Preparation method of N-tert-butyl-3-amino indole derivative and N-tert-butyl-3-amino indole derivative

Abstract

The invention provides a preparation method of an N-tert-butyl-3-amino indole derivative, which comprises the following specific steps: 1) mixing a compound IV, N-propyl-4-methyl benzenesulfonamide, copper sulfate pentahydrate, 1, 10-felotourmaline, potassium carbonate and a first solvent, and after the reaction is finished, performing post-treatment to obtain a compound II; 2) mixing tert-butylamine, triethylene diamine, di-tert-butyl dicarbonate ester and dichloromethane at room temperature, and reacting for 12 hours to obtain N, N-di-tert-butyl urea; further reacting N, N-di-tert-butyl urea to obtain a compound III; and 3) mixing the compound II, the compound III, iodobenzene, a palladium catalyst, a diphosphine ligand, alkali and a second solvent, and reacting to obtain the N-tert-butyl-3-amino indole derivative with the structural formula of # imgabs0 #. The method provided by the invention can directly carry out amination ring formation reaction with iodobenzene through one-pot reaction.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a preparation method of N-tert-butyl-3-aminoindole derivatives and N-tert-butyl-3-aminoindole derivatives. Background Art

[0002] 3-aminoindole compounds are an important class of nitrogen-containing heterocyclic structures, which are widely present in natural products and active molecules, and have important applications in the fields of medicine, pesticides, organic synthesis, etc. At the same time, 3-aminoindole compounds are a very valuable class of synthetic intermediates, especially in the synthesis of some natural alkaloids, such as the total synthesis of natural products (-)-mersicapine and 8-desbromohinckdentine A. Therefore, the synthesis of 3-aminoindole derivatives has been highly valued by the majority of chemists.

[0003] In the traditional synthesis of 3-aminoindole, the 3-position nitration reduction reaction of indole is often used. The nitration reaction is a hazardous process with very strict requirements on equipment and management. The currently promoted microchannel reactor has high capital investment in equipment. The waste of nitration products is hazardous waste with strict treatment requirements and high costs. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing N-tert-butyl-3-aminoindole derivatives in view of the above shortcomings.

[0005] In order to solve the deficiencies of the prior art, the present invention provides a preparation method of tandem amination of alkynylamine and iodobenzene, which is simple to operate, has few side reactions, and has a high molar yield, and can directly prepare a series of N-tert-butyl-3-aminoindole derivatives. The specific steps are:

[0006] 1) Compound IV, N-propyl-4-methylbenzenesulfonamide, copper sulfate pentahydrate, 1,10-phenoline, potassium carbonate and the first solvent are mixed and reacted at 80-90° C. for 8-12 hours under a nitrogen atmosphere. After the reaction is completed, the mixture is diluted with ethyl acetate, filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column to obtain a structural formula of Compound II; the synthesis route is shown below:

[0007]

[0008] 2) 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; N,N-di-tert-butyl urea, tert-butyl hypochlorite, potassium tert-butoxide, and triethylamine were mixed in anhydrous ether, and after the reaction, a compound having the structural formula Compound III.

[0009] 3) Compound II, compound III, iodobenzene V, palladium catalyst, bisphosphine ligand, base and second solvent are mixed, and an amination reaction is carried out under an inert atmosphere to obtain a compound having the structural formula N-tert-butyl-3-aminoindole derivatives, wherein R1 represents hydrogen, methyl, phenyl, cyano or halogen; R2 represents hydrogen, methyl, phenyl, methoxy, chlorine atom, bromine atom, trifluoromethyl, cyano or methyl formate, and the synthesis route is shown in the following formula:

[0010]

[0011] Furthermore, in the step 1), the molar ratio of the compound IV, N-propyl-4-methylbenzenesulfonamide, copper sulfate pentahydrate, 1,10-phenanthroline, and potassium carbonate is (1.1-1.2):1:(0.1-0.2):(0.2-0.4):(2.0-2.5).

[0012] Furthermore, the method for preparing N-tert-butyl-3-aminoindole derivatives is characterized in that in step (3), the base is cesium carbonate.

[0013] Furthermore, in the step (3), the second solvent is 1,4-dioxane.

[0014] Furthermore, in the step (3), the bisphosphine ligand is 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene.

[0015] Furthermore, in the step (2), the concentration of the compound II in the second solvent is 0.2 mol / L.

[0016] Furthermore, in the step (3), the molar ratio of compound II, compound III, iodobenzene, palladium catalyst, bisphosphine ligand and base is 1:1.5:1.5:(0.05-0.10):(0.05-0.10):(2.0-2.5).

[0017] Furthermore, in the step (3), the reaction temperature of the amination reaction is 115-130° C., and the reaction time is 10-14 h.

[0018] Furthermore, in the step (3), the palladium catalyst is palladium acetate.

[0019] The second aspect of the present invention also provides an N-tert-butyl-3-aminoindole derivative prepared by the above preparation method.

[0020] Beneficial effects of the present invention:

[0021] (1) The preparation method of N-tert-butyl-3-aminoindole derivatives provided by the present invention has simple and easy-to-obtain raw materials for the synthesis of acetylamide compound II, a wide range of substrates, simple synthesis operations, and excellent molar yield. It does not require pre-replacement of specific functional groups on the carbon position to be reacted, and can directly react with iodobenzene in a one-pot reaction to undergo amination and ring-forming reaction to synthesize N-tert-butyl-3-aminoindole derivatives with diverse substituent types.

[0022] (2) The halogen-carbon bond is a relatively weak chemical bond. Compared with other chemical bonds, its bond energy is lower. The chemical bond energy of the CI bond in iodobenzene is the lowest among carbon-halogen bonds and is easier to break and react.

[0023] (3) The present invention uses N,N-di-tert-butyldiazacycloketone as a nitrogen source to prepare N-tert-butyl-3-aminoindole derivatives containing N-tert-butyl. The N-tert-butyl group is easy to remove and can also serve as a protecting group in the indole nitrogen, thus having a good protective effect in the further derivatization reaction of the N-tert-butyl-3-aminoindole derivatives. DETAILED DESCRIPTION

[0024] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification. The methods described are all conventional methods unless otherwise specified, and the raw materials described can be obtained from public commercial channels unless otherwise specified.

[0025] The term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0026] The present invention provides a method for preparing N-tert-butyl-3-aminoindole derivatives, which specifically comprises the following steps:

[0027] 1) Compound IV, N-propyl-4-methylbenzenesulfonamide, copper sulfate pentahydrate, 1,10-phenanthene, carbon

[0028] Potassium sulfate and the first solvent are mixed, reacted at 80-90°C for 8-12 hours under a nitrogen atmosphere, and after the reaction is completed, diluted with ethyl acetate, filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column to obtain a structural formula of Compound II; the synthesis route is shown below:

[0029]

[0030] 2) a. Mix tert-butylamine, triethylenediamine, di-tert-butyl dicarbonate and dichloromethane at room temperature and react for 12 hours to obtain N,N-di-tert-butyl urea;

[0031] b. Mix N,N-di-tert-butyl urea, tert-butyl hypochlorite, potassium tert-butoxide, and triethylamine in anhydrous ether. After the reaction is completed, the structural formula is obtained. Compound III.

[0032] 3) Compound II, compound III, iodobenzene V, palladium catalyst, bisphosphine ligand, base and second solvent are mixed, and an amination reaction is carried out under an inert atmosphere to obtain a compound having the structural formula N-tert-butyl-3-aminoindole derivatives, wherein R1 represents hydrogen, methyl, phenyl, cyano or halogen; R2 represents hydrogen, methyl, phenyl, methoxy, chlorine atom, bromine atom, trifluoromethyl, cyano or methyl formate, and the synthesis route is shown in the following formula:

[0033]

[0034] With R1 and R2 being hydrogen atoms, the reaction mechanism of the present invention is described:

[0035]

[0036] Wherein, L represents a phosphine ligand; iodobenzene 1 is subjected to oxidative addition reaction on a palladium catalyst to generate an intermediate 2, which is subjected to carbon palladiumization reaction with alkynamine II to generate an intermediate 3; the intermediate 2 is subsequently activated by an aromatic CH to generate a corresponding cyclopalladium intermediate 4, which is subjected to oxidative addition reaction with a three-membered ring nitrogen-containing reagent III to generate a corresponding cyclopalladium (IV) intermediate 5, which releases tBuNCO to give a nitrene intermediate 6, which is subjected to continuous reduction elimination to give an N-tert-butyl-3-aminoindole product I and a palladium catalyst.

[0037] In an optional embodiment of the present invention, the palladium catalyst is palladium acetate, the bisphosphine ligand is 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, and the base is cesium carbonate.

[0038] In an optional embodiment of the present invention, the second solvent is 1,4-dioxane.

[0039] In an optional embodiment of the present invention, the concentration of compound II in the second solvent mixture is 0.2 mol / L.

[0040] In an optional embodiment of the present invention, the molar ratio of compound II, compound III, iodobenzene V, palladium catalyst, monophosphine ligand and base is 1:1.5:1.5:(0.05~0.10):(0.05~0.10):(2.0~2.5).

[0041] In an optional embodiment of the present invention, the reaction temperature of the amination reaction is 115-130° C., preferably 115° C. The reaction time is 10-14 h, preferably 12 h.

[0042] Compounds Ⅰ-a to Ⅰ-p are some examples of N-tert-butyl-3-aminoindole derivatives prepared by the present invention.

[0043]

[0044] Unless otherwise specified, the materials and reagents used in the following examples are commercially available or prepared according to existing literature.

[0045] The reagents used in the following examples are all commercially available, among which palladium acetate, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene, and 1,4-dioxane were purchased from Anage Chemical; and cesium carbonate was purchased from Leyan.

[0046] Preparation of Compound Ia:

[0047] 1) Preparation of compound II-a:

[0048]

[0049] Weigh phenylacetylene bromide IV-a (1.9913 g, 11 mmol), N-propyl-4-methylbenzenesulfonamide (2.1329 g, 10 mmol), copper sulfate pentahydrate (0.2497 g, 1.0 mmol), 1,10-phenanthroline (0.3604 g, 2.0 mmol), potassium carbonate (2.7640 g, 20 mmol), place in a dry round-bottom flask, replace nitrogen, then add dry toluene (15 mL); the reaction mixture is reacted at 80 ° C for 12 h. After the reaction is completed, ethyl acetate is added to dilute, filtered through 300-400 mesh silica gel, concentrated under reduced pressure to remove the solvent, and separated by chromatographic column to obtain 2.21 g of compound II-a, with a molar yield of 70%.

[0050] NMR data of compound II-a: 1 H NMR (400MHz, CDCl3) δ7.84 (d, J = 8.4Hz, 2H), 7.39-7.33 (m, 4H), 7.32-7.26 (m, 3H) ),3.36(t,J=6.8Hz,2H),2.45(s,3H),1.79-1.68(m,2H),0.95(t,J=7.6Hz,3H); 13 C NMR (400MHz, CDCl3) δ144.7,134.8,131.4,129.9,128.4,127.8,127.77,123.1,82.5,70.7,53.4,21.7,21.4,11.0.

[0051] 2) Preparation of compound III:

[0052]

[0053] 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.

[0054] 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 III as a colorless liquid (11.6 g, molar yield 59%).

[0055] NMR data of compound III: 1 H NMR (400MHz, CDCl3): δ1.30 (s, 18H); 13 C NMR (100MHz, CDCl3): δ158.8, 59.1, 26.8.

[0056] 3) Preparation of compound Ia:

[0057]

[0058] Compound II-a (0.0940 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 5 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (1.0 mL), iodobenzene Va (0.0918 g, 0.45 mmol), and compound III (0.1022 g, 0.6 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 115°C and stirred for 12 hours. After the reaction was completed, it 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 to obtain a light yellow solid compound Ia (0.1310 g, molar yield 95%).

[0059] NMR data of compound Ia: 1 H NMR(400MHz, CDCl3) δ7.73(d,J=8.4Hz,1H),7.68(dt,J=7.2,1.6Hz,1H),7.53(d,J=8.4 Hz,2H),7.42-7.34(m,2H),7.33-7.28(m,1H),7.23-7.17(m,3H),7.14(ddd,J=8.4,6.8, 1.6Hz,1H),6.93(t,J=7.6Hz,1H),6.90-6.82(dd,J=8.0,1.2Hz,1H),3.37-3.26(m,1H) ,3.25-3.14(m,1H),2.43(s,3H),1.58(s,9H),1.25-1.06(m,2H),0.51(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ143.0,141.4,137.9,135.5,134.7,132.1,131.2,129.4,128.2,127. 9,126.8,126.1,121.1,119.43,119.35,115.3,114.8,59.8,52.8,32.2,22.0,21.7,11.0.

[0060] Example 2

[0061] Preparation of Compound Ib:

[0062] 1) Preparation of compound II-a: Same as in Example 1

[0063] 2) Preparation of compound III: Same as in Example 1

[0064] 3) Preparation of compound Ib:

[0065]

[0066] Compound II-a (0.0940 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 5 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (1.0 mL), iodobenzene Vb (0.0981 g, 0.45 mmol), and compound III (0.0766 g, 0.45 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 115°C and stirred for 12 hours. After the reaction was completed, it 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 to obtain a light yellow solid compound Ib (0.130 g, molar yield 91%).

[0067] NMR data of compound Ib: 1 H NMR(400MHz, CDCl3)δ7.65(dt,J=7.2,1.6Hz,1H),7.58-7.49(m,3H),7.40-7.33(m,2H),7.32-7.27(m,1H),7.22-7.15(m,3H),6.80- 6.70(m,2H),3.34-3.25(m,1H),3.23-3.13(m,1H),2.48(s,3H),2.44(s,3H),1.56(s,9H),1.23-1.04(m,2H),0.50(t,J=7.6Hz,3H); 13 C NMR (100MHz, CDCl3) δ143.0,140.8,137.9,136.0,134.9,131.9,131.2,130.7,129.4,128.2,12 8.1,127.9,126.8,123.9,121.0,119.1,115.4,114.7,59.6,52.7,32.1,22.3,21.9,21.6,11.0.

[0068] Example 3

[0069] Preparation of compound Ic:

[0070] 1) Preparation of compound II-a: Same as in Example 1

[0071] 2) Preparation of compound III: Same as in Example 1

[0072] 3) Preparation of compound Ic:

[0073]

[0074] Compound II-a (0.0940 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 5 mL pressure tube, and argon was filled into the tube after vacuuming. Then, ultra-dry 1,4-dioxane (1.0 mL), iodobenzene Vc (0.1260 g, 0.45 mmol), and compound III (0.0766 g, 0.45 mmol) were added in sequence, and the mixture was sealed and placed in a magnetic heating stirrer at 115°C and stirred for 12 hours. After the reaction was completed, the mixture 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 to obtain a light yellow solid compound Ic (0.1380 g, molar yield 86%).

[0075] NMR data of compound Ic: 1 H NMR (400MHz, CDCl3) δ7.91 (s, 1H), 7.71-7.62 (m, 3H), 7.55 (d, J = 8.4Hz, 2H), 7.51-7.43 (m, 2H), 7.42-7.30 (m, 4H), 7.25-7.14 (m, 4H) ),6.95(d,J=8.4Hz,1H),3.42-3.30(m,1H),3.28-3.14(m,1H),2.44(s,3H),1.62(s,9H),1.26-1.09(m,2H),0.54(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ143.1,142.8,142.1,137.8,136.1,134.8,134.7,132.0,131.2,129.5,128.9,128.3, 128.2,128.0,127.7,126.9,126.8,125.4,119.6,119.5,114.8,114.2,60.0,52.8,32.3,22.0,21.7,11.1.

[0076] Example 4

[0077] Preparation of Compound Id:

[0078] 1) Preparation of compound II-a: Same as in Example 1

[0079] 2) Preparation of compound III: Same as in Example 1

[0080] 3) Preparation of compound Id:

[0081]

[0082] Compound II-a (0.0940 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 5 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (1.0 mL), iodobenzene Vd (0.1053 g, 0.45 mmol), and compound III (0.0766 g, 0.45 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 115°C and stirred for 12 hours. After the reaction was completed, it 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 to obtain a light yellow solid compound Id (0.0808 g, molar yield 55%).

[0083] NMR data of compound Id: 1 H NMR (400MHz, CDCl3) δ7.65-7.58(m,1H),7.52(d,J=8.4Hz,2H),7.39-7.32(m,2H),7.32-7.27(m,1H),7.23-7.16(m,4H),6.76(d,J=8.8Hz,1H),6. 63(dd,J=8.8,2.4Hz,1H),3.88(s,3H),3.36-3.23(m,1H),3.22-3.11(m, 1H),2.43(s,3H),1.56(s,9H),1.25-1.04(m,2H),0.51(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ155.2,143.0,140.4,137.8,136.4,134.9,132.0,131.3,129.4,128.2,12 8.1,127.9,126.8,120.6,119.9,114.7,108.4,100.2,59.6,56.0,52.8,32.0,21.9,21.7,11.0.

[0084] Example 5

[0085] Preparation of Compound Ie:

[0086] 1) Preparation of compound II-a: Same as in Example 1

[0087] 2) Preparation of compound III: Same as in Example 1

[0088] 3) Preparation of Compound Ie:

[0089]

[0090] Compound II-a (0.0940 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 5 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (1.0 mL), iodobenzene Vd (0.1053 g, 0.45 mmol), and compound III (0.0766 g, 0.45 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 115°C and stirred for 12 hours. After the reaction was completed, it 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 to obtain a light yellow solid compound Ie (0.0808 g, molar yield 55%).

[0091] NMR data of compound Ie: 1 H NMR (400MHz, CDCl3) δ7.71(d,J=1.6Hz,1H),7.59(dt,J=7.2,1.6Hz,1H),7.59(d,J=8.0Hz,2H),7.40-7.29(m,3H),7.22-7.17(m,3H),6.91(dd,J= 8.4,1.6Hz,1H),6.79(d,J=8.4Hz,1H),3.32-3.24(m,1H),3.20-3.11(m, 1H),2.44(s,3H),1.55(s,9H),1.23-1.06(m,2H),0.52(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ143.3,142.1,137.6,135.8,134.2,131.9,131.1,129.5,128.4,128.1, 128.0,127.0,126.95,124.7,120.2,120.1,115.1,114.9,60.2,52.8,32.1,21.9,21.7,11.0.

[0092] Example 6

[0093] Preparation of Compound If:

[0094] 1) Preparation of compound II-a: Same as in Example 1

[0095] 2) Preparation of compound III: Same as in Example 1

[0096] 3) Preparation of compound If:

[0097]

[0098] Compound II-a (0.0940 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 5 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (1.0 mL), iodobenzene V-fb (0.1273 g, 0.45 mmol), and compound III (0.0766 g, 0.45 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 115°C and stirred for 12 hours. After the reaction was completed, it 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 to obtain a light yellow solid compound If (0.0808 g, molar yield 55%).

[0099] NMR data of compound If: 1 H NMR (400MHz, CDCl3) δ7.87(d,J=1.6Hz,1H),7.60(dt,J=7.2,1.6Hz,1H),7.49(d,J=8.0Hz,2H),7.40-7.29(m,3H),7.21-7.15(m,3H),7.03(dd,J= 8.4,1.2Hz,1H),6.74(d,J=8.4Hz,1H),3.31-3.23(m,1H),3.19-3.11(m, 1H),2.44(s,3H),1.55(s,9H),1.22-1.06(m,2H),0.52(t,J=7.2Hz,3H); 13C NMR (100MHz, CDCl3) δ143.2,142.0,137.6,136.2,134.2,131.9,131.0,129.5,128.5,128.1, 128.0,126.9,125.0,122.7,120.5,118.0,115.0,114.8,60.2,52.7,32.1,21.9,21.7,11.0.

[0101] Example 7

[0102] Preparation of Compound Ig:

[0103] 1) Preparation of compound II-a: Same as in Example 1

[0104] 2) Preparation of compound III: Same as in Example 1

[0105] 3) Preparation of Compound Ig:

[0106]

[0107] Compound II-a (0.0940 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 5 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (1.0 mL), iodobenzene Vg (0.1224 g, 0.45 mmol), and compound III (0.0766 g, 0.45 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 115°C and stirred for 12 hours. After the reaction was completed, it 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 to obtain a light yellow solid compound Ig (0.1060 g, molar yield 67%).

[0108] NMR data of compound Ig: 1 H NMR (400MHz, CDCl3) δ7.99 (s, 1H), 7.60 (dt, J = 7.6, 2.0Hz, 1H), 7.49 (d, J = 8.4Hz, 2H), 7.44-7.31 (m, 3H), 7.23-7.16 (m, 4H), 7. 01(d,J=8.4Hz,1H),3.35-3.25(m,1H),3.21-3.10(m,1H),2.44(s,3H),1.59(s,9H),1.23-1.08(m,2H),0.53(t,J=7.2Hz,3H);13 C NMR (100MHz, CDCl3) δ144.1,143.4,137.5,134.3,133.9,131.8,130.9,129.6,128.7,128.1,128.06,127.0,125.3(q,J=2 69.9Hz), 123.1 (q, J = 31.4Hz), 119.8, 116.2 (q, J = 3.6Hz), 115.0, 112.6 (q, J = 4.7Hz), 60.5, 52.8, 32.3, 22.0, 21.7, 11.0.

[0109] Example 8

[0110] Preparation of compound Ih:

[0111] 1) Preparation of compound II-a: Same as in Example 1

[0112] 2) Preparation of compound III: Same as in Example 1

[0113] 3) Preparation of compound Ih:

[0114]

[0115] Compound II-a (0.0940 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 5 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (1.0 mL), iodobenzene Vh (0.1031 g, 0.45 mmol), and compound III (0.0766 g, 0.45 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 115°C and stirred for 12 hours. After the reaction was completed, it 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 to obtain a light yellow solid compound Ih (0.1060 g, molar yield 67%).

[0116] NMR data of compound Ih: 1H NMR (400MHz, CDCl3) δ8.06(s,1H),7.57(dt,J=7.6,2.0Hz,1H),7.47(d,J=8.4Hz,2H),7.44-7.39(m,1H),7.39-7.32(m,2H),7.22-7.15( m,4H),6.99(d,J=8.0Hz,1H),3.32-3.24(m,1H),3.18-3.09(m,1H),2.44(s,3H),1.58(s,9H),1.22-1.06(m,2H),0.54(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ145.3,143.5,137.4,134.1,133.4,131.8,130.7,129.6,129.4,128.9,128 .1,128.09,127.1,122.3,120.9,120.1,120.0,115.6,103.8,60.9,52.8,32.3,22.0,21.7,11.0.

[0117] Example 9

[0118] Preparation of Compound Ii:

[0119] 1) Preparation of compound II-a: Same as in Example 1

[0120] 2) Preparation of compound III: Same as in Example 1

[0121] 3) Preparation of compound Ii:

[0122]

[0123] Compound II-a (0.0940 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 5 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (1.0 mL), iodobenzene Vi (0.1179 g, 0.45 mmol), and compound III (0.0766 g, 0.45 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 115°C and stirred for 12 hours. After the reaction was completed, it 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 to obtain a light yellow solid compound Ii (0.1320 g, molar yield 85%).

[0124] NMR data of compound Ii: 1 H NMR(400MHz, CDCl3)δ8.50(s,1H),7.72-7.66(m,1H),7.60(dd,J=8.4,1.2Hz,1H),7.51(d,J=8.4Hz,2H),7.44-7.36(m,2H),7.35-7.30(m,1H) ,7.23-7.16(m,3H),6.83(d,J=8.4Hz,1H),3.95(s,3H),3.35-3.15(m,2 H),2.44(s,3H),1.61(s,9H),1.24-1.05(m,2H),0.52(t,J=7.6Hz,3H); 13 C NMR (100MHz, CDCl3) δ168.2,144.9,143.3,137.6,134.7,134.0,131.9,130.9,129.6,128.6,12 8.2,128.0,127.0,122.7,120.5,118.8,117.6,115.2,60.5,52.8,52.2,32.4,21.9,21.7,11.0.

[0125] Example 10

[0126] Preparation of Compound Ij:

[0127] 1) Preparation of compound II-a: Same as in Example 1

[0128] 2) Preparation of compound III: Same as in Example 1

[0129] 3) Preparation of compound Ij:

[0130]

[0131] Compound II-a (0.0940 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (1.0 mL), iodobenzene Vj (0.1260 g, 0.45 mmol), and compound III (0.0766 g, 0.45 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 115 ° C and stirred for 12 hours. After the reaction was completed, it 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 to obtain a light yellow solid compound Ij (0.1310 g, molar yield 81%).

[0132] NMR data of compound Ij: 1 H NMR (400MHz, CDCl3) δ7.88(dt,J=7.2,1.6Hz,1H),7.77(d,J=8.8Hz,1H),7.61(d,J=8.4Hz,2H),7.46-7.36(m,7H),7.34-7.27(m,2H ),7.22-7.15(m,3H),6.70(d,J=2.0Hz,1H),3.45-3.28(m,2H),2.28(s,3H),1.60(s,9H),1.22-1.06(m,2H),0.51(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ143.4,142.6,141.7,138.1,135.1,134.5,132.4,132.1,131.3,129.6,128.7,128.3, 128.2,128.0,127.2,126.7,126.5,125.9,120.5,117.5,115.6,115.2,60.0,53.0,32.2,22.1,21.4,11.0...

[0133] Embodiment 11

[0134] 1) Preparation of compound II-b:

[0135]

[0136] Weigh phenylacetylene bromide IV-b (1.2874 g, 6.6 mmol), N-propyl-4-methylbenzenesulfonamide (1.2797 g, 6.0 mmol), copper sulfate pentahydrate (0.1498 g, 0.6 mmol), 1,10-phenanthroline (0.2163 g, 1.2 mmol), potassium carbonate (1.6584 g, 12 mmol), place in a dry round-bottom flask, replace nitrogen, then add dry toluene (10 mL); the reaction mixture is reacted at 80 ° C for 12 h. After the reaction is completed, ethyl acetate is added to dilute, filtered through 300-400 mesh silica gel, concentrated under reduced pressure to remove the solvent, and separated by chromatographic column to obtain 1.61 g of compound II-a, with a molar yield of 75%.

[0137] NMR data of compound II-a: 1 H NMR (400MHz, CDCl3) δ7.85(d,J=8.0Hz,2H),7.35(d,J=8.4Hz,2H),7.28(d,J=8.0Hz,2H),7.11(d,J=8 .0Hz,2H),3.37(t,J=6.8Hz,2H),2.45(s,3H),2.34(s,3H),1.80-1.68(m,2H),0.96(t,J=7.2Hz,3H); 13 C NMR (400MHz, CDCl3) δ144.6,138.0,134.6,131.5,129.8,129.1,127.7,119.8,81.7,70.5,53.3,21.7,21.5,21.3,10.9.

[0138] 2) Preparation of compound III: Same as in Example 1.

[0139] 3) Preparation of compound Ik:

[0140]

[0141] Compound II-b (0.0940 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (1.0 mL), iodobenzene Va (0.0918 g, 0.45 mmol), and compound III (0.0766 g, 0.45 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 115°C and stirred for 12 hours. After the reaction was completed, it 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 to obtain a light yellow solid compound Ik (0.1250 g, molar yield 88%).

[0142] NMR data of compound Ik: 1 H NMR (400MHz, CDCl3) δ7.71(d,J=8.4Hz,1H),7.57-7.48(m,3H),7.20-7.09(m,5H),7.07(dd,J=7.6,2.0Hz,1H),6.91(td,J=7.6,0.6Hz,1H),6.8 6(dd,J=8.4,1.6Hz,1H),3.36-3.27(m,1H),3.24-3.15(m,1H),2.44(s, 3H),2.42(s,3H),1.57(s,9H),1.24-1.08(m,2H),0.53(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ142.9,141.5,138.0,137.9,135.4,131.8,131.6,131.0,129.4,128.5,12 8.2,127.5,126.1,120.9,119.3,119.2,115.2,114.6,59.7,52.8,32.1,22.0,21.6,21.5,11.1.

[0143] Example 12

[0144] Preparation of compound I1:

[0145] 1) Preparation of compound II-c:

[0146]

[0147] Weigh phenylacetylene bromide IV-c (2.4684 g, 9.6 mmol), N-propyl-4-methylbenzenesulfonamide (1.8556 g, 8.7 mmol), copper sulfate pentahydrate (0.2172 g, 0.87 mmol), 1,10-phenanthroline (0.3136 g, 1.74 mmol), potassium carbonate (2.4047 g, 17.4 mmol), place in a dry round-bottom flask, replace nitrogen, then add dry toluene (12 mL); the reaction mixture is reacted at 80 ° C for 12 h. After the reaction is completed, ethyl acetate is added to dilute, filtered through 300-400 mesh silica gel, concentrated under reduced pressure to remove the solvent, and separated by chromatographic column to obtain 1.81 g of compound II-c, with a molar yield of 53%.

[0148] NMR data of compound II-c: 1 H NMR(400MHz, CDCl3) δ7.86(d,J=8.4Hz,2H),7.61-7.57(m,2H),7.54(d,J=8.4Hz,2H),7.47-7.42(m, 4H),7.39-7.33(m,3H),3.39(t,J=7.2Hz,2H),2.46(s,3H),1.81-1.70(m,2H),0.97(t,J=7.6Hz,3H); 13 CNMR(400MHz, CDCl3)δ144.7,140.6,140.5,134.7,131.9,129.9,129.0,127.8,127.7,127.1,127.08,122.0,83.1,70.6,53.4,21.8,21.5,11.1.

[0149] 2) Preparation of compound III: Same as in Example 1.

[0150] 3) Preparation of compound I1:

[0151]

[0152] Compound II-c (0.1169 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (1.0 mL), iodobenzene Va (0.0918 g, 0.45 mmol), and compound III (0.0766 g, 0.45 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 115 ° C and stirred for 12 hours. After the reaction was completed, it 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 to obtain a light yellow solid compound Il (0.1524 g, molar yield 94%).

[0153] NMR data of compound I1: 1 H NMR (400MHz, CDCl3) δ7.80-7.72(m,2H),7.71-7.66(m,2H),7.62(d,J=8.0,2.0Hz,1H),7.5 6(dd,J=8.0,2.0Hz,1H),7.54-7.45(m,4H),7.39(tt,J=7.6,1.2Hz,1H),7.28-7.24(m,1H), 7.20-7.12(m,3H),6.93(td,J=8.0,0.8Hz,1H),6.88(dd,J=8.0,1.2Hz,1H),3.40-3.31(m, 1H),3.30-3.21(m,1H),2.40(s,3H),1.62(s,9H),1.25-1.08(m,2H),0.53(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ143.0,141.1,140.8,140.7,137.9,135.7,133.7,132.4,131.6,129.4,129.0,128.2, 127.6,127.2,126.4,126.1,125.4,121.1,119.4,119.39,115.3,115.0,59.8,52.9,32.2,22.0,21.6,11.1.

[0154] Example 13

[0155] Preparation of Compound Im:

[0156] 1) Preparation of compound II-d:

[0157]

[0158] Weigh phenylacetylene bromide IV-d (2.0398 g, 9.9 mmol), N-propyl-4-methylbenzenesulfonamide (1.9196 g, 9.0 mmol), copper sulfate pentahydrate (0.2247 g, 0.9 mmol), 1,10-phenanthroline (0.3244 g, 1.8 mmol), potassium carbonate (2.4876 g, 18 mmol), place in a dry round-bottom flask, replace nitrogen, then add dry toluene (13 mL); the reaction mixture is reacted at 80 ° C for 12 h. After the reaction is completed, ethyl acetate is added to dilute, filtered through 300-400 mesh silica gel, concentrated under reduced pressure to remove the solvent, and separated by chromatographic column to obtain 3.0 g of compound II-d, with a molar yield of 98%.

[0159] NMR data of compound II-d: 1 H NMR (400MHz, CDCl3) δ7.80(d,J=8.4Hz,2H),7.53(d,J=8.4Hz,2H),7.38(d,J=8.4Hz,2H),7.35 (d,J=8.4Hz,2H),3.37(t,J=7.2Hz,2H),2.41(s,3H),1.75-1.65(m,2H),0.92(t,J=7.6Hz,3H); 13 CNMR(400MHz, CDCl3)δ145.0,134.4,131.9,130.9,129.9,128.2,127.5,118.6,110.3,87.2,70.3,53.1,21.6,21.3,10.8.

[0160] 2) Preparation of compound III: Same as in Example 1.

[0161] 3) Preparation of Compound Im:

[0162]

[0163] Compound II-c (0.1015 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (1.0 mL), iodobenzene Va (0.0918 g, 0.45 mmol), and compound III (0.0766 g, 0.45 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 115 ° C and stirred for 12 hours. After the reaction was completed, it 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 to obtain a light yellow solid compound Il (0.1320 g, molar yield 91%).

[0164] NMR data of compound Im: 1 H NMR (400MHz, CDCl3) δ8.06 (dd, J=8.0, 1.6Hz, 1H), 7.77-7.70 (m, 2H), 7.62 (dd, J=8.0, 2.0Hz ,1H),7.56(d,J=8.4Hz,2H),7.32(dd,J=8.0,2.0Hz,1H),7.23(d,J=8.0Hz,2H),7.16(ddd,J= 8.4,7.2,1.2Hz,1H),6.86(ddd,J=8.0,6.8,0.8Hz,1H),6.57(d,J=7.6Hz,1H),3.39-3.31(m ,1H),3.29-3.21(m,1H),2.45(s,3H),1.58(s,9H),1.13-0.96(m,2H),0.50(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ143.5,139.8,139.4,137.4,136.2,132.7,131.9,131.87,130.4,129.6,12 8.2,125.2,121.8,119.7,119.5,118.9,115.9,115.5,112.0,60.1,52.8,32.3,22.1,21.7,10.9.

[0165] Embodiment 14

[0166] Preparation of compound In:

[0167] 1) Preparation of compound II-e:

[0168]

[0169] Weigh phenylacetylene bromide IV-e (1.4995 g, 6 mmol), N-propyl-4-methylbenzenesulfonamide (1.487 g, 6.6 mmol), copper sulfate pentahydrate (0.1498 g, 0.6 mmol), 1,10-phenanthroline (0.2162 g, 1.2 mmol), potassium carbonate (1.6584 g, 12 mmol), place in a dry round-bottom flask, replace nitrogen, then add dry toluene (12 mL); the reaction mixture is reacted at 80 ° C for 12 h. After the reaction is completed, ethyl acetate is added to dilute, filtered through 300-400 mesh silica gel, concentrated under reduced pressure to remove the solvent, and separated by chromatographic column to obtain 2.29 g of compound II-e, with a molar yield of 99%.

[0170] NMR data of compound II-e: 1 H NMR (400MHz, CDCl3) δ7.81(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),7.25(t,J=2.0Hz,1H),7.21 (d,J=2.0Hz,2H),3.36(t,J=7.2Hz,2H),2.46(s,3H),1.77-1.65(m,2H),0.94(t,J=7.2Hz,3H); 13 C NMR (400MHz, CDCl3) δ145.0,134.9,134.6,130.0,129.1,127.9,127.7,126.1,85.1,69.0,53.3,21.8,21.5,11.0.

[0171] 2) Preparation of compound III: Same as in Example 1.

[0172] 3) Preparation of compound In:

[0173]

[0174] Compound II-e (0.1147 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (1.0 mL), iodobenzene Va (0.0918 g, 0.45 mmol), and compound III (0.0766 g, 0.45 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 115 ° C and stirred for 12 hours. After the reaction was completed, it 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 to obtain a light yellow solid compound In (0.1300 g, molar yield 82%).

[0175] NMR data of compound In: 1 H NMR (400MHz, CDCl3) δ7.73(d,J=8.8Hz,1H),7.67(t,J=1.6Hz,1H),7.59(d,J=8.4H z,2H),7.40(t,J=1.6Hz,1H),7.23(d,J=8.0Hz,2H),7.17(ddd,J=8.4,6.8,1.6Hz, 1H),7.10(t,J=1.6Hz,1H),6.94(td,J=8.0,0.8Hz,1H),6.87(d,J=8.0Hz,1H),3.4 1-3.26(m,2H),2.44(s,3H),1.61(s,9H),1.25-1.08(m,2H),0.55(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ143.4,138.1,137.7,137.3,135.9,134.6,133.3,130.5,129.6,129 .5,128.4,128.2,125.6,121.8,119.8,115.8,115.4,60.1,52.7,32.3,22.0,21.7,10.9.

[0176] Embodiment 15

[0177] Preparation of compound Io:

[0178] 1) Preparation of compound II-e:

[0179]

[0180] Weigh alkenyl bromide VI (2.2924 g, 9.1 mmol), N-propyl-4-methylbenzenesulfonamide (1.4930 g, 7.0 mmol), copper sulfate pentahydrate (0.1250 g, 0.5 mmol), 1,10-phenanthroline (0.1802 g, 1.0 mmol), potassium carbonate (1.3820 g, 10 mmol) in a dry round-bottom flask, replace nitrogen, and then add dry tetrahydrofuran (10 mL); the reaction mixture is reacted at 55 ° C for 12 h. After the reaction is completed, ethyl acetate is added to dilute, filtered through 300-400 mesh silica gel, and concentrated under reduced pressure to remove the solvent. After separation by chromatographic column, 1.83 g of compound II-e is obtained, and the molar yield is 86%.

[0181] NMR data of compound II-e: 1 H NMR (400MHz, CDCl3) δ7.82 (d, J = 8.4Hz, 2H), 7.42-7.33 (m, 3H), 6.60 (d, J = 3.6Hz, 1H), 6.39 (dd, J=3.6,2.0Hz,1H),3.36(t,J=7.2Hz,2H),2.46(s,3H),1.75-1.65(m,2H),0.92(d,J=7.6Hz,3H); 13 C NMR (400MHz, CDCl3) δ144.9,144.0,136.9,134.8,130.0,127.7,117.2,111.2,86.5,61.5,53.5,21.8,21.4,11.0.

[0182] 2) Preparation of compound III: Same as in Example 1.

[0183] 3) Preparation of compound Io:

[0184]

[0185] Compound II-f (0.0910 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (1.0 mL), iodobenzene Va (0.0918 g, 0.45 mmol), and compound III (0.0766 g, 0.45 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 115°C and stirred for 12 hours. After the reaction was completed, it 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 to obtain a light yellow solid compound Io (0.1346 g, molar yield 99%).

[0186] NMR data of compound Io: 1 H NMR (400MHz, CDCl3) δ7.73 (dt, J=8.4, 0.8Hz, 1H), 7.64 (d, J=8.4Hz, 2H), 7.50 (dd, J=2.0, 0.8Hz ,1H),7.24(d,J=8.0Hz,2H),7.14(ddd,J=8.8,7.2,1.6Hz,1H),6.86(ddd,J=7.6,6.8,0.8Hz,1H) ,6.73(dd,J=3.2,0.8Hz,1H),6.64(dt,J=8.0,0.8Hz,1H),6.48(dd,J=3.2,1.6Hz,1H),3.46-3.3 5(m,1H),3.31-3.21(m,1H),2.45(s,3H),1.63(s,9H),1.22-1.09(m,2H),0.61(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ144.8,143.1,142.0,138.0,135.8,130.8,129.5,128.0,125.0, 122.0,119.6,119.3,117.3,115.3,114.1,111.7,59.6,52.7,30.5,21.9,21.7,10.9..

[0187] Example 16

[0188] Preparation of Compound Ip:

[0189] 1) Preparation of compound II-g:

[0190]

[0191] Weigh alkenyl bromide VI (1.0950 g, 5 mmol), N-propyl-4-methylbenzenesulfonamide (1.2390 g, 5.5 mmol), cuprous iodide (0.2666 g, 1.4 mmol), 1,10-phenanthroline (0.5046 g, 2.8 mmol), cesium carbonate (6.8424 g, 21 mmol), place in a dry round-bottom flask, replace nitrogen, then add dry toluene (10 mL); the reaction mixture is reacted at 80 ° C for 12 h. After the reaction is completed, ethyl acetate is added to dilute, filtered through 300-400 mesh silica gel, concentrated under reduced pressure to remove the solvent, and separated by chromatographic column to obtain 1.25 g of compound II-g, with a molar yield of 71%.

[0192] NMR data of compound II-g: 1 H NMR (400MHz, CDCl3) δ7.78(d,J=8.4Hz,2H),7.33(d,J=8.0Hz,2H),5.49(s,1H),3.76(d,J=11.2Hz,2H),3.41(d, J=11.2Hz,2H),3.27(t,J=7.2Hz,3H),2.43(s,3H),1.72-1.61(m,2H),0.97(d,J=14Hz,6H),0.89(t,J=7.2Hz,3H) 13 CNMR (400MHz, CDCl3) δ144.8,134.7,129.9,127.7,90.6,79.2,74.7,65.7,53.0,30.5,22.7,22.5,21.8,21.4,11.0.

[0194] 2) Preparation of compound III: Same as in Example 1.

[0195] 3) Preparation of Compound Ip:

[0196]

[0197] Compound II-g (0.1054 g, 0.3 mmol), palladium acetate (0.0034 g, 0.015 mmol), Xantphos (0.0087 g, 0.015 mmol), cesium carbonate (0.1955 g, 0.6 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (1.0 mL), iodobenzene Va (0.0918 g, 0.45 mmol), and compound III (0.0766 g, 0.45 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 115 ° C and stirred for 12 hours. After the reaction was completed, it 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 to obtain a light yellow solid compound Ip (0.1166 g, molar yield 78%).

[0198] NMR data of compound Ip: 1 H NMR (400MHz, CDCl3) δ7.72(d,J=8.4Hz,1H),7.60(d,J=8.0Hz,2H),7.18(d,J=7.6Hz,2H) ,7.07(ddd,J=8.8,7.2,1.6Hz,1H),6.70(t,J=7.6Hz,1H),6.35(d,J=8.0Hz,1H),6.05(s ,1H),3.90-3.75(m,3H),3.72-3.62(m,2H),3.37-3.28(m,1H),2.41(s,3H),1.98(s,9H) ,1.65-1.57(m,1H),1.50-1.41(m,1H),1.28(s,3H),0.86(t,J=7.2Hz,3H),0.80(s,3H); 13 C NMR (100MHz, CDCl3) δ143.2,137.5,135.6,135.5,129.5,127.9,124.1,121.8,119.1,118 .8,117.5,116.0,99.0,79.4,79.1,59.9,53.6,31.5,30.6,24.9,22.6,22.58,21.6,11.3.

[0199] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing N-tert-butyl-3-aminoindole derivatives, characterized in that: The specific steps include: 1) Compound IV N-propyl-4-methylbenzenesulfonamide, copper sulfate pentahydrate, 1,10-phenoline, potassium carbonate and the first solvent were mixed and reacted at 80-90°C for 8-12 hours under a nitrogen atmosphere. After the reaction, it was diluted with ethyl acetate, filtered with diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column to obtain a structural formula of Compound II, wherein the first solvent is any one of toluene, ethylbenzene and benzene; 2) 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; N,N-di-tert-butyl urea, tert-butyl hypochlorite, potassium tert-butoxide, and triethylamine were mixed in anhydrous ether, and after the reaction, a compound having the structural formula Compound III; 3) Compound II, compound III, iodobenzene, palladium catalyst, bisphosphine ligand, base and second solvent are mixed, and an amination reaction is carried out under an inert atmosphere to obtain a compound having the structural formula N-tert-butyl-3-aminoindole derivatives, wherein R1 represents hydrogen, methyl, phenyl, cyano or halogen; R2 represents hydrogen, methyl, phenyl, methoxy, chlorine atom, bromine atom, trifluoromethyl, cyano or methyl formate, and the second solvent is any one of 1,4-dioxane and cyclopentane sulfone.

2. The method for preparing N-tert-butyl-3-aminoindole derivatives according to claim 1, characterized in that: In the step 1), the molar ratio of the compound IV, N-propyl-4-methylbenzenesulfonamide, copper sulfate pentahydrate, 1,10-phenanthroline, and potassium carbonate is (1.1-1.2):1:(0.1-0.2):(0.2-0.4):(2.0-2.5).

3. The method for preparing N-tert-butyl-3-aminoindole derivatives according to claim 1, characterized in that: In the step (3), the base is cesium carbonate.

4. The method for preparing N-tert-butyl-3-aminoindole derivatives according to claim 1, characterized in that: In the step (3), the bisphosphine ligand is 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene.

5. The method for preparing N-tert-butyl-3-aminoindole derivatives according to claim 1, characterized in that: In the step (2), the concentration of the compound II in the second solvent is 0.2 mol / L.

6. The method for preparing N-tert-butyl-3-aminoindole derivatives according to claim 1, characterized in that: In the step (3), the molar ratio of compound II, compound III, iodobenzene, palladium catalyst, bisphosphine ligand and base is 1:1.5:1.5:(0.05-0.10):(0.05-0.10):(2.0-2.5).

7. The method for preparing N-tert-butyl-3-aminoindole derivatives according to claim 1, characterized in that: In the step (3), the reaction temperature of the amination reaction is 115-130° C., and the reaction time is 10-14 h.

8. The method for preparing N-tert-butyl-3-aminoindole derivatives according to claim 1, characterized in that: In the step (3), the palladium catalyst is palladium acetate.

9. An N-tert-butyl-3-aminoindole derivative prepared by the method for preparing N-tert-butyl-3-aminoindole derivatives as claimed in any one of claims 1 to 8.

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