3-formyl indole derivative and preparation method thereof

Abstract

The invention discloses a preparation method of a 3-formyl indole derivative, which comprises the following steps: mixing iodobenzene II, an alkyne compound III, a dinitrogen ring acetone compound IV, a palladium catalyst, a diphosphine ligand, alkali and a first solvent, and carrying out amination reaction in an inert gas atmosphere to obtain a compound I and the 3-formyl indole derivative. The benzyne compound adopted in the preparation method is simple and easy to obtain, and the substrate range is wide; an indole ring is directly constructed by adopting a one-step reaction, and formyl groups directly exist on the C3 position of the indole ring, so that compared with a traditional formylation method (firstly constructing an indole structure and then carrying out reaction on the basis of the existing indole structure), the operation is simple, side reactions are few, tandem amination can be directly carried out with iodobenzene, and the yield is high. And 3-formyl indole derivatives with diversified substituent types are synthesized.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing 3-aldehyde indole derivatives. Background Art

[0002] 3-aldehyde indole compounds are widely present in natural products and active molecules. They are also used as important synthetic intermediates in the synthesis of natural alkaloids. For example, the natural product Camalexin

[0003] [3-(2-thiazolyl)indole] is a natural indole product with anti-tumor and antibacterial activities. In its reported synthesis, 3-formyl indole is the key intermediate; therefore, the synthesis of 3-formyl indole derivatives has received great attention from a large number of chemists.

[0004] However, the synthesis methods of 3-formyl indole derivatives reported so far mainly involve the formylation reaction of the C3 position of indole. Although it provides a powerful tool for the synthesis of 3-formyl indole derivatives, it still has defects such as harsh reaction conditions or high toxicity of reaction waste. For example, the formylation reaction of the C3 position of indole reported in Chinese Chemical Letters, 2024, 35, 109280; Angewandte Chemie, International Edition, 2024, 63, e202316739 uses strong acidic reagents such as phosphorus oxychloride, which increases the difficulty of experimental operation and post-processing. Summary of the invention

[0005] In order to solve the shortcomings of the prior art, the present invention provides a method for preparing 3-formyl indole derivatives, which has simple operation, few side reactions, and high yield of direct formylation at the C3 position of indole. A series of 3-formyl indole derivatives can be directly prepared through the tandem amination reaction of alkynes and iodobenzene.

[0006] In order to solve the deficiencies of the prior art, the technical solution provided by the present invention is:

[0007] A method for preparing 3-aldehyde indole derivatives comprises the following steps:

[0008] Iodobenzene II, alkyne compound III, diazinonacyclopropanone compound IV, palladium catalyst, bisphosphine ligand, base and first solvent are mixed, and an amination reaction is carried out under an inert gas atmosphere to obtain compound I, which is a 3-formyl indole derivative. The synthesis route is shown in the following formula:

[0009]

[0010] in,

[0011] R1 represents a hydrogen atom, a methyl group, a phenyl group, a chlorine atom, a trifluoromethyl group, a methyl group or a cyano group;

[0012] R2 represents a hydrogen atom, a methyl group, a phenyl group or a methyl group;

[0013] Me is methyl.

[0014] Preferably, the preparation method of compound III is as follows:

[0015] The acetal compound V, iodobenzene VII, tetrakistriphenylphosphine palladium, cuprous iodide and triethylamine are mixed, reacted at room temperature, the solvent is dried and purified by silica gel column chromatography to generate compound VI;

[0016] Compound VI is mixed with neopentyl glycol, p-toluenesulfonic acid and toluene, and compound III is obtained after reaction. The synthesis route is shown in the following formula:

[0017]

[0018] in,

[0019] R2 represents a hydrogen atom, a methyl group, a phenyl group or a methyl group.

[0020] Preferably, the palladium catalyst is palladium trifluoroacetate, palladium chloride or palladium bromide, the bisphosphine ligand is Xantphos, dppf, DEPphos, dppp, dppe or dppm, the base is cesium carbonate, and the first solvent is 1,4-dioxane, THF or toluene.

[0021] Preferably, the molar ratio of iodobenzene II, alkyne compound III, diazirine cyclopropane compound IV, palladium catalyst, bisphosphine ligand, and base is 1:1:1.3:0.05:0.1:2.

[0022] Preferably, the concentration of iodobenzene II in the mixed solution of iodobenzene II, alkyne compound III, diazirine cyclopentane compound IV, palladium catalyst, bisphosphine ligand, base and the first solvent is 0.2 mol / L.

[0023] Preferably, the reaction temperature of the amination reaction is 85-125° C., and the reaction time is 10 to 14 hours.

[0024] Preferably, the molar ratio of compound V, iodobenzene VII, tetrakistriphenylphosphine palladium and cuprous iodide is 1:1.2:0.02:0.02.

[0025] Preferably, the molar ratio of compound VI, neopentyl glycol and p-toluenesulfonic acid is 1:1.2:0.1.

[0026] The present invention also provides a 3-aldehyde indole derivative, the structural formula of which is shown below:

[0027]

[0028] Wherein, R1 represents a hydrogen atom, a methyl group, a phenyl group, a chlorine atom, a trifluoromethyl group, a methyl group or a cyano group;

[0029] R2 represents a hydrogen atom, a methyl group, a phenyl group or a methyl group.

[0030] Beneficial effects of the present invention:

[0031] The preparation method of 3-formyl indole derivatives provided by the present invention adopts a benzyl compound that is simple and easy to obtain and has a wide range of substrates (the traditional formylation substrate can only select compounds with an indole group); and the present application adopts a one-step reaction to directly construct an indole ring and a formyl group is directly provided at the C3 position of the indole ring. Compared with the traditional formylation method (first constructing an indole structure and then reacting on the basis of the existing indole structure), the operation is simple and the side reactions are few. The derivative can be directly aminized in series with iodobenzene to synthesize 3-formyl indole derivatives with diverse substituent types.

[0032] The invention uses N,N-di-tert-butyldiazacycloketone as a nitrogen source to prepare 3-aldehyde indole derivatives containing N-tert-butyl. The N-tert-butyl is easy to remove and can be used as a protecting group in the nitrogen of aromatic amines, thus having a good protecting effect in the further derivatization reaction of 3-tert-butylamino acrylamide derivatives. DETAILED DESCRIPTION

[0033] The present invention is further described below in conjunction with the embodiments. The following embodiments are only used to more clearly illustrate the technical solution of the present invention, and cannot be used to limit the protection scope of the present invention.

[0034] The present invention provides a method for preparing a 3-aldehyde indole derivative, comprising:

[0035] 1) Preparation of compound III (benzyne derivative):

[0036] The synthetic route is as follows:

[0037]

[0038] Compound V, iodobenzene VII, tetrakistriphenylphosphine palladium, cuprous iodide and a second solvent are mixed and reacted at room temperature to obtain compound VI, and then the solvent is dried and purified by silica gel column chromatography for later use.

[0039] The purified compound VI, neopentyl glycol, p-toluenesulfonic acid and the third solvent are mixed to obtain compound III. After the reaction is completed, the solvent is dried by spin drying, ethyl acetate is added to dilute, washed with saturated NaHCO3 water, dried over anhydrous sodium sulfate, filtered, the solvent is removed under reduced pressure, and separated by a chromatographic column for later use.

[0040] Wherein, R2 represents a hydrogen atom, a methyl group, a phenyl group or a methyl group.

[0041] In an optional embodiment of the present invention, preferably, the molar ratio of the compound V, iodobenzene VII and tetrakistriphenylphosphine palladium is 1:1.2:0.02.

[0042] The molar ratio of the compound VI, neopentyl glycol and p-toluenesulfonic acid is 1:1.2:0.1.

[0043] In an optional embodiment of the present invention, the second solvent is triethylamine, and the third solvent is toluene.

[0044] 2) Preparation of compound IV (N,N-di-tert-butyldiazepine)

[0045] Tert-butylamine, triethylenediamine, di-tert-butyl dicarbonate and dichloromethane were mixed at room temperature and reacted for 12 hours to obtain N,N-di-tert-butyl urea;

[0046] N,N-di-tert-butyl urea, tert-butyl hypochlorite, potassium tert-butoxide and triethylamine are mixed in anhydrous ether, and after the reaction is completed, compound IV is obtained.

[0047] In an optional embodiment of the present invention, the molar ratio of tert-butylamine, triethylenediamine and di-tert-butyl dicarbonate is 1:0.5:0.1.

[0048] In an optional embodiment of the present invention, the molar ratio of N,N-di-tert-butyl urea, tert-butyl hypochlorite, potassium tert-butoxide, and triethylamine is 1:1.1:1.3:0.02.

[0049] 3) Preparation of Compound Ⅰ (3-aldehyde indole derivatives)

[0050] Iodobenzene II, alkyne compound III, diazirocyclopropanone compound IV, palladium catalyst, bisphosphine ligand, base and the first solvent are mixed, and an amination reaction is carried out under an inert atmosphere to obtain compound I (3-formyl indole derivative).

[0051] Isolation and purification of compound I: After the reaction is completed, ethyl acetate is added for dilution, and filtered through 300-400 mesh silica gel, eluted with ethyl acetate, the solvent is removed under reduced pressure, and separated by chromatography on a 300-400 mesh silica gel column. The column solvent is petroleum ether; the eluent is petroleum ether or a mixed solution of petroleum ether / dichloromethane, and the filler is 300-400 mesh silica gel.

[0052] The synthetic route is shown below:

[0053]

[0054] in,

[0055] R1 represents a hydrogen atom, a methyl group, a phenyl group, a chlorine atom, a trifluoromethyl group, a methyl group or a cyano group;

[0056] R2 represents a hydrogen atom, a methyl group, a phenyl group or a methyl group;

[0057] Taking R1 and R2 as hydrogen atoms, the reaction mechanism of the present invention is described:

[0058]

[0059] Iodobenzene 1 undergoes oxidative addition reaction with a Pd(0) catalyst to generate an intermediate Pd(II)2, which is then carbon-palladium-containing intermediate 3 with a benzyne derivative III, and then undergoes intramolecular carbon-hydrogen activation to generate a cyclopalladium intermediate 4. Intermediate 4 undergoes oxidative addition reaction with a three-membered ring nitrogen-containing reagent IV to generate an intermediate palladium (5), which releases tBuNCO to give a nitrene intermediate 6, which is then subjected to reductive elimination to obtain an amination product Ia and a palladium catalyst Pd(0).

[0060] In an optional embodiment of the present invention, the palladium catalyst is palladium trifluoroacetate, palladium chloride or palladium bromide, the base is cesium carbonate, the diphosphine ligand is Xantphos, dppf, DEPphos, dppp, dppe or dppm, and the first solvent is 1,4-dioxane, toluene or tetrahydrofuran (THF), preferably 1,4-dioxane.

[0061] In an optional embodiment of the present invention, the concentration of iodobenzene II in the mixed solution of iodobenzene II, alkyne compound III, diazirine cyclopropane compound IV, palladium catalyst, bisphosphine ligand, base and the first solvent is 0.2 mol / L.

[0062] In an optional embodiment of the present invention, the molar ratio of iodobenzene II, alkyne compound III, diazirine cyclopropane compound IV, palladium catalyst, bisphosphine ligand, and base is 1:1:1.3:0.05:0.1:2.

[0063] In an optional embodiment of the present invention, the reaction temperature of the amination reaction is 85-125° C. The reaction time is 10-14 h, preferably 12 h.

[0064] The present invention also provides a 3-aldehyde indole derivative, the structural formula of which is shown below:

[0065]

[0066] Wherein, R1 represents a hydrogen atom, a methyl group, a phenyl group, a chlorine atom, a trifluoromethyl group, a methyl group or a cyano group;

[0067] R2 represents a hydrogen atom, a methyl group, a phenyl group or a methyl group.

[0068] In an optional embodiment of the present invention, the 3-aldehyde indole derivative is selected from the compounds represented by the formula compounds Ⅰ-a to Ⅰ-1:

[0069]

[0070] Unless otherwise specified, the materials and reagents used in the following examples are all commercially available; among them, palladium trifluoroacetate and Xantphos are purchased from Anaiji Chemical. Note: Since the propargyl aldehyde (i.e., compound VI) required for the intermediate product III-a of Examples 1-7 can be obtained through commercial channels, Examples 1-7 can directly undergo an acetalization reaction to obtain III-a; Examples 8-12 cannot directly obtain the corresponding acetylenic aldehyde raw materials, so it is necessary to first perform a sonogashira coupling reaction of iodobenzene, and then perform an acetalization reaction to obtain the intermediate product III.

[0071] The preparation method of compound IV (N,N-di-tert-butyldiazepinone) used in the following examples is as follows:

[0072]

[0073] Add tert-butylamine (52.5mL, 500.0mmol), triethylenediamine (DABCO) (5.6g, 250.0mmol), dichloromethane (200.0mL) to the reactor, then dissolve di-tert-butyl dicarbonate (57.5mL, 50.0mmol) in dichloromethane (50.0mL), and react at room temperature for 12h. After completion, cool the reaction solution to 0℃, add 250mL of n-hexane, filter, and wash with supercooled water and ether to obtain white solid N,N-di-tert-butylurea.

[0074] Add N,N-di-tert-butylurea (20.0 g, 116.1 mmol), ether (200.0 mL) to the reactor, then add tert-butyl hypochlorite (13.9 mL, 127.7 mmol) dropwise, and finally add triethylamine (0.16 mL, 2 mmol). After stirring at room temperature for 30 minutes, cool the reaction solution to 5°C, add potassium tert-butoxide (17.0 g, 150.9 mmol) in batches, heat naturally, and react for 12 hours. Add 150 mL of n-hexane to the reaction solution, wash with water and saturated brine, dry over anhydrous sodium sulfate, filter, spin dry, and distill under reduced pressure to obtain compound IV as a colorless liquid (11.6 g, yield 59%).

[0075] NMR data of compound IV: 1 H NMR (400MHz, CDCl3): δ1.30 (s, 18H); 13 C NMR (100MHz, CDCl3): δ158.8, 59.1, 26.8.

[0076] Example 1

[0077] Preparation of Compound Ia:

[0078] 1) Preparation of compound III-a:

[0079]

[0080] In a 50mL dry round-bottom flask, p-toluenesulfonic acid (0.5166g, 3.0mmol), toluene (10mL), propargylaldehyde 7 (3.9042g, 30mmol) and neopentyl glycol (3.750g, 36mmol) were added, and the mixture was refluxed and stirred for 12h to obtain compound III-a. After the reaction, the toluene was dried, diluted with ethyl acetate, washed with saturated NaHCO3, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by reduced pressure distillation. The purified compound III-a was separated by chromatographic column to obtain 5.20g, with a yield of 80%.

[0081] NMR data of compound III-a: 1 HNMR (400MHz, CDCl3) δ7.54-7.46(m,2H),7.37-7.29(m,3H),5.54(s,1H),3.83(d,J=11.2Hz,2H),3.52(d,J=11.2Hz,2H),1.12(s,3H),0.93(s,3H); 13 CNMR (100MHz, CDCl3) δ132.0,129.0,128.3,121.6,91.0,85.6,83.6,75.5,30.5,22.7,22.3.

[0082] 2) Preparation of compound Ia:

[0083]

[0084] In a 15 mL pressure tube, compound III-a (0.1081 g, 0.5 mmol), palladium trifluoroacetate (0.0083 g, 0.025 mmol), Xantphos (0.0289 g, 0.05 mmol), and cesium carbonate (0.3258 g, 1.0 mmol) were added in sequence, and the tube was evacuated and filled with nitrogen. Then, ultra-dry 1,4-dioxane (2.5 mL), iodobenzene (0.1020 g, 0.5 mmol) and N,N-di-tert-butyldiazacyclopentane (0.1107 g, 0.65 mmol) were added in sequence. The tube was sealed and placed in a magnetic heating stirrer at 100 ° C. and stirred for 12 hours to obtain compound Ia.

[0085] Isolation and purification: After the reaction, compound Ia was cooled to room temperature, diluted with ethyl acetate, filtered through 300-400 mesh silica gel, eluted with ethyl acetate, the solvent was removed under reduced pressure, and separated by 300-400 mesh silica gel column chromatography (eluent: petroleum ether) to obtain a light yellow solid purified compound Ia (0.1308 g, yield 68%).

[0086] NMR data of compound Ia: 1 HNMR(400MHz, CDCl3)δ8.18(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),7.49-7.38(m,5H),7.22-7.14(m,2 H),4.93(s,1H),3.71(d,J=10.4Hz,2H),3.39(d,J=11.2Hz,2H),1.57(s,9H),1.45(s,3H),0.72(s,3H); 13 C NMR (100MHz, CDCl3) δ139.4,136.7,135.7,131.3,128.1,127.4,126.5,121 .2,121.16,119.8,114.9,113.2,99.9,78.0,59.1,32.0,30.1,23.5,22.0.

[0087] Example 2

[0088] Preparation of Compound Ib:

[0089] 1) Preparation of compound III-a:

[0090]

[0091] In a 50mL dry round-bottom flask, p-toluenesulfonic acid (0.5166g, 3.0mmol), toluene (10mL), propargylaldehyde 7 (3.9042g, 30mmol) and neopentyl glycol (3.750g, 36mmol) were added, and the mixture was refluxed and stirred for 12h to obtain compound III-a. After the reaction, the toluene was dried, diluted with ethyl acetate, washed with saturated NaHCO3, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by reduced pressure distillation. The purified compound III-a was separated by chromatographic column to obtain 5.20g, with a yield of 80%.

[0092] NMR data of compound III-a: 1HNMR (400MHz, CDCl3) δ7.54-7.46(m,2H),7.37-7.29(m,3H),5.54(s,1H),3.83(d,J=11.2Hz,2H),3.52(d,J=11.2Hz,2H),1.12(s,3H),0.93(s,3H); 13 CNMR (100MHz, CDCl3) δ132.0,129.0,128.3,121.6,91.0,85.6,83.6,75.5,30.5,22.7,22.3.

[0093] 2) Preparation of compound Ib:

[0094]

[0095] In a 15 mL pressure tube, compound III-a (0.1081 g, 0.5 mmol), palladium trifluoroacetate (0.0083 g, 0.025 mmol), Xantphos (0.0289 g, 0.05 mmol), and cesium carbonate (0.3258 g, 1.0 mmol) were added in sequence, and the tube was evacuated and filled with nitrogen. Then, ultra-dry 1,4-dioxane (2.5 mL), p-methyl iodobenzene (0.1090 g, 0.5 mmol) and N,N-di-tert-butyldiazacyclopentane (0.1107 g, 0.65 mmol) were added in sequence. The tube was sealed and placed in a magnetic heating stirrer at 100 ° C. and stirred for 12 hours to obtain compound Ib.

[0096] Isolation and purification: After the reaction, compound Ib was cooled to room temperature, diluted with ethyl acetate, filtered through 300-400 mesh silica gel, eluted with ethyl acetate, the solvent was removed under reduced pressure, and separated by 300-400 mesh silica gel column chromatography (eluent: petroleum ether) to obtain a light yellow solid purified compound Ib (0.1093 g, yield 58%).

[0097] NMR data of compound Ib: 1 HNMR (400MHz, CDCl3) δ8.00(d,J=8.4Hz,1H),7.46(s,1H),7.44-7.33(m,5H),6.97(d,J=8.0Hz,1H),4.97(s,1H),3.67(d,J=11.2Hz,2H),3.34(d,J=

[0098] 10.8Hz,2H),2.49(s,3H),1.53(s,9H),1.40(s,3H),0.69(s,3H); 13C NMR (100MHz, CDCl3) δ138.8,137.3,136.0,131.4,130.6,128.0,127.4,124.4 ,121.6,120.8,114.9,113.2,100.0,78.0,59.0,32.1,30.2,23.6,22.5,22.0.

[0099] Example 3

[0100] Preparation of compound Ic:

[0101] 1) Preparation of compound III-a:

[0102]

[0103] In a 50mL dry round-bottom flask, p-toluenesulfonic acid (0.5166g, 3.0mmol), toluene (10mL), propargylaldehyde 7 (3.9042g, 30mmol) and neopentyl glycol (3.750g, 36mmol) were added, and the mixture was refluxed and stirred for 12h to obtain compound III-a. After the reaction, the toluene was dried, diluted with ethyl acetate, washed with saturated NaHCO3, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by reduced pressure distillation. The purified compound III-a was separated by chromatographic column to obtain 5.20g, with a yield of 80%.

[0104] NMR data of compound III-a: 1 HNMR (400MHz, CDCl3) δ7.54-7.46(m,2H),7.37-7.29(m,3H),5.54(s,1H),3.83(d,J=11.2Hz,2H),3.52(d,J=11.2Hz,2H),1.12(s,3H),0.93(s,3H); 13 CNMR (100MHz, CDCl3) δ132.0,129.0,128.3,121.6,91.0,85.6,83.6,75.5,30.5,22.7,22.3.

[0105] 2) Preparation of compound Ic:

[0106]

[0107] In a 15 mL pressure tube, compound III-a (0.1081 g, 0.5 mmol), palladium trifluoroacetate (0.0083 g, 0.025 mmol), Xantphos (0.0289 g, 0.05 mmol), and cesium carbonate (0.3258 g, 1.0 mmol) were added in sequence, and the tube was evacuated and filled with nitrogen. Then, ultra-dry 1,4-dioxane (2.5 mL), p-phenyliodobenzene (0.1041 g, 0.5 mmol) and N,N-di-tert-butyldiazacyclopentane (0.1107 g, 0.65 mmol) were added in sequence. The tube was sealed and placed in a magnetic heating stirrer at 100 ° C and stirred for 12 hours to obtain compound Ic.

[0108] Isolation and purification: After the reaction, compound Ic was cooled to room temperature, diluted with ethyl acetate, filtered through 300-400 mesh silica gel, eluted with ethyl acetate, the solvent was removed under reduced pressure, and separated by 300-400 mesh silica gel column chromatography (eluent: petroleum ether) to obtain a light yellow solid purified compound Ic (0.1121 g, yield 51%).

[0109] NMR data of compound Ic: 1 HNMR (400MHz, CDCl3) δ8.20(d,J=8.0Hz,1H),7.88(s,1H),7.68(d,J=8.0Hz,2H),7.49-7.40(m,8H),7.36-7.3 2(m,1H),4.92(s,1H),3.71(d,J=11.6Hz,2H),3.38(d,J=11.2Hz,2H),1.60(s,9H),1.45(s,3H),0.72(s,3H); 13 C NMR (100MHz, CDCl3) δ143.4,140.1,137.3,135.7,134.7,131.3,128.8,128.2,127.7,12 7.5,126.5,125.9,121.3,119.9,113.8,113.3,99.8,78.0,59.3,32.2,30.2,23.6,22.0.

[0110] Example 4

[0111] Preparation of Compound Id:

[0112] 1) Preparation of compound III-a:

[0113]

[0114] In a 50mL dry round-bottom flask, p-toluenesulfonic acid (0.5166g, 3.0mmol, toluene (10mL), propargylaldehyde 7 (3.9042g, 30mmol) and neopentyl glycol (3.750g, 36mmol) were added, and the mixture was refluxed and stirred for 12h to obtain compound III-a. After the reaction, the toluene was dried, diluted with ethyl acetate, washed with saturated NaHCO3, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by reduced pressure distillation. The purified compound III-a 5.20g was separated by chromatographic column, and the yield was 80%.

[0115] NMR data of compound III-a: 1 HNMR (400MHz, CDCl3) δ7.54-7.46(m,2H),7.37-7.29(m,3H),5.54(s,1H),3.83(d,J=11.2Hz,2H),3.52(d,J=11.2Hz,2H),1.12(s,3H),0.93(s,3H); 13 CNMR (100MHz, CDCl3) δ132.0,129.0,128.3,121.6,91.0,85.6,83.6,75.5,30.5,22.7,22.3.

[0116] 2) Preparation of compound Id:

[0117]

[0118] In a 15 mL pressure tube, compound III-a (0.1081 g, 0.5 mmol), palladium trifluoroacetate (0.0083 g, 0.025 mmol), Xantphos (0.0289 g, 0.05 mmol), and cesium carbonate (0.3258 g, 1.0 mmol) were added in sequence, and the tube was evacuated and filled with nitrogen. Then, ultra-dry 1,4-dioxane (2.5 mL), p-chloroiodobenzene (0.1192 g, 0.5 mmol) and N,N-di-tert-butyldiazacyclopentane (0.1107 g, 0.65 mmol) were added in sequence. The tube was sealed and placed in a magnetic heating stirrer at 100 ° C. and stirred for 12 hours to obtain compound Id.

[0119] Isolation and purification: After the reaction, compound Id was cooled to room temperature, diluted with ethyl acetate, filtered through 300-400 mesh silica gel, eluted with ethyl acetate, and the solvent was removed under reduced pressure. The product was separated by 300-400 mesh silica gel column chromatography (eluent: petroleum ether) to obtain a light yellow solid purified compound Id (0.1103 g, yield 55%).

[0120] NMR data of compound Id: 1HNMR(400MHz, CDCl3)δ8.05(d,J=8.4Hz,1H),7.67(d,J=2.0Hz,1H),7.44-7.37(m,5H),7.12(dd,J=8.8,2.0 Hz,1H),4.86(s,1H),3.68(d,J=11.6Hz,2H),3.35(d,J=12.0Hz,2H),1.52(s,9H),1.40(s,3H),0.70(s,3H); 13 C NMR (100MHz, CDCl3) δ140.3,137.1,135.2,131.2,128.4,127.6,127.1,12 5.0,122.0,120.5,114.7,113.4,99.6,78.0,59.5,32.0,30.2,23.6,22.0.

[0121] Example 5

[0122] Preparation of Compound Ie:

[0123] 1) Preparation of compound III-a:

[0124]

[0125] In a 50mL dry round-bottom flask, p-toluenesulfonic acid (0.5166g, 3.0mmol), toluene (10mL), propargylaldehyde 7 (3.9042g, 30mmol) and neopentyl glycol (3.750g, 36mmol) were added, and the mixture was refluxed and stirred for 12h to obtain compound III-a. After the reaction, the toluene was dried, diluted with ethyl acetate, washed with saturated NaHCO3, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by reduced pressure distillation. The purified compound III-a was separated by chromatographic column to obtain 5.20g, with a yield of 80%.

[0126] NMR data of compound III-a: 1 HNMR (400MHz, CDCl3) δ7.54-7.46(m,2H),7.37-7.29(m,3H),5.54(s,1H),3.83(d,J=11.2Hz,2H),3.52(d,J=11.2Hz,2H),1.12(s,3H),0.93(s,3H); 13 CNMR (100MHz, CDCl3) δ132.0,129.0,128.3,121.6,91.0,85.6,83.6,75.5,30.5,22.7,22.3.

[0127] 2) Preparation of Compound Ie:

[0128]

[0129] In a 15 mL pressure tube, compound III-a (0.1081 g, 0.5 mmol), palladium trifluoroacetate (0.0083 g, 0.025 mmol), Xantphos (0.0289 g, 0.05 mmol), and cesium carbonate (0.3258 g, 1.0 mmol) were added in sequence, and the tube was evacuated and filled with nitrogen. Then, ultra-dry 1,4-dioxane (2.5 mL), p-trifluoromethyl iodobenzene (0.1360 g, 0.5 mmol) and N,N-di-tert-butyldiazacyclopentane (0.1107 g, 0.65 mmol) were added in sequence. The tube was sealed and placed in a magnetic heating stirrer at 100 ° C. and stirred for 12 hours to obtain compound Ie.

[0130] Isolation and purification: After the reaction, compound Ie was cooled to room temperature, diluted with ethyl acetate, filtered through 300-400 mesh silica gel, eluted with ethyl acetate, the solvent was removed under reduced pressure, and separated by 300-400 mesh silica gel column chromatography (eluent: petroleum ether) to obtain a light yellow solid purified compound Ie (0.1072 g, yield 50%).

[0131] NMR data of compound Ie: 1 HNMR (400MHz, CDCl3) δ8.24 (d, J = 8.4Hz, 1H), 7.97 (s, 1H), 7.47-7.39 (m, 6H), 4.90 (s, 1H) ),3.70(d,J=11.6Hz,2H),3.37(d,J=12.0Hz,2H),1.57(s,9H),1.42(s,3H),0.71(s,3H); 13 C NMR (100MHz, CDCl3) δ142.2, 135.6, 134.9, 131.1, 128.8, 128.6, 125.6 (q, J = 270.0Hz), 123.1 (q, J = 31. 2Hz), 121.6, 116.6 (q, J = 3.6Hz), 113.7, 112.1 (q, J = 4.7Hz), 99.5, 78.0, 59.8, 32.2, 30.2, 23.5, 22.0.

[0132] Example 6

[0133] Preparation of Compound If:

[0134] 1) Preparation of compound III-a:

[0135]

[0136] In a 50mL dry round-bottom flask, p-toluenesulfonic acid (0.5166g, 3.0mmol), toluene (10mL), propargylaldehyde 7 (3.9042g, 30mmol) and neopentyl glycol (3.750g, 36mmol) were added, and the mixture was refluxed and stirred for 12h to obtain compound III-a. After the reaction, the toluene was dried, diluted with ethyl acetate, washed with saturated NaHCO3, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by reduced pressure distillation. The purified compound III-a was separated by chromatographic column to obtain 5.20g, with a yield of 80%.

[0137] NMR data of compound III-a: 1 HNMR (400MHz, CDCl3) δ7.54-7.46(m,2H),7.37-7.29(m,3H),5.54(s,1H),3.83(d,J=11.2Hz,2H),3.52(d,J=11.2Hz,2H),1.12(s,3H),0.93(s,3H); 13 CNMR (100MHz, CDCl3) δ132.0,129.0,128.3,121.6,91.0,85.6,83.6,75.5,30.5,22.7,22.3.

[0138] 2) Preparation of compound If:

[0139]

[0140] In a 15 mL pressure tube, compound III-a (0.1081 g, 0.5 mmol), palladium trifluoroacetate (0.0083 g, 0.025 mmol), Xantphos (0.0289 g, 0.05 mmol), and cesium carbonate (0.3258 g, 1.0 mmol) were added in sequence, and the mixture was evacuated and filled with nitrogen. Then, ultra-dry 1,4-dioxane (2.5 mL), methyl iodobenzene (0.1310 g, 0.5 mmol) and N,N-di-tert-butyldiazacyclopentane (0.1107 g, 0.65 mmol) were added in sequence. The tube was sealed and placed in a magnetic heating stirrer at 100 ° C and stirred for 12 hours to obtain compound If.

[0141] Isolation and purification: After the reaction, the compound If was cooled to room temperature, diluted with ethyl acetate, filtered through 300-400 mesh silica gel, eluted with ethyl acetate, and the solvent was removed under reduced pressure. The compound was separated by 300-400 mesh silica gel column chromatography (eluent: petroleum ether) to obtain a light yellow solid purified compound If (0.1216 g, yield 59%).

[0142] NMR data of compound If: 1H NMR (400MHz, CDCl3) δ8.49 (s, 1H), 8.16 (d, J = 8.4Hz, 1H), 7.85 (dd, J = 8.4, 1.2Hz, 1H), 7.46-7.39 (m, 5H), 4.8 9(s,1H),3.95(s,3H),3.69(d,J=11.6Hz,2H),3.36(d,J=10.8Hz,2H),1.58(s,9H),1.41(s,3H),0.70(s,3H); 13 C NMR (100MHz, CDCl3) δ168.6,142.8,136.0,135.0,131.0,130.1,128.5,127.6,12 2.6,120.9,120.7,117.2,113.6,99.5,78.0,59.8,52.0,32.2,30.1,23.5,21.9.

[0143] Example 7

[0144] Preparation of Compound Ig:

[0145] 1) Preparation of compound III-a:

[0146]

[0147] In a 50mL dry round-bottom flask, p-toluenesulfonic acid (0.5166g, 3.0mmol), toluene (10mL), propargylaldehyde 7 (3.9042g, 30mmol) and neopentyl glycol (3.750g, 36mmol) were added, and the mixture was refluxed and stirred for 12h to obtain compound III-a. After the reaction, the toluene was dried, diluted with ethyl acetate, washed with saturated NaHCO3, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The purified compound III-a 5.20g was separated by chromatographic column, and the yield was 80%.

[0148] NMR data of compound III-a: 1 HNMR (400MHz, CDCl3) δ7.54-7.46(m,2H),7.37-7.29(m,3H),5.54(s,1H),3.83(d,J=11.2Hz,2H),3.52(d,J=11.2Hz,2H),1.12(s,3H),0.93(s,3H); 13 CNMR (100MHz, CDCl3) δ132.0,129.0,128.3,121.6,91.0,85.6,83.6,75.5,30.5,22.7,22.3.

[0149] 2) Preparation of Compound Ig:

[0150]

[0151] In a 15 mL pressure tube, compound III-a (0.1081 g, 0.5 mmol), palladium trifluoroacetate (0.0083 g, 0.025 mmol), Xantphos (0.0289 g, 0.05 mmol), and cesium carbonate (0.3258 g, 1.0 mmol) were added in sequence, and the tube was evacuated and filled with nitrogen. Then, ultra-dry 1,4-dioxane (2.5 mL), p-cyaniodobenzene (0.1145 g, 0.5 mmol) and N,N-di-tert-butyldiazacyclopentane (0.1107 g, 0.65 mmol) were added in sequence. The tube was sealed and placed in a magnetic heating stirrer at 100 ° C. and stirred for 12 hours to obtain compound Ig.

[0152] Isolation and purification: After the reaction, compound Ig was cooled to room temperature, diluted with ethyl acetate, filtered through 300-400 mesh silica gel, eluted with ethyl acetate, the solvent was removed under reduced pressure, and separated by 300-400 mesh silica gel column chromatography (eluent: petroleum ether) to obtain a light yellow solid purified compound Ig (0.0874 g, yield 45%).

[0153] NMR data of compound Ig: 1 HNMR (400MHz, CDCl3) δ8.21 (d, J = 8.0Hz, 1H), 8.03 (s, 1H), 7.47-7.37 (m, 6H), 4.87 (s, 1H) ),3.68(d,J=11.2Hz,1H),3.35(d,J=11.2Hz,2H),1.55(s,9H),1.40(s,3H),0.71(s,3H); 13 C NMR (100MHz, CDCl3) δ143.4,135.4,134.4,130.9,129.7,128.9,127.8,122.7 ,122.1,121.4,119.6,114.2,103.7,99.3,78.0,60.2,32.2,30.2,23.5,21.9.

[0154] Example 8

[0155] Preparation of compound Ih:

[0156] 1) Preparation of compound III-h:

[0157]

[0158] In a 100mL dry round-bottom flask, (PPh3)2PdCl2 (0.2106g, 0.3mmol), CuI (0.0571g, 0.3mmol), triethylamine (55mL), acetal V (1.922g, 15mmol) and p-methyl iodobenzene IIb (3.925g, 18mmol) were added, and the mixture was stirred at room temperature for 1-2h to obtain compound VI-h. After the reaction, triethylamine was dried, diluted with dichloromethane, washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel chromatography to obtain 3.10g of purified compound VI-h with a yield of 95%.

[0159] 50 mL of neopentyl glycol (1.25 g, 12 mmol) and TsOH (0.1722 g, 1.0 mmol) were added, and after nitrogen was replaced, toluene (5 mL) and compound VI-h (2.18 g, 10 mmol) were added, and refluxed for 4 h to obtain compound III-h. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 1.70 g of purified compound III-h, with a yield of 74%.

[0160] NMR data of compound III-h: 1 H NMR (400MHz, CDCl3) δ7.42~7.36(m,2H),7.12(d,J=8Hz,2H),5.53(s,1H),3.8 3(d,J=12Hz,2H),3.51(d,J=12Hz,2H),2.34(s,3H),1.11(s,3H),0.92(s,3H); 13 C NMR (400MHz, CDCl3) δ139.3,132.0,129.2,118.6,91.2,85.9,83.0,75.7,30.6,22.9,22.4,21.7.

[0161] 2) Preparation of compound Ih:

[0162]

[0163] In a 15 mL pressure tube, compound III-h (0.1152 g, 0.5 mmol), palladium trifluoroacetate (0.0083 g, 0.025 mmol), Xantphos (0.0289 g, 0.05 mmol), and cesium carbonate (0.3258 g, 1.0 mmol) were added in sequence, the tube was evacuated and filled with nitrogen, and then ultra-dry 1,4-dioxane (2.5 mL), iodobenzene (0.1020 g, 0.5 mmol) and N,N-di-tert-butyldiazacyclopentane (0.1107 g, 0.65 mmol) were added in sequence. The tube was sealed and placed in a magnetic heating stirrer at 100 ° C. and stirred for 12 hours to obtain compound Ih.

[0164] Isolation and purification: After the reaction, compound Ih was cooled to room temperature, diluted with ethyl acetate, filtered through 300-400 mesh silica gel, eluted with ethyl acetate, the solvent was removed under reduced pressure, and separated by 300-400 mesh silica gel column chromatography (eluent: petroleum ether) to obtain a light yellow solid purified compound Ih (0.1201 g, yield 64%).

[0165] NMR data of compound Ih: 1 H NMR (400MHz, CDCl3) δ8.14(dd,J=7.2,2.0Hz,1H),7.67(dd,J=7.2,2.0Hz,1H),7.29(d,J=8.0Hz,2H),7.20-7.11(m,4 H),4.92(s,1H),3.79(d,J=11.2Hz,2H),3.38(d,J=10.8Hz,2H),2.44(s,3H),1.54(s,9H),1.43(s,3H),0.71(s,3H); 13 C NMR (100MHz, CDCl3) δ139.7,137.9,136.8,132.7,131.1,128.2,126.5,121.2 ,121.1,119.7,114.9,113.1,100.0,78.0,59.1,32.1,30.2,23.6,22.0,21.6.

[0166] Example 9

[0167] Preparation of Compound Ii:

[0168] 1) Preparation of compound III-i:

[0169]

[0170] In a 100mL dry round-bottom flask, add (PPh3)2PdCl2 (0.2106g, 0.3mmol), CuI (0.0571g, 0.3mmol), then add triethylamine (55mL), acetal V (1.922g, 15mmol) and p-phenyliodobenzene IIc (5.042g, 18mmol), and stir at room temperature for 1-2h to obtain compound VI-i. After the reaction is completed, spin-dry triethylamine, dilute with dichloromethane, wash with saturated NaCl, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify by silica gel chromatography to obtain 4.00g of purified compound VI-i, with a yield of 95%.

[0171] 50 mL of neopentyl glycol (1.25 g, 12 mmol) and TsOH (0.1722 g, 1.0 mmol) were added, and after nitrogen was replaced, toluene (5 mL) and compound Ⅵ-i (2.804 g, 10 mmol) were added, and refluxed for 4 h to obtain compound III-i. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2.20 g of purified compound III-i, with a yield of 75%.

[0172] NMR data of compound III-i: 1 HNMR(400MHz, CDCl3)δ7.62-7.53(m,6H),7.48-7.41(m,2H),7.39-7.34(m,1H),5.5 7(s,1H),3.85(d,J=11.2Hz,2H),3.53(d,J=11.2Hz,2H),1.13(s,3H),0.94(s,3H); 13 C NMR (400MHz, CDCl3) δ141.9,140.3,132.6,129.0,127.9,127.2,127.1,120.6,91.2,85.6,84.2,75.7,30.6,22.9,22.4.

[0173] 2) Preparation of compound Ii:

[0174]

[0175] In a 15 mL pressure tube, compound III-i (0.1462 g, 0.5 mmol), palladium trifluoroacetate (0.0083 g, 0.025 mmol), Xantphos (0.0289 g, 0.05 mmol), and cesium carbonate (0.3258 g, 1.0 mmol) were added in sequence, and the tube was evacuated and filled with nitrogen. Then, ultra-dry 1,4-dioxane (2.5 mL), iodobenzene (0.1020 g, 0.5 mmol) and N,N-di-tert-butyldiazacyclopentane (0.1107 g, 0.65 mmol) were added in sequence. The tube was sealed and placed in a magnetic heating stirrer at 100 ° C. and stirred for 12 hours to obtain compound Ii.

[0176] Isolation and purification: After the reaction, compound Ii was cooled to room temperature, diluted with ethyl acetate, filtered through 300-400 mesh silica gel, eluted with ethyl acetate, the solvent was removed under reduced pressure, and separated by 300-400 mesh silica gel column chromatography (eluent: petroleum ether) to obtain a light yellow solid purified compound Ii (0.1526 g, yield 69%).

[0177] NMR data of compound Ii: 1 H NMR (400MHz, CDCl3) δ8.21-8.13(m,1H),7.75-7.68(m,3H),7.65(d,J=8.4Hz,2H),7.53-7.45(m,4H),7.42-7.37(m,1H) ,7.21-7.13(m,2H),4.98(s,1H),3.70(d,J=11.2Hz,2H),3.40(d,J=11.2Hz,2H),1.59(s,9H),1.43(s,3H),0.71(s,3H); 13 CNMR (100MHz, CDCl3) δ140.7,140.5,139.1,136.9,134.8,131.7,129.0,127.7,127.1,12 6.6,126.0,121.3,121.26,119.9,114.9,113.4,99.9,78.0,59.2,32.2,30.2,23.6,22.0.

[0178] Example 10

[0179] Preparation of Compound Ij:

[0180] 1) Preparation of compound III-j:

[0181]

[0182] In a 100mL dry round-bottom flask, add (PPh3)2PdCl2 (0.2106g, 0.3mmol), CuI (0.0571g, 0.3mmol), then add triethylamine (55mL), acetal V (1.922g, 15mmol) and methyl iodobenzene IIf (4.720g, 18mmol), and stir at room temperature for 1-2h to obtain compound VI-j. After the reaction is completed, spin-dry triethylamine, dilute with dichloromethane, wash with saturated NaCl, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify by silica gel chromatography to obtain 3.80g of purified compound VI-j, with a yield of 97%.

[0183] 50 mL of neopentyl glycol (1.25 g, 12 mmol) and TsOH (0.1722 g, 1.0 mmol) were added, and after nitrogen was replaced, toluene (5 mL) and compound Ⅵ-j (2.623 g, 10 mmol) were added, and refluxed for 4 h to obtain compound III-j. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 1.50 g of purified compound III-j, with a yield of 55%.

[0184] NMR data of compound III-j: 1 H NMR(400MHz, CDCl3) δ7.99(d,J=8.4Hz,2H),7.55(d,J=8.8Hz,2H),5.55(s,1H),3.9 1(s,3H),3.82(d,J=11.6Hz,2H),3.52(d,J=11.2Hz,2H),1.11(s,3H),0.93(s,3H); 13 C NMR (400MHz, CDCl3) δ166.5,132.1,130.4,129.6,126.3,90.9,86.4,84.7,52.4,30.6,22.8,22.4.

[0185] 2) Preparation of compound Ij:

[0186]

[0187] In a 15 mL pressure tube, compound III-j (0.1372 g, 0.5 mmol), palladium trifluoroacetate (0.0083 g, 0.025 mmol), Xantphos (0.0289 g, 0.05 mmol), and cesium carbonate (0.3258 g, 1.0 mmol) were added in sequence, the tube was evacuated and filled with nitrogen, and then ultra-dry 1,4-dioxane (2.5 mL), iodobenzene (0.1020 g, 0.5 mmol) and N,N-di-tert-butyldiazacyclopentane (0.1107 g, 0.65 mmol) were added in sequence. The tube was sealed and placed in a magnetic heating stirrer at 100 ° C. and stirred for 12 hours to obtain compound Ij.

[0188] Isolation and purification: After the reaction, compound Ij was cooled to room temperature, diluted with ethyl acetate, filtered through 300-400 mesh silica gel, eluted with ethyl acetate, and the solvent was removed under reduced pressure. The product was separated by 300-400 mesh silica gel column chromatography (eluent: petroleum ether) to obtain a light yellow solid purified compound Ij (0.1536 g, yield 73%).

[0189] NMR data of compound Ij: 1 H NMR (400MHz, CDCl3) δ8.15(d,J=8.0Hz,1H),8.08(d,J=8.0Hz,2H),7.69(d,J=8.0Hz,1H),7.52(d,J=8.0Hz,2H),7.23-7.1 2(m,2H),4.86(s,1H),3.97(s,3H),3.68(d,J=11.2Hz,2H),3.35(d,J=10.8Hz,2H),1.55(s,9H),1.41(s,3H),0.70(s,3H); 13 C NMR (100MHz, CDCl3) δ167.0,140.8,138.0,137.0,131.3,129.9,128.7,126.5,12 1.6,121.4,120.1,114.9,113.6,99.6,78.0,59.3,52.4,32.1,30.2,23.5,22.0.

[0190] Embodiment 11

[0191] Preparation of Compound Ik:

[0192] 1) Preparation of compound III-k:

[0193]

[0194] In a 100mL dry round-bottom flask, add (PPh3)2PdCl2 (0.2106g, 0.3mmol), CuI (0.0571g, 0.3mmol), then add triethylamine (55mL), acetal V (1.922g, 15mmol) and m-phenyliodobenzene IIk (5.04g, 18mmol), and stir at room temperature for 1-2h to obtain compound VI-k. After the reaction is completed, spin-dry triethylamine, dilute with dichloromethane, wash with saturated NaCl, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify by silica gel chromatography to obtain 3.90g of purified compound VI-k, with a yield of 93%.

[0195] 50 mL of neopentyl glycol (1.25 g, 12 mmol) and TsOH (0.1722 g, 1.0 mmol) were added, and after nitrogen was replaced, toluene (5 mL) and compound Ⅵ-k (2.804 g, 10 mmol) were added, and refluxed for 4 h to obtain compound III-k. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 0.90 g of purified compound III-k, with a yield of 31%.

[0196] NMR data of compound III-k: 1 H NMR (400MHz, CDCl3) δ7.76 (t, J = 1.6Hz, 1H), 7.61-7.55 (m, 3H), 7.51-7.34 (m, 5H), 5. 58(s,1H),3.86(d,J=11.6Hz,2H),3.54(d,J=11.2Hz,2H),1.14(s,3H),0.94(s,3H); 13 C NMR (400MHz, CDCl3) δ141.4,140.1,130.77,130.75,128.9,128.85,127.9,127.8,127.1,122.1,91.0,85.6,83.7,75.7,30.6,22.8,22.3.

[0197] 2) Preparation of compound Ik:

[0198]

[0199] In a 15 mL pressure tube, compound III-k (0.1462 g, 0.5 mmol), palladium trifluoroacetate (0.0083 g, 0.025 mmol), Xantphos (0.0289 g, 0.05 mmol), and cesium carbonate (0.3258 g, 1.0 mmol) were added in sequence, the tube was evacuated and filled with nitrogen, and then ultra-dry 1,4-dioxane (2.5 mL), iodobenzene (0.1020 g, 0.5 mmol) and N,N-di-tert-butyldiazacyclopentane (0.1107 g, 0.65 mmol) were added in sequence. The tube was sealed and placed in a magnetic heating stirrer at 100 ° C. and stirred for 12 hours to obtain compound Ik.

[0200] Isolation and purification: After the reaction, compound Ik was cooled to room temperature, diluted with ethyl acetate, filtered through 300-400 mesh silica gel, eluted with ethyl acetate, and the solvent was removed under reduced pressure. The product was separated by 300-400 mesh silica gel column chromatography (eluent: petroleum ether) to obtain a light yellow solid purified compound Ik (0.1278 g, yield 58%).

[0201] NMR data of compound Ik: 1 HNMR (400MHz, CDCl3) δ8.18 (d, J = 7.6Hz, 1H), 7.74-7.65 (m, 5H), 7.51-7.45 (m, 3H), 7.44-7.36 (m, 2H), 7.23-7. 14(m,2H),4.99(s,1H),7.44(d,J=10.8Hz,2H),3.40(d,J=11.2Hz,2H),1.59(s,9H),1.44(s,3H),0.71(s,3H); 13 C NMR (100MHz, CDCl3) δ140.5,140.1,139.3,136.8,136.3,130.2,129.9,129.0,127.9,127.7,127.1 ,126.8,126.5,121.3,121.2,119.9,114.9,113.3,99.9,78.0,77.9,59.2,32.1,30.2,23.6,22.0.

[0202] Example 12

[0203] Preparation of compound I1:

[0204] 1) Preparation of compound III-1:

[0205]

[0206] In a 100mL dry round-bottom flask, (PPh3)2PdCl2 (0.2106g, 0.3mmol), CuI (0.0571g, 0.3mmol), triethylamine (55mL), acetal V (1.922g, 15mmol) and o-methyl iodobenzene IIl (3.920g, 18mmol) were added, and the mixture was stirred at room temperature for 1-2h to obtain compound VI-1. After the reaction, triethylamine was dried, diluted with dichloromethane, washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel chromatography to obtain 2.30g of purified compound VI-1 with a yield of 70%.

[0207] 50 mL of neopentyl glycol (1.25 g, 12 mmol) and TsOH (0.1722 g, 1.0 mmol) were added, and after nitrogen was replaced, toluene (5 mL) and compound Ⅵ-1 (2.183 g, 10 mmol) were added, and refluxed for 4 h to obtain compound III-1. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 1.70 g of purified compound III-1, with a yield of 78%.

[0208] NMR data of compound III-1: 1 H NMR (400MHz, CDCl3) δ7.46 (d, J=7.6Hz, 1H), 7.26-7.17 (m, 2H), 7.13 (td, J=7.2, 1.6Hz, 1H), 5.6 2(s,1H),3.86(d,J=10.8Hz,2H),3.50(d,J=10.8Hz,2H),2.47(s,3H),1.07(s,3H),0.96(s,3H); 13 C NMR (400MHz, CDCl3) δ140.5,132.3,129.4,128.9,125.5,121.4,90.7,87.4,84.6,75.0,30.4,22.7,22.4,20.7,15.2.

[0209] 2) Preparation of compound I1:

[0210]

[0211] In a 15 mL pressure tube, compound III-1 (0.1152 g, 0.5 mmol), palladium trifluoroacetate (0.0083 g, 0.025 mmol), Xantphos (0.0289 g, 0.05 mmol), and cesium carbonate (0.3258 g, 1.0 mmol) were added in sequence, the tube was evacuated and filled with nitrogen, and then ultra-dry 1,4-dioxane (2.5 mL), iodobenzene (0.1020 g, 0.5 mmol) and N,N-di-tert-butyldiazacyclopentane (0.1107 g, 0.65 mmol) were added in sequence. The tube was sealed and placed in a magnetic heating stirrer at 100 ° C. and stirred for 12 hours to obtain compound Il.

[0212] Isolation and purification: After the reaction, compound Il was cooled to room temperature, diluted with ethyl acetate, filtered through 300-400 mesh silica gel, eluted with ethyl acetate, the solvent was removed under reduced pressure, and separated by 300-400 mesh silica gel column chromatography (eluent: petroleum ether) to obtain a light yellow solid purified compound Il (0.1135 g, yield 60%).

[0213] NMR data of compound I1: 1 H NMR (400MHz, CDCl3)δ 1 HNMR(400MHz, CDCl3)δ8.15(d,J=7.2Hz,1H),7.69(d,J=7.2,2.0Hz,1H),7.36-7.29(m,2H),7.26-7.13(m,4H),4 .82(s,1H),3.68(d,J=11.6Hz,1H),3.34(d,J=10.8Hz,2H),2.16(s,3H),1.53(s,9H),1.42(s,3H),0.69(s,3H); 13 C NMR (100MHz, CDCl3) δ138.7,138.3,136.6,135.5,131.7,129.5,128.6,126.7,125.0,12 1.1,121.0,119.8,114.8,112.3,99.8,78.09,78.05,58.9,31.3,30.2,23.6,22.0,20.4.

[0214] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing 3-formyl indole derivatives, characterized in that: The steps include: Iodobenzene II, alkyne compound III, diazinonacyclopropanone compound IV, palladium catalyst, bisphosphine ligand, base and first solvent are mixed, and an amination reaction is carried out under an inert gas atmosphere to obtain indole compound I. Compound I is a 3-formyl indole derivative. The synthesis route is shown in the following formula: in, R1 represents a hydrogen atom, a methyl group, a phenyl group, a chlorine atom, a trifluoromethyl group, a methyl group or a cyano group; R2 represents a hydrogen atom, a methyl group, a phenyl group or a methyl group.

2. The method for preparing 3-aldehyde indole derivatives according to claim 1, characterized in that: The preparation method of the alkyne compound III is as follows: The acetal compound V, iodobenzene VII, tetrakistriphenylphosphine palladium, cuprous iodide and triethylamine are mixed, reacted at room temperature, the solvent is dried and separated and purified to generate compound VI; Compound VI, neopentyl glycol, p-toluenesulfonic acid and toluene are mixed and reacted to obtain compound III. The synthesis route is shown in the following formula: in, R2 represents a hydrogen atom, a methyl group, a phenyl group or a methyl group.

3. The method for preparing 3-aldehyde indole derivatives according to claim 1, characterized in that: The palladium catalyst is palladium trifluoroacetate, palladium chloride or palladium bromide, the diphosphine ligand is Xantphos, dppf, DEPphos, dppp, dppe or dppm, the base is cesium carbonate, and the first solvent is 1,4-dioxane, THF or toluene.

4. The method for preparing 3-aldehyde indole derivatives according to claim 1, characterized in that: The molar ratio of the iodobenzene II, the alkyne compound III, the diaziridinone compound IV, the palladium catalyst, the diphosphine ligand and the base is 1:1:1.3:0.05:0.1:

2.

5. The method for preparing 3-aldehyde indole derivatives according to claim 1, characterized in that: The concentration of iodobenzene II in the mixed solution of iodobenzene II, alkyne compound III, diazirine cyclopropane compound IV, palladium catalyst, diphosphine ligand, base and the first solvent is 0.2 mol / L.

6. The method for preparing 3-aldehyde indole derivatives according to claim 1, characterized in that: The reaction temperature of the amination reaction is 85-125°C, and the reaction time is 10-14h.

7. The method for preparing 3-aldehyde indole derivatives according to claim 2, characterized in that: The molar ratio of the acetal compound V, iodobenzene, tetrakistriphenylphosphine palladium and cuprous iodide is 1:1.2:0.02:0.

02.

8. The method for preparing 3-aldehyde indole derivatives according to claim 2, characterized in that: The molar ratio of the compound VI, neopentyl glycol and p-toluenesulfonic acid is 1:1.2:0.

1.

9. A 3-formyl indole derivative, characterized in that: The structural formula is shown below: Wherein, R1 represents a hydrogen atom, a methyl group, a phenyl group, a chlorine atom, a trifluoromethyl group, a methyl group or a cyano group; R2 represents a hydrogen atom, a methyl group, a phenyl group or a methyl group.

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