EA = 5:1 to 1:1) afforded the target compound 25k (46.9 mg, 92%).

[0092] Structural characterization data of compound (E)-2,2,2-trifluoro-1-(6-(3-hydroxy-3-methylbut-1-en-1-yl)-1-methyl-1H-indol-3-yl)ethan-1-one:

[0093] 1 H NMR(400MHz, Acetone-d6)8.34(s,1H),8.20(d,J=8.3Hz,1H),7.66(s,1H),7.53-7.45(dd,J =8.3,1.4Hz,1H),6.77(d,J=16.0Hz,1H),6.57(d,J=16.0Hz,1H),4.06(s,3H),1.38(s,6H); 13C NMR (101MHz, Acetone-d6)174.76,141.00,140.95,139.65,139.20,135.39,126.78,126.51,123.23,122.50,109.56,109.47,70. 65,34.22,30.48;IR(KBr):3477.79,3136.92,2968.93,1633.44,1532.80,1450.59,1376.12,1112.42,969.60,814.05,738.60cm -1 .

[0094] Example 12: Preparation of (E)-2,2,2-trifluoro-1-(1-methyl-6-(3-methylbut-1,3-dien-1-yl)-1H-indol-3-yl)ethan-1-one:

[0095]

[0096] Under nitrogen, a two-necked flask with a condenser was charged with a magnetron, substrate 24f (50.0 mg, 0.164 mmol, 1.0 eq.), Pd(t-Bu3P)2 (6.7 mg, 0.01312 mmol, 0.08 eq.), and BHT (3.6 mg, 0.0164 mmol, 0.1 eq.). The flask was sealed and ventilated three times with an oil pump to completely replace the air inside with nitrogen. Ultra-dry DMA (1.1 mL), (n-C3H7)3N (30.03 μL, 0.164 mmol, 1.0 eq.), and 15 (77 μL, 0.738 mmol, 4.5 eq.) were then added. The flask was then sealed and placed in an oil bath at 115°C for 20 h. After completion of the reaction, the reaction mixture was cooled to room temperature and stirred for 2 min with the addition of 1 mL of saturated aqueous NaHCO3. The crude reaction product was then filtered through a short silica gel column. The filtrate was diluted with EA (100 mL) and washed with water (2×10 mL) and brine (1×10 mL). Another 50 mL of EA was taken to extract the aqueous phase in sequence. The organic phases were combined, dried over anhydrous Na2SO4, and then concentrated in vacuo to obtain the crude product. Dry loading: The crude product was dissolved in acetone, silica gel was added, and the solvent was dried. The powdered solid produced by mixing the crude product with silica gel was transferred to a chromatographic column. Purification was performed by column chromatography (PE:EA=5:1 to 3:1) to obtain the target compound 25l (41.4 mg, 86%).

[0097] Structural characterization data of compound (E)-2,2,2-trifluoro-1-(1-methyl-6-(3-methylbut-1,3-dien-1-yl)-1H-indol-3-yl)ethan-1-one:

[0098] 1 H NMR (400MHz, Methanol-d4)8.17(m,1H),8.12(d,J=8.3,1H),7.54(s,1H),7.44(dd,J=8.4,1.6Hz, 1H),6.98(d,J=16.3Hz,1H),6.65(d,J=16.2Hz,1H),5.12-5.00(m,2H),3.87(s,3H),1.94(s,3H); 13 C NMR(101MHz,Methanol-d4)175.41,143.53,141.54,139.66,135.83,132.61 ,130.04,127.53,123.54,122.96,120.00,117.70,110.15,109.81,34.13,18 .79; IR(KBr):3124.17,3026.73,2970.03,1654.49,1527.50,1468.40,1375 .18,1288.17,1177.47,1081.97,1033.77,961.97,863.78,814.61,725.06cm -1 ;HRMS(ESI-APPI)m / z calcd for C 16 H 14 NOF3Na[M+Na] + 316.0921,found 316.0920.

[0099] Finally, it should be noted that the above embodiments are only used to illustrate rather than limit the technical solutions of the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that the present invention can still be modified or replaced by equivalents. Any modification or partial replacement that does not depart from the spirit and scope of the present invention should be included in the scope of the claims of the present invention.

Claims

1. A method for preparing indole alkaloids, wherein the reaction formula is: in, Said X is a halogen; R1 is H or C1-C6 alkyl; The R2 is selected from When R2 is The preparation conditions are: Under a nitrogen environment, a sufficient amount of ultra-dry solvent (water content ≤50 ppm), an alkaline reagent, and substrate B are added to substrate A, a palladium catalyst, and BHT (2,6-di-tert-butyl-4-methylphenol), and the mixed system is placed in an oil bath at 90-95° C. for reaction for 1-11 hours. After the reaction is completed, the reaction mixture is cooled to room temperature and an alkaline solution is added and stirred; then filtered through a silica gel column, the filtrate is extracted with ethyl acetate, washed with water, and then washed with brine, and the aqueous phase is stripped with ethyl acetate. The organic phases are combined, dried, and concentrated in vacuo to obtain a crude product, which is purified to obtain the final product. The molar ratio of substrate A, palladium catalyst, BHT, alkaline reagent and substrate B is: 1:0.05-0.1:0.08-0.15:1.5:4-5; when R2 is The preparation conditions are: Under a nitrogen environment, a sufficient amount of ultra-dry solvent (water content ≤50 ppm), an alkaline reagent, and substrate B are added to substrate A, a palladium catalyst, and BHT (2,6-di-tert-butyl-4-methylphenol), and the mixed system is placed in an oil bath at 110-115° C. for reaction for 8-20 hours. After the reaction is completed, the reaction mixture is cooled to room temperature and an alkaline solution is added and stirred; the mixture is then filtered through a silica gel column, the filtrate is extracted with ethyl acetate, washed with water, and then washed with brine, and the aqueous phase is stripped with ethyl acetate. The organic phases are combined, dried, and concentrated in vacuo to obtain a crude product, which is purified to obtain the final product. The molar ratio of the substrate A, palladium catalyst, BHT, alkaline reagent and substrate B is: 1:0.05-0.1:0.08-0.15:1:4-5; the palladium catalyst is selected from one or more of di(tri-tert-butylphosphine)palladium, palladium chloride, tris(dibenzylideneacetone)dipalladium, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium-chloroform adduct, palladium acetate, palladium carbon, tetrakistriphenylphosphine palladium chloride, palladium trifluoroacetate, and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), preferably di(tri-tert-butylphosphine)palladium; The ultra-dry solvent is selected from one or more of ultra-dry N,N-dimethylacetamide, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, benzene, xylene, 1,4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, 1,2-dichloroethane, polyethylene glycol, acetonitrile, chlorobenzene, and dimethyl sulfoxide, preferably dry N,N-dimethylacetamide; The alkaline reagent is selected from one or more of tri-n-propylamine, triethylamine, N,N-diisopropylethylamine, N,N-diethylaniline, tri-n-octylamine, N,N-cyclohexylmethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, tetrabutylammonium chloride, tetrabutylammonium bromide, triethylenediamine, N-methyldicyclohexylamine, tetrabutylammonium hydroxide, potassium acetate, sodium acetate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, sodium carbonate, potassium carbonate, ammonium carbonate, calcium carbonate, cesium carbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, sodium phosphate, and calcium phosphate, preferably tri-n-propylamine. The alkaline solution is selected from one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, sodium phosphate, and calcium phosphate solution, preferably sodium bicarbonate solution.

2. The method of claim 1, wherein X is Br.

3. The method of any one of claims 1-2, wherein R1 is H.

4. The method of claim 1 , wherein R1 is methyl.

5. The method of any one of claims 1 to 4, wherein R2 is The molar ratio of the substrate A, Pd(t-Bu3P)2, BHT, (n-C3H7)3N, and substrate B is: 1:0.08:0.1:1.5:4.

5.

6. The method of any one of claims 1 to 4, wherein R2 is The molar ratio of the substrate A, Pd(t-Bu3P)2, BHT, (n-C3H7)3N, and substrate B is: 1:0.08:0.1:1:4.

5.

7. The method of any one of claims 1 to 6, wherein R2 is The reaction temperature of the mixed system is 90°C.

8. The method of any one of claims 1 to 6, wherein R2 is The reaction temperature of the mixed system is 115°C.

9. The method according to any one of claims 1 to 8, wherein the structure of the compound C is selected from one of the following structures:

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