A preparation method of o-tert-butylaminobenzamide derivatives

Abstract

The present invention belongs to the technical field of organic synthesis, and in particular to a method for preparing an o-tert-butylaminobenzamide derivative. The preparation method comprises mixing an 8-aminoquinoline-derived benzamide derivative, N,N-di-tert-butyldiazacycloketone, a palladium catalyst, a monophosphine ligand, a base and a first solvent, and performing an amination reaction under an inert atmosphere to obtain an o-tert-butylaminobenzamide derivative. The preparation method of the o-tert-butylaminobenzamide derivative provided by the present invention has the advantages of simple operation, few side reactions, high yield, direct amination of aromatic rings, and synthesis of o-tert-butylaminobenzamide derivatives with diverse substituent types.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing o-tert-butylaminobenzamide derivatives. Background Art

[0002] O-aminobenzamide compounds are an important class of organic chemicals with important applications in the fields of medicine, pesticides, organic synthesis, etc. For example, o-aminobenzamide compounds are widely used as anticancer drugs, anti-inflammatory analgesics, nerve soothing drugs, lipid-lowering drugs, etc. in the field of medicine; they are widely used as insecticides, fungicides, etc. in the field of pesticides; in organic synthesis, they can be used to synthesize quinazolinone, o-aminobenzoic acid esters, o-aminobenzonitrile, benzotriazine ketone and other fine chemicals with important application value. Therefore, the synthesis of o-tert-butylaminobenzamide derivatives has been highly valued by the majority of chemists.

[0003] However, there are two main types of synthetic methods for o-tert-butylaminobenzamide derivatives that have been reported so far. One is the aromatic nitration reduction reaction, and the other is the metal-catalyzed coupling reaction. These two types of reactions have defects such as being limited by the harsh reaction conditions or requiring the prior substitution of specific functional groups at the carbon position to be reacted (such as the generation of halogenated benzene). Summary of the invention

[0004] In order to solve the deficiencies of the prior art, the present invention provides a method for preparing o-tert-butylaminobenzamide derivatives, which has simple operation, few side reactions and high yield, and can directly aminize the aromatic ring to synthesize o-tert-butylaminobenzamide derivatives with diverse substituent types.

[0005] In order to solve the deficiencies of the prior art, the technical solution provided by the present invention is:

[0006] A method for preparing o-tert-butylaminobenzamide derivatives, comprising:

[0007] Compound II, compound III, a palladium catalyst, a monophosphine ligand, a base and a first solvent are mixed and subjected to an amination reaction under an inert atmosphere to obtain an o-tert-butylaminobenzamide derivative represented by formula I. The synthesis route is shown in the following formula:

[0008]

[0009] in,

[0010] R1 represents a hydrogen atom, a methyl group, a phenyl group, a methoxy group, a fluorine atom, a chlorine atom, a trifluoromethyl group, an aldehyde group, a methyl ester group or a cyano group;

[0011] R2 represents a hydrogen atom, a methyl group, a phenyl group or a fluorine atom;

[0012] R4 represents a tert-butylamino group, a hydrogen atom, a methyl group, a fluorine atom or a chlorine atom.

[0013] Preferably, the preparation method of compound II is as follows:

[0014] Compound IV, 8-aminoquinoline, 4-dimethylaminopyridine, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and a second solvent are mixed and reacted to obtain compound II. The synthesis route is shown in the following formula:

[0015]

[0016] in,

[0017] R3 represents a hydrogen atom, a methyl group, a fluorine atom or a chlorine atom.

[0018] Preferably, the palladium catalyst is palladium iodide.

[0019] Preferably, the base is cesium carbonate.

[0020] Preferably, the first solvent is 1,4-dioxane.

[0021] Preferably, the monophosphine ligand is tris(4-trifluoromethylphenyl)phosphine.

[0022] Preferably, the concentration of compound II in the mixed solution of compound II, compound III, palladium catalyst, monophosphine ligand, base and the first solvent is 0.2 mol / L.

[0023] Preferably, the molar ratio of compound II, palladium catalyst, monophosphine ligand, base and compound III is 1:(0.06-0.12):(0.12-0.24):(1.25-2.5):(1.1-2.1).

[0024] Preferably, the reaction temperature of the amination reaction is 125-135° C., and the reaction time is 10-14 h.

[0025] Preferably, the molar ratio of compound IV, 8-aminoquinoline, 4-dimethylaminopyridine and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:(0.9-1.0):(1-1.5):(1.3-1.5).

[0026] Beneficial effects of the present invention:

[0027] The method for preparing o-tert-butylaminobenzamide derivatives provided by the present invention has the advantages that the substrate benzoic acid compound is simple and easy to obtain, the substrate range is wide, the operation is simple, the side reaction is less, the yield is high, and the aromatic ring can be directly aminized to synthesize o-tert-butylaminobenzamide derivatives with diverse substituent types.

[0028] The invention uses N,N-di-tert-butyldiazacycloketone as a nitrogen source to prepare o-tert-butylaminobenzamide 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. It has a good protecting effect in the further derivatization reaction of the o-tert-butylaminobenzamide derivatives. DETAILED DESCRIPTION

[0029] 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.

[0030] The present invention provides a method for preparing an o-tert-butylaminobenzamide derivative, comprising:

[0031] 1) Preparation of compound II (benzamide derivative derived from 8-aminoquinoline):

[0032] The synthetic route is as follows:

[0033]

[0034] Compound IV (benzoic acid derivative), 8-aminoquinoline, 4-dimethylaminopyridine, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and a second solvent were mixed and stirred at room temperature for 12 hours to generate compound II (benzamide derivative derived from 8-aminoquinoline); after the reaction, dichloromethane was added to dilute, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure, and compound II was separated by chromatographic column.

[0035] Among them, R1 represents a hydrogen atom, a methyl group, a phenyl group, a methoxy group, a fluorine atom, a chlorine atom, a trifluoromethyl group, an aldehyde group, a methyl ester group or a cyano group; R2 represents a hydrogen atom, a methyl group, a phenyl group or a fluorine atom; R3 represents a hydrogen atom, a methyl group, a fluorine atom or a chlorine atom.

[0036] In an optional embodiment of the present invention, the molar ratio of compound IV, 8-aminoquinoline, 4-dimethylaminopyridine and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:(0.9-1.0):(1-1.5):(1.3-1.5).

[0037] In an optional embodiment of the present invention, the second solvent is dichloromethane.

[0038] b) Preparation of compound III (N,N-di-tert-butyldiazepine)

[0039] 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;

[0040] 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 III is obtained.

[0041] 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.

[0042] 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.

[0043] c) Preparation of o-tert-butylaminobenzamide derivatives represented by formula I

[0044] Compound II, compound III, a palladium catalyst, a monophosphine ligand, a base and a first solvent are mixed, and an amination reaction is carried out under an inert atmosphere to obtain an o-tert-butylaminobenzamide derivative shown in formula I.

[0045] After the reaction is completed, ethyl acetate is added for dilution, and the mixture is filtered through 300-400 mesh silica gel, eluted with ethyl acetate, the solvent is removed under reduced pressure, and separated by chromatography using 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.

[0046] The synthetic route is shown below:

[0047]

[0048] in,

[0049] R1 represents a hydrogen atom, a methyl group, a phenyl group, a methoxy group, a fluorine atom, a chlorine atom, a trifluoromethyl group, an aldehyde group, a methyl ester group or a cyano group;

[0050] R2 represents a hydrogen atom, a methyl group, a phenyl group or a fluorine atom;

[0051] R4 represents a tert-butylamino group, a hydrogen atom, a methyl group, a fluorine atom or a chlorine atom.

[0052] Taking R1 and R2 as hydrogen atoms and R4 as a methyl group as an example, the reaction mechanism of the present invention is described:

[0053]

[0054] Wherein, L represents a phosphine ligand; after the substrate 9r is complexed with the palladium catalyst, it is activated by carbon-hydrogen activation to generate an ortho-activated palladium ring intermediate 16, which is oxidatively added to the three-membered ring nitrogen-containing reagent III to generate the corresponding palladium (IV) intermediate 17, which releases tBuNCO to give the nitrene intermediate 18, which is reduced and eliminated to give the amination product 10r and the palladium catalyst; the amide group has the role of a directing group, and 8-aminoquinoline acts as a directing group in the reaction.

[0055] In an optional embodiment of the present invention, the palladium catalyst is palladium iodide, the base is cesium carbonate, and the monophosphine ligand is tris(4-trifluoromethylphenyl)phosphine.

[0056] In an optional embodiment of the present invention, the first solvent is 1,4-dioxane or tetrahydrofuran, preferably 1,4-dioxane.

[0057] In an optional embodiment of the present invention, the concentration of compound II in the mixed solution of compound II, compound III, palladium catalyst, monophosphine ligand, base and the first solvent is 0.2 mol / L.

[0058] In an optional embodiment of the present invention, the molar ratio of compound II, palladium catalyst, monophosphine ligand, base and compound III is 1:(0.06-0.12):(0.12-0.24):(1.25-2.5):(1.1-2.1).

[0059] In an optional embodiment of the present invention, the reaction temperature of the amination reaction is 125-135° C., preferably 125° C. The reaction time is 10-14 h, preferably 12 h.

[0060] Compounds Ⅰ-a to Ⅰ-o are some examples of o-tert-butylaminobenzamide derivatives prepared by the present invention. When R3 is a hydrogen atom, an amination reaction can occur to generate a disubstituted o-tert-butylaminobenzamide derivative. When R2 is not a hydrogen atom, the steric hindrance effect will hinder the amination reaction of R3, and at this time, only a monosubstituted o-tert-butylaminobenzamide derivative can be generated.

[0061]

[0062] Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0063] The reagents used in the following examples are all commercially available, among which 8-aminoquinoline was purchased from Leyan Reagent, and palladium iodide, tris(4-trifluoromethylphenyl)phosphine, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were purchased from Anaiji Chemical.

[0064] Example 1

[0065] Preparation of Compound Ia:

[0066] 1) Preparation of compound II-a:

[0067]

[0068] Benzoic acid (1.2212 g, 10 mmol), 8-aminoquinoline (1.2975 g, 9 mmol), 4-dimethylaminopyridine (DMAP) (1.2217 g, 10 mmol) were weighed and dissolved in dichloromethane (20 mL) at room temperature, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl, EDCL in the above formula) (2.4921 g, 13 mmol) was added and stirred at room temperature for 12 h. After the reaction was completed, dichloromethane was added to dilute, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. Compound II-a 1.1918 g was obtained by separation by chromatographic column with a yield of 48%.

[0069] NMR data of compound II-a: 1 H NMR (400MHz, CDCl3) δ10.76(s,1H),8.95(dd,J=7.5,1.5Hz,1H),8.86(dd,J=4.2,1.7Hz,1H ),8.20(dd,J=8.2,1.6Hz,1H),8.14-8.04(m,2H),7.65-7.52(m,5H),7.49(q,J=4.2Hz,1H); 13 C NMR (400MHz, CDCl3) δ165.6,148.4,138.9,136.5,135.3,134.7,132.0,128.9,128.1,127.6,127.4,121.8,116.7.

[0070] 2) Preparation of compound Ia:

[0071]

[0072] Compound II-a (0.0993 g, 0.4 mmol), palladium iodide (0.0173 g, 0.048 mmol), tris(4-trifluoromethylphenyl)phosphine (0.0448 g, 0.096 mmol), cesium carbonate (0.3258 g, 1.0 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (2.0 mL) and compound III (0.1430 g, 0.84 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 125°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 (eluent: petroleum ether) to obtain a light yellow solid compound Ia (0.1230 g, yield 79%).

[0073] NMR data of compound Ia: 1 H NMR(400MHz,CDCl3)δ11.88(br s,1H),8.97(dd,J=7.6,1.6Hz,1H),8.79(dd,J=4.0,1.6Hz,1H),8.15(dd,J=8.0,1.6Hz,1H),7.57(t,J=8.0Hz,1H ),7.50(dd,J=8.4,1.2Hz,1H),7.43(dd,J=8.4,4.0Hz,1H),7.09(t,J=8.4Hz,1H),6.46(d,J=8.0Hz,2H),5.40(br s,2H),1.32(s,18H); 13 C NMR (100MHz, CDCl3) δ169.0,149.2,147.1,139.1,136.2,135.5,130.6,128.3,127.6,121.6,121.4,117.0,112.6,108.9,52.0,30.0.

[0074] Example 2

[0075] Preparation of Compound Ib:

[0076] 1) Preparation of compound II-b:

[0077]

[0078] Weigh p-toluic acid (1.3615 g, 10 mmol), 8-aminoquinoline (1.2975 g, 9 mmol), and 4-dimethylaminopyridine (1.2217 g, 10 mmol) and dissolve in dichloromethane (20 mL) at room temperature, then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4921 g, 13 mmol), and stir at room temperature for 12 h. After the reaction is completed, dilute with dichloromethane, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtering, remove the solvent by distillation under reduced pressure, and separate by chromatographic column to obtain 1.4427 g of compound II-b with a yield of 55%.

[0079] NMR data of compound Ⅱ-b: 1 H NMR (400MHz, CDCl3) δ10.73(s,1H),8.94(dd,J=7.5,1.4Hz,1H),8.85(dd,J=4.2,1.6Hz,1H),8.19(dd,J=8.3,1.7Hz,1H),7.99 (d,J=8.2Hz,2H),7.60(t,J=8.1Hz,1H),7.54(dd,J=8.2,1.5Hz,1H),7.48(q,J=4.2Hz,1H),7.35(d,J=7.6Hz,2H),2.46(s,3H); 13 C NMR (400MHz, CDCl3) δ165.6,148.4,142.5,138.9,136.5,134.9,132.5,129.6,128.2,127,7,127.5,121.8,121.7,116.6,21.7.

[0080] 2) Preparation of compound Ib:

[0081]

[0082] Compound II-b (0.1049 g, 0.4 mmol), palladium iodide (0.0173 g, 0.048 mmol), tris(4-trifluoromethylphenyl)phosphine (0.0448 g, 0.096 mmol), cesium carbonate (0.3258 g, 1.0 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (2.0 mL) and compound III (0.1430 g, 0.84 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 125°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 (eluent: petroleum ether) to obtain a light yellow solid compound Ib (0.1130 g, yield 70%).

[0083] NMR data of compound Ib: 1 H NMR(400MHz, CDCl3)δ12.07(br s,1H),8.977(dd,J=8.0,1.6Hz,1H),8.78(dd,J=4.4,1.6Hz,1H),8.14(dd,J=8.4,1.6Hz,1H),7.5 6(t,J=8.0Hz,1H),7.48(dd,J=8.4,1.2Hz,1H),7.42(dd,J=8.4,4.4Hz,1H),6.30(s,2H),5.47(br s,2H),2.28(s,3H),1.32(s,18H); 13 C NMR (100MHz, CDCl3) δ169.2,148.1,147.2,140.7,139.2,136.2,135.7,128.3,127.6,121.6,121.1,116.9,110.3,110.2,52.1,30.0,22.5.

[0084] Example 3

[0085] Preparation of compound Ic:

[0086] 1) Preparation of compound II-c:

[0087]

[0088] Weigh p-phenylbenzoic acid (1.9822 g, 10 mmol), 8-aminoquinoline (1.2975 g, 9 mmol), and 4-dimethylaminopyridine (1.2217 g, 10 mmol) and dissolve them in dichloromethane (20 mL) at room temperature, then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4921 g, 13 mmol), and stir at room temperature for 12 h. After the reaction is completed, dilute with dichloromethane, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtering, remove the solvent by distillation under reduced pressure, and separate by chromatographic column to obtain 1.6219 g of compound II-c with a yield of 50%.

[0089] NMR data of compound II-c: 1 H NMR (400MHz, CDCl3) δ10.81(s,1H),8.97(dd,J=7.5,1.5Hz,1H),8.87(dd,J=4.3, 1.7Hz,1H),8.24-8.12(m,3H),7.78(d,J=8.4Hz,2H),7.67(dJ=7.0Hz,2H),7.62(t J=8.1Hz,1H),7.56(dd J=8.3,1.5Hz,1H),7.53-7.45(m,3H),7.41(t J=7.4Hz,1H); 13 C NMR (400MHz, CDCl3) δ165.3,148.4,144.8,140.2,138.9,136.6,134.7,133 .9,129.1,128.2,128.2,128.0,127.6,127.6,127.4,121.9,121.8,116.7.

[0090] 2) Preparation of compound Ic:

[0091]

[0092] Compound II-c (0.1298 g, 0.4 mmol), palladium iodide (0.0173 g, 0.048 mmol), tris(4-trifluoromethylphenyl)phosphine (0.0448 g, 0.096 mmol), cesium carbonate (0.3258 g, 1.0 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (2.0 mL) and compound III (0.1430 g, 0.84 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at 125°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 (eluent: petroleum ether) to obtain brown solid compound Ic (0.1399 g, yield 75%).

[0093] NMR data of compound Ic: 1 H NMR(400MHz,CDCl3)δ12.06(br s,1H),9.00(dd,J=7.6,1.6Hz,1H),8.81(dd,J=4.4,2.0Hz,1H),8.16(dd,J=8.4,2.0Hz,1H),7.67-7.61(m,2H),7.5 9(t,J=8.0Hz,1H),7.51(dd,J=8.0,1.6Hz,1H),7.50-7.42(m,3H),7.39(tt,J=7.6,2.0Hz,1H),6.68(s,2H),5.58(br s,2H),1.38(s,18H); 13 C NMR (100MHz, CDCl3) δ168.9,148.2,147.5,143.5,142.0,139.2,136.2,135.6,12 8.8,128.3,127.7,127.6,127.3,121.6,121.4,117.0,111.3,108.1,52.2,30.1.

[0094] Example 4

[0095] Preparation of Compound Id:

[0096] 1) Preparation of compound II-d:

[0097]

[0098] Weigh p-methoxybenzoic acid (1.5215 g, 10 mmol), 8-aminoquinoline (1.2975 g, 9 mmol), and 4-dimethylaminopyridine (1.2217 g, 10 mmol) and dissolve in dichloromethane (20 mL) at room temperature, then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4921 g, 13 mmol), and stir at room temperature for 12 h. After the reaction is completed, dilute with dichloromethane, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtering, remove the solvent by distillation under reduced pressure, and separate by chromatographic column to obtain 1.5585 g of compound II-d with a yield of 56%.

[0099] NMR data of compound II-d: 1 H NMR (400MHz, CDCl3) δ10.68(s,1H),8.93(d,J=7.5Hz,1H),8.88-8.81(m,1H),8.18(d,J=8.3Hz,1H),8.06(d J=7.1Hz,2H),7.64-7.42(m,3H),7.04(d J=7.1Hz,1H),3.94-3.84(m,3H); 13 C NMR (400MHz, CDCl3) δ165.1,162.6,148.3,138.9,136.5,134.9,129.3,128.1,127.6,127.6,121.8,121.5,116.5,114.1,55.6.

[0100] 2) Preparation of compound Id:

[0101]

[0102] Compound II-d (0.1113 g, 0.4 mmol), palladium iodide (0.0173 g, 0.048 mmol), tris(4-trifluoromethylphenyl)phosphine (0.0448 g, 0.096 mmol), cesium carbonate (0.3258 g, 1.0 mmol) were added in sequence to a 15 mL pressure tube, and argon was filled in the tube under vacuum. Then, ultra-dry 1,4-dioxane (2.0 mL) and compound III (0.1430 g, 0.84 mmol) were added in sequence, and the mixture was sealed and placed in a magnetic heating stirrer at 125°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 (eluent: petroleum ether) to obtain a light yellow solid compound Id (0.1080 g, yield 64%).

[0103] NMR data of compound Id:1 H NMR(400MHz,CDCl3)δ11.87(br s,1H),8.94(dd,J=7.6,1.6Hz,1H),8.78(dd,J=4.4,1.6Hz,1H),8.14(dd,J=8.0,1.6Hz,1H),7.5 6(t,J=8.0Hz,1H),7.48(dd,J=8.4,1.6Hz,1H),7.42(dd,J=8.4,4.4Hz,1H),6.00(s,2H),5.70(br s,2H),3.82(s,3H),1.34(s,18H); 13 C NMR (100MHz, CDCl3) δ168.9,161.5,149.0,148.1,139.2,136.2,135.7,128.3,127.7,121.6,121.0,116.8,105.1,94.3,55.1,52.0,30.0.

[0104] Example 5

[0105] Preparation of Compound Ie:

[0106] 1) Preparation of compound II-e:

[0107]

[0108] Weigh p-chlorobenzoic acid (1.5656 g, 10 mmol), 8-aminoquinoline (1.2975 g, 9 mmol), and 4-dimethylaminopyridine (1.2217 g, 10 mmol) and dissolve them in dichloromethane (20 mL) at room temperature, then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4921 g, 13 mmol) and stir at room temperature for 12 h. After the reaction is completed, dilute with dichloromethane, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and distill under reduced pressure to remove the solvent. Separate by chromatographic column to obtain 1.8943 g of compound II-e with a yield of 67%.

[0109] NMR data of compound II-e: 1 H NMR (400MHz, CDCl3) δ10.72(s,1H),8.91(dd,J=7.3,1.7Hz,1H),8.85(dd,J=4.2,1.6 Hz,1H),8.20(dd,J=8.3,1.7Hz,1H),8.03(dt,J=8.6,2.6Hz,2H),7.64-7.46(m,5H); 13C NMR (400MHz, CDCl3) δ164.5,148.5,138.9,138.3,136.6,134.5,133.7,129.2,128.9,128.2,127.6,122.1,121.9,116.8.

[0110] 2) Preparation of Compound Ie:

[0111]

[0112] Compound II-e (0.1131 g, 0.4 mmol), palladium iodide (0.0173 g, 0.048 mmol), tris(4-trifluoromethylphenyl)phosphine (0.0448 g, 0.096 mmol), cesium carbonate (0.3258 g, 1.0 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (2.0 mL) and compound III (0.1430 g, 0.84 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at 125°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 (eluent: petroleum ether) to obtain a light yellow solid compound Ie (0.1080 g, yield 74%).

[0113] NMR data of compound Ie: 1 H NMR(400MHz, CDCl3)δ11.48(br s,1H),8.92(dd,J=7.6,1.2Hz,1H),8.79(dd,J=4.4,1.6Hz,1H),8.16(dd,J=8.4,2.0Hz,1H),7.5 7(t,J=8.4Hz,1H),7.52(dd,J=8.4,1.6Hz,1H),7.44(dd,J=8.4,4.4Hz,1H),6.40(s,2H),5.50(br s,2H),1.34(s,18H); 13 C NMR (100MHz, CDCl3) δ168.1,148.3,147.9,139.0,136.8,136.3,135.1,128.3,127.6,121.8,121.6,117.0,109.0,106.9,52.0,29.9.

[0114] Example 6

[0115] Preparation of Compound If:

[0116] 1) Preparation of compound II-f:

[0117]

[0118] Weigh p-trifluoromethylbenzoic acid (1.9012 g, 10 mmol), 8-aminoquinoline (1.2975 g, 9 mmol), and 4-dimethylaminopyridine (1.2217 g, 10 mmol) and dissolve in dichloromethane (20 mL) at room temperature, then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4921 g, 13 mmol), and stir at room temperature for 12 h. After the reaction is completed, dilute with dichloromethane, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtering, remove the solvent by distillation under reduced pressure, and separate by chromatographic column to obtain 2.0558 g of compound II-f with a yield of 65%.

[0119] NMR data of compound Ⅱ-f: 1 H NMR (400MHz, CDCl3) δ10.79(s,1H),8.92(dd,J=7.1,1.9Hz,1H),8.86(dd,J=4.2,1.7Hz, 1H),8.25-8.15(m,3H),7.82(d,J=8.1Hz,2H),7.65-7.55(m,2H),7.50(q,J=4.2Hz,1H); 13 C NMR (400MHz, CDCl3) δ164.2,148.6,138.8,138.6(q,J C-F =6.0Hz),136.6,134.3,133.6(q,J C-F =32.5Hz)128.1,127.9,127.6,126.0(q,J C-F =3.8Hz),123.9(q,J C-F =270.8Hz)122.3,122.0,116.9.

[0120] 2) Preparation of compound If:

[0121]

[0122] Compound II-f (0.1265 g, 0.4 mmol), palladium iodide (0.0173 g, 0.048 mmol), tris(4-trifluoromethylphenyl)phosphine (0.0448 g, 0.096 mmol), cesium carbonate (0.3258 g, 1.0 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (2.0 mL) and compound III (0.1430 g, 0.84 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 125°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 (eluent: petroleum ether) to obtain a light yellow solid compound If (0.0930 g, yield 51%).

[0123] NMR data of compound If: 1 H NMR(400MHz,CDCl3)δ11.39(br s,1H),8.94(dd,J=7.2,1.6Hz,1H),8.79(dd,J=4.0,1.6Hz,1H),8.17(dd,J=8.0,1.6Hz,1H ),7.59(t,J=8.0Hz,1H),7.54(dd,J=8.0,1.6Hz,1H),7.46(dd,J=8.4,4.0Hz,1H),6.62(br s,2H),5.43(br s,2H),1.35(s,18H); 13 C NMR (100MHz, CDCl3) δ167.7,148.4,147.1,138.9,136.4,134.8,132.3(q, 2 J C-F =31.1Hz),128.3,127.6,124.3(q, 1 J C-F =271.1Hz),122.0,121.9,117.1,113.0,103.0(q, 3 J C-F =3.8Hz),52.0,29.9.

[0124] Example 7

[0125] Preparation of Compound Ig:

[0126] 1) Preparation of compound II-g:

[0127]

[0128] Weigh p-cyanobenzoic acid (1.4713 g, 10 mmol), 8-aminoquinoline (1.2975 g, 9 mmol), and 4-dimethylaminopyridine (1.2217 g, 10 mmol) and dissolve in dichloromethane (20 mL) at room temperature, then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4921 g, 13 mmol), and stir at room temperature for 12 h. After the reaction is completed, dilute with dichloromethane, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtering, remove the solvent by distillation under reduced pressure, and separate by chromatographic column to obtain 1.6398 g of compound II-g with a yield of 60%.

[0129] NMR data of compound II-g: 1 H NMR (400MHz, CDCl3) δ10.80(s,1H),8.90(dd,J=6.3,2.6Hz,1H),8.86(dd,J=4.2,1.6Hz,1H),8.22(dd,J =8.3,1.7Hz,1H),8.18(d,J=8.2Hz,2H),7.86(d,J=8.2Hz,2H),7.66-7.57(m,2H),7.51(q,J=4.2Hz,1H); 13 C NMR (400MHz, CDCl3) δ163.6,148.7,139.1,138.8,136.7,134.1,132.8,128.2,128.1,127.6,122.6,122.1,118.2,117.0,115.5.

[0130] 2) Preparation of Compound Ig:

[0131]

[0132] Compound II-g (0.1093 g, 0.4 mmol), palladium iodide (0.0173 g, 0.048 mmol), tris(4-trifluoromethylphenyl)phosphine (0.0448 g, 0.096 mmol), cesium carbonate (0.3258 g, 1.0 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (2.0 mL) and compound III (0.1430 g, 0.84 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 125°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 (eluent: petroleum ether) to obtain a light yellow solid compound Ig (0.5480 g, yield 32%).

[0133] NMR data of compound Ig: 1 H NMR(400MHz, CDCl3)δ11.11(br s,1H),8.91(d,J=6.8Hz,1H),8.79(dd,J=4.4,1.6Hz,1H),8.19(dd,J=8.4,1.6Hz,1H), 7.63-7.54(m,2H),7.47(dd,J=8.4,4.4Hz,1H),6.60(s,2H),5.35(s,2H),1.34(s,18H); 13 C NMR (100MHz, CDCl3) δ167.1,148.5,147.0,138.8,136.5,134.5,128.3,127.6,122.2,122.0,120.1,117.2,114.0,113.3,108.5,52.0,29.9.

[0134] Example 8

[0135] Preparation of compound Ih:

[0136] 1) Preparation of compound II-h:

[0137]

[0138] Weigh p-formylbenzoic acid (1.5013 g, 10 mmol), 8-aminoquinoline (1.2975 g, 9 mmol), and 4-dimethylaminopyridine (1.2217 g, 10 mmol) and dissolve them in dichloromethane (20 mL) at room temperature, then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4921 g, 13 mmol), and stir at room temperature for 12 h. After the reaction is completed, dilute with dichloromethane, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtering, remove the solvent by distillation under reduced pressure, and separate by chromatographic column to obtain 1.4091 g of compound II-h with a yield of 51%.

[0139] NMR data of compound II-h: 1 H NMR (400MHz, CDCl3) δ10.83(s,1H),10.14(s,1H),8.94(dd,J=7.0,2.0Hz,1H),8.87(dd,J=4.2,1. 6Hz,1H),8.28-8.19(m,3H),8.07(dt,J=8.5,1.6Hz,2H),7.66-7.57(m,2H),7.51(q,J=4.2Hz,1H); 13C NMR (400MHz, CDCl3) δ191.7,164.4,148.6,140.4,138.9,138.6,136.7,134.3,130.2,128.2,127.6,122.4,122.0,116.9.

[0140] 2) Preparation of compound Ih:

[0141]

[0142] Compound II-h (0.1105 g, 0.4 mmol), palladium iodide (0.0173 g, 0.048 mmol), tris(4-trifluoromethylphenyl)phosphine (0.0448 g, 0.096 mmol), cesium carbonate (0.3258 g, 1.0 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (2.0 mL) and compound III (0.1430 g, 0.84 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 125°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 (eluent: petroleum ether) to obtain a light yellow solid compound Ig (0.5480 g, yield 32%).

[0143] NMR data of compound Ih: 1 H NMR(400MHz,CDCl3)δ11.37(br s,1H),9.90(s,1H),8.94(d,J=7.6Hz,1H),8.79(dd,J=4.4,1.6Hz,1H),8.18(dd,J=8.4,1.6Hz,1H), 7.59(t,J=8.0Hz,1H),7.55(dd,J=8.4,1.6Hz,1H),7.46(dd,J=8.0,4.0Hz,1H),6.89(s,2H),5.35(br s,2H),1.37(s,18H); 13 C NMR (100MHz, CDCl3) δ193.3,167.7,148.4,147.3,138.9,137.7,136.4,134.8,128.3,127.6,122.1,121.9,117.2,115.6,107.6,52.0,30.0.

[0144] Example 9

[0145] Preparation of Compound Ii:

[0146] 1) Preparation of compound II-i:

[0147]

[0148] Weigh 4-ester benzoic acid (1.8016 g, 10 mmol), 8-aminoquinoline (1.2975 g, 9 mmol), and 4-dimethylaminopyridine (1.2217 g, 10 mmol) and dissolve in dichloromethane (20 mL) at room temperature, then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4921 g, 13 mmol), and stir at room temperature for 12 h. After the reaction is completed, dilute with dichloromethane, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtering, distill under reduced pressure to remove the solvent, separate by chromatographic column to obtain 1.2950 g of compound II-i with a yield of 42%.

[0149] NMR data of compound II-i: 1 H NMR (400MHz, CDCl3) δ10.75(s,1H),8.90(dt,J=7.3,1.6Hz,1H),8.82(dd,J=4.3,1. 9Hz,1H),8.22-8.06(m,5H),7.61-7.50(m,2H),7.45(q,J=4.4Hz,1H),3.95(s,3H); 13 C NMR (400MHz, CDCl3) δ166.4,164.4,148.5,139.0,138.8,136.5,134.3,133.0,130.1,128.0,127.5,127.4,122.1,121.9,116.8,52.5.

[0150] 2) Preparation of compound Ii:

[0151]

[0152] Compound II-i (0.1233 g, 0.4 mmol), palladium iodide (0.0173 g, 0.048 mmol), tris(4-trifluoromethylphenyl)phosphine (0.0448 g, 0.096 mmol), cesium carbonate (0.3258 g, 1.0 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (2.0 mL) and compound III (0.1430 g, 0.84 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 125°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 (eluent: petroleum ether) to obtain a light yellow solid compound Ii (0.1400 g, yield 78%).

[0153] NMR data of compound Ii: 1 H NMR(400MHz,CDCl3)δ11.72(br s,1H),8.95(d,J=7.2Hz,1H),8.79(dd,J=4.0,1.6Hz,1H),8.16(dd,J=8.4,1.6Hz,1H),7.58(t ,J=8.0Hz,1H),7.53(dd,J=8.4,1.6Hz,1H),7.44(dd,J=8.4,4.4Hz,1H),7.11(s,2H),5.37(br s,2H),3.92(s,3H),1.34(s,18H); 13 C NMR (100MHz, CDCl3) δ168.2,167.6,148.3,146.8,139.0,136.3,135.1,13 1.6,128.3,127.6,121.80,121.77,117.2,115.3,108.9,52.4,52.2,30.0.

[0154] Example 10

[0155] Preparation of Compound Ij:

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

[0157]

[0158] Weigh m-toluic acid (1.3615 g, 10 mmol), 8-aminoquinoline (1.2975 g, 9 mmol), and 4-dimethylaminopyridine (1.2217 g, 10 mmol) and dissolve in dichloromethane (20 mL) at room temperature. Then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4921 g, 13 mmol) and stir at room temperature for 12 h. After the reaction is completed, dilute with dichloromethane, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtering, distill under reduced pressure to remove the solvent, separate by chromatographic column to obtain 1.2423 g of compound II-j with a yield of 47%.

[0159] NMR data of compound II-j: 1 H NMR (400MHz, CDCl3) δ10.70 (s, 1H), 8.94 (dd, J = 7.6, 1.4Hz, 1H), 8.84 (dd, J = 4. 2,1.7Hz,1H),8.15(dd,J=8.3,1.7Hz,1H),7.92-7.84(m,2H),7.58(t,J=8.1Hz 1H),7.52(dd,J=8.3,1.4Hz,1H),7.48-7.34(m,3H),2.48(s,3H); 13 CNMR (400MHz, CDCl3) δ165.8,148.4,138.8,138.7,136.4,135.2,134.7,132.7,128.7,128.1,128.1,127.5,124.3,121.7,121.7,116.6,21.6.

[0160] 2) Preparation of compound Ij:

[0161]

[0162] Compound II-j (0.1057 g, 0.4 mmol), palladium iodide (0.0087 g, 0.024 mmol), tris(4-trifluoromethylphenyl)phosphine (0.0224 g, 0.048 mmol), cesium carbonate (0.1629 g, 0.5 mmol) were added in sequence to a 15 mL pressure tube, vacuumed and filled with argon, then ultra-dry 1,4-dioxane (2.0 mL) and compound III (0.1430 g, 0.84 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at 125°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 (eluent: petroleum ether) to obtain a light yellow solid compound Ij (0.0300 g, yield 41%).

[0163] NMR data of compound Ij: 1 H NMR(400MHz,CDCl3)δ10.7(br s,1H),8.85(d,J=1.6Hz,1H),8.83(dd,J=2.8,1.6Hz,1H),8.17(dd,J=8.4,1.6Hz,1H) ,7.62-7.55(m,2H),7.52(dd,J=8.0,1.6Hz,1H),7.47(dd,J=8.4,4.4Hz,1H),7.33(br s,1H),7.16(dd,J=8.4,1.6Hz,1H),6.96(d,J=8.4Hz,1H),2.34(s,3H),1.42(s,9H); 13 C NMR (100MHz, CDCl3) δ168.7,148.3,146.8,139.1,136.5,135.2,133.3,128. 9,128.2,127.6,124.6,121.7,121.4,118.3,116.6,116.5,51.1,30.0,20.6.

[0164] Embodiment 11

[0165] Preparation of Compound Ik:

[0166] 1) Preparation of compound II-k:

[0167]

[0168] Weigh m-phenylbenzoic acid (1.9822 g, 10 mmol), 8-aminoquinoline (1.2975 g, 9 mmol), and 4-dimethylaminopyridine (1.2217 g, 10 mmol) and dissolve in dichloromethane (20 mL) at room temperature, then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4921 g, 13 mmol), and stir at room temperature for 12 h. After the reaction is completed, dilute with dichloromethane, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtering, distill under reduced pressure to remove the solvent, and separate by chromatographic column to obtain 1.4688 g of compound II-k with a yield of 45%.

[0169] NMR data of compound II-k: 1H NMR (400MHz, CDCl3) δ10.80 (s, 1H), 8.98 (dd, J = 7.5, 1.4Hz, 1H), 8.85 (dd, J = 4 .2,1.6Hz,1H),8.32(t,J=1.9Hz,1H),8.19(dd,J=8.3,1.7Hz,1H),8.05(dt,J =7.7,1.4Hz,1H),7.81(dt,J=7.8,1.5Hz,1H),7.73-7.68(m,2H),7.66-7.59( m,2H),7.56(dd,J=8.3,1.5Hz,1H),7.54-7.45(m,3H),7.42(t,J=7.4Hz,1H); 13 CNMR (400MHz, CDCl3) δ165.6,148.5,142.1,140.4,138.9,136.5,135.9,134.7,13 0.7,129.4,129.1,128.1,127.9,127.6,127.4,126.4,126.0,121.9,121.8,116.7.

[0170] 2) Preparation of compound Ik:

[0171]

[0172] Compound II-k (0.1306 g, 0.4 mmol), palladium iodide (0.0087 g, 0.024 mmol), tris(4-trifluoromethylphenyl)phosphine (0.0224 g, 0.048 mmol), cesium carbonate (0.1629 g, 0.5 mmol) were added in sequence to a 15 mL pressure tube, and argon was filled in the tube under vacuum. Then, ultra-dry 1,4-dioxane (2.0 mL) and compound III (0.1430 g, 0.84 mmol) were added in sequence, and the mixture was sealed and placed in a magnetic heating stirrer at 125°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 (eluent: petroleum ether) to obtain a light yellow solid compound Ik (0.1360 g, yield 86%).

[0173] NMR data of compound Ik: 1H NMR(400MHz,CDCl3)δ10.68(br s,1H),8.85(dt,J=7.6,1.2Hz,1H),8.82(dd,J=4.0,1.6Hz,1H),8.17(dd,J=8.4,1.6Hz,1H),8.04(d,J=2.0Hz,1H),7.84(br s,1H),7.67-7.57(m,4H),7.54(dd,J=8.4,1.6Hz,1H),7.50-7.43(m,3H),7.36-7.29(m,1H),7.11(d,J=8.0Hz,1H),1.51(s,9H); 13 C NMR (100MHz, CDCl3) δ168.8,148.51,148.47,140.8,139.0,136.4,135.0,131.2,129.0,12 8.2,127.53,127.50,127.1,126.4,126.3,121.8,121.6,117.5,116.6,115.4,51.0,29.9.

[0174] Example 12

[0175] Preparation of compound I1:

[0176] 1) Preparation of compound II-1:

[0177]

[0178] Weigh m-fluorobenzoic acid (1.4011 g, 10 mmol), 8-aminoquinoline (1.2975 g, 9 mmol), and 4-dimethylaminopyridine (1.2217 g, 10 mmol) and dissolve them in dichloromethane (20 mL) at room temperature. Then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4921 g, 13 mmol) and stir at room temperature for 12 h. After the reaction is completed, dilute with dichloromethane, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtering, distill off the solvent under reduced pressure and separate by chromatographic column to obtain 1.2610 g of compound II-1 with a yield of 47%.

[0179] NMR data of compound II-1: 1H NMR (400MHz, CDCl3) δ10.71(s,1H),8.90(d,J=7.2Hz,1H),8.84(d,J=3.8Hz,1H),8.16(d,J=8 .4Hz,1H),7.84(d,J=7.5Hz,1H),7.78(d,J=9.4Hz,1H),7.62-7.43(m,4H),7.31-7.23(m,1H); 13 C NMR(400MHz, CDCl3)δ164.1(d,J C-F =2.8Hz),163.0(d,J C-F =146.1Hz),148.5,138.8,137.5(d,J C-F =6.8Hz),136.5,134.3,130.6(d,J C-F =7.9Hz),128.1,127.5,122.8(d,J C-F =3.0Hz),122.1,121.9,119.0(d,J C-F =21.2Hz),116.7,114.8(d,J C-F =22.8Hz).

[0180] 2) Preparation of compound I1:

[0181]

[0182] Compound II-1 (0.1073 g, 0.4 mmol), palladium iodide (0.0173 g, 0.048 mmol), tris(4-trifluoromethylphenyl)phosphine (0.0448 g, 0.096 mmol), cesium carbonate (0.3258 g, 1.0 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (2.0 mL) and compound III (0.1430 g, 0.84 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 125°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 (eluent: petroleum ether) to obtain a light yellow solid compound Il (0.0932 g, yield 57%).

[0183] NMR data of compound I1: 1H NMR (400MHz, CDCl3) δ12.89(br s,1H),8.98(dt,J=8.0,1.6Hz,1H),8.83(dd,J=4.4,1.6Hz,1H),8.15(dd,J=8.0,1.6Hz,1H),7.72(br s,1H),7.57(t,J=8.0 1H),7.50(dd,J=8.0,1.6Hz,1H),7.43(dd,J=8.0,4.4Hz,1H),7.03(t,J=8.8Hz,1H),6.75(dd,J=9.2,4.4Hz 1H),3.55(br s,1H),1.40(s,9H),1.09(s,9H); 13 C NMR (100MHz,CDCl3)δ168.6(d, 3 J C-F =3.2Hz),150.5(d, 1 J C-F =226.6Hz),148.2,146.0,139.5,136.2,135.8,131.9(d, 2 J C-F =15.9Hz),128.4,127.6,121.6,121.4,118.0,117.6(d, 2 J C-F =23.6Hz),117.4,112.9(d, 3 J C-F =6.8Hz),56.0,51.4,30.2,29.4.

[0184] Example 13

[0185] Preparation of Compound Im:

[0186] 1) Preparation of compound II-m:

[0187]

[0188] Weigh o-toluic acid (1.3615 g, 10 mmol), 8-aminoquinoline (1.2975 g, 9 mmol), and 4-dimethylaminopyridine (1.2217 g, 10 mmol) and dissolve in dichloromethane (20 mL) at room temperature, then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4921 g, 13 mmol), and stir at room temperature for 12 h. After the reaction is completed, dilute with dichloromethane, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtering, distill under reduced pressure to remove the solvent, separate by chromatographic column to obtain 1.6653 g of compound II-m with a yield of 63%.

[0189] NMR data of compound II-m: 1 H NMR (400MHz, CDCl3) δ10.21(s,1H),8.94(d,J=7.5Hz,1H),8.78(dd,J=4.2,1.7Hz,1H),8.19(dd,J=8.3,1.7Hz,1H),7.69( d,J=7.5Hz,1H),7.64-7.53(m,2H),7.46(q,J=4.2Hz,1H),7.41(td,J=7.6,1.5Hz,1H),7.33(t,J=7.6Hz,2H),2.61(s,3H); 13 C NMR (400MHz, CDCl3) δ168.4,148.4,138.8,136.8,136.8,136.5,134.9,131.5,130.5,128.2,127.6,127.4,126.2,121.9,121.8,116.7,20.4.

[0190] 2) Preparation of Compound Im:

[0191]

[0192] Compound II-m (0.1057 g, 0.4 mmol), palladium iodide (0.0087 g, 0.024 mmol), tris(4-trifluoromethylphenyl)phosphine (0.0224 g, 0.048 mmol), cesium carbonate (0.1629 g, 0.5 mmol) were added in sequence to a 15 mL pressure tube, vacuumed and filled with argon, then ultra-dry 1,4-dioxane (2.0 mL) and compound III (0.1430 g, 0.84 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at 125°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 (eluent: petroleum ether) to obtain a white solid compound Im (0.1190 g, yield 89%).

[0193] NMR data of compound Im: 1H NMR(400MHz, CDCl3)δ10.11(br s,1H),8.97(d,J=8.0Hz,1H),8.76(dd,J=4.0,1.6Hz,1H),8.17(dd,J=8.4,1.6Hz,1H),7.60(t,J=8.4Hz,1H),7.56(dd,J= 8.4,1.6Hz,1H),7.45(dd,J=8.4,4.0Hz,1H),7.17(t,J=8.0Hz,1H),6.89(d,J=8.0Hz,1H),6.63(d,J=7.6Hz,1H),4.97(br s,1H),2.45(s,3H),1.36(s,9H); 13 C NMR (100MHz, CDCl3) δ168.6,148.4,145.4,138.7,136.4,135.8,134.6,129. 9,128.1,127.5,125.1,122.0,121.8,119.4,116.8,113.6,51.4,30.1,21.0.

[0194] Embodiment 14

[0195] Preparation of compound In:

[0196] 1) Preparation of compound II-n:

[0197]

[0198] Weigh o-fluorobenzoic acid (1.4011 g, 10 mmol), 8-aminoquinoline (1.2975 g, 9 mmol), and 4-dimethylaminopyridine (1.2217 g, 10 mmol) and dissolve in dichloromethane (20 mL) at room temperature, then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4921 g, 13 mmol), and stir at room temperature for 12 h. After the reaction is completed, dilute with dichloromethane, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtering, remove the solvent by distillation under reduced pressure, and separate by chromatographic column to obtain 1.4488 g of compound II-n with a yield of 54%.

[0199] NMR data of compound II-n: 1H NMR (400MHz, CDCl3) δ11.16(d,J=12.5Hz,1H),8.98(dd,J=7.3,1.7Hz,1H),8.87(dd,J=4.2,1.6Hz, 1H),8.23(td,J=7.8,1.9Hz,1H),8.17(dd,J=8.3,1.8Hz,1H),7.63-7.50(m,3H),7.49-7.42(m,1H); 13 C NMR(100MHz,CDCl3)δ161.8(d,J C-F =3.0Hz),160.7(d,J C-F =247.6Hz),148.6,138.9,136.4,135.0,133.7(d,J C-F =9.3Hz),132.1(d,J C-F =2.0Hz),128.1,127.5,125.0(d,J C-F =3.4Hz),122.20(d,J C-F =1.5Hz),122.19,121.8,117.4,116.5(d,J C-F =24.3Hz).

[0200] 2) Preparation of compound In:

[0201]

[0202] Compound II-n (0.1073 g, 0.4 mmol), palladium iodide (0.0087 g, 0.024 mmol), tris(4-trifluoromethylphenyl)phosphine (0.0224 g, 0.048 mmol), cesium carbonate (0.1629 g, 0.5 mmol) were added to a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (2.0 mL) and compound III (0.1430 g, 0.84 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 125°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 (eluent: petroleum ether) to obtain a white solid compound In (0.0900 g, yield 67%).

[0203] NMR data of compound In: 1H NMR (400MHz, CDCl3) δ10.91(d,J=12.4Hz 1H),8.93(d,J=1.6Hz,1H),8.84(dd,J=4.4,1.6Hz,1H),8.16(d,J=8.0Hz,1H),8.10(br s,1H),7.58(t,J=8.0Hz,1H),7.53(dd,J=8.4,4.4Hz,1H),7.25-7.17(m,1 H),6.76(d,J=8.4Hz,1H),6.41(ddd,J=12.4,8.0,1.2Hz,1H),1.46(s,9H); 13 C NMR (100MHz,CDCl3)δ165.2(d, 4 J C-F =2.2Hz),162.5(d, 1 J C-F =243.5Hz),150.9(d, 3 J C-F =5.1Hz),148.5,139.0,136.3,135.1,132.3(d, 3 J C-F =12.9Hz),128.1,127.5,121.8,121.7,117.1,110.4(d, 4 J C-F =2.4Hz),105.5(d, 2 J C-F =13.9Hz),101.6(d, 2 J C-F =25.5Hz),51.0,29.8.

[0204] Embodiment 15

[0205] Preparation of compound Io:

[0206] 1) Preparation of compound II-o:

[0207]

[0208] Weigh o-chlorobenzoic acid (1.5656 g, 10 mmol), 8-aminoquinoline (1.2975 g, 9 mmol), and 4-dimethylaminopyridine (1.2217 g, 10 mmol) and dissolve them in dichloromethane (20 mL) at room temperature, then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4921 g, 13 mmol), and stir at room temperature for 12 h. After the reaction is completed, dilute with dichloromethane, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtering, remove the solvent by distillation under reduced pressure, and separate by chromatographic column to obtain 1.1390 ​​g of compound II-o with a yield of 40%.

[0209] NMR data of compound II-o: 1 H NMR (400MHz, CDCl3) δ10.49 (s, 1H), 8.96 (d, J = 7.2Hz, 1H), 8.78 (d, J = 4.2Hz, 1H), 8.16 (d, J = 8.2Hz, 1H), 7.81 (d, J = 7.2Hz, 1H), 7.64-7.34 (m, 6H); 13 CNMR (400MHz, CDCl3) δ165.0,148.5,138.7,136.4,135.9,134.5,131.6,131.3,130.6,130.1,128.1,127.5,127.3,122.3,121.8,117.0.

[0210] 2) Preparation of compound Io:

[0211]

[0212] Compound II-o (0.1139 g, 0.4 mmol), palladium iodide (0.0087 g, 0.024 mmol), tris(4-trifluoromethylphenyl)phosphine (0.0224 g, 0.048 mmol), cesium carbonate (0.1629 g, 0.5 mmol) were added in sequence in a 15 mL pressure tube, vacuumed and filled with argon, and then ultra-dry 1,4-dioxane (2.0 mL) and compound III (0.1430 g, 0.84 mmol) were added in sequence, sealed and placed in a magnetic heating stirrer at a temperature of 125°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 (eluent: petroleum ether) to obtain a white solid compound Io (0.1100 g, yield 78%).

[0213] NMR data of compound Io: 1H NMR(400MHz,CDCl3)δ10.3(br s,1H),8.96(dd,J=7.2,1.2Hz,1H),8.79(dd,J=4.4,1.6Hz,1H),8.17(dd,J=8.4,1.6Hz,1H),7.67-7.52(m,2H),7. 45(dd,J=8.4,4.0Hz,1H),7.16(t,J=8.4Hz,1H),6.90(dd,J=8.8,1.2Hz,1H),6.76(dd,J=8.0,0.8Hz,1H),5.37(br s,1H),1.37(s,9H); 13 C NMR (100MHz, CDCl3) δ165.9,148.5,147.3,138.8,136.4,134.5,131.8,13 0.8,128.1,127.5,122.4,122.3,121.9,117.5,117.0,113.3,51.5,29.9.

[0214] Example 16

[0215] Preparation of N,N-di-tert-butyldiazepinone, i.e. compound III:

[0216]

[0217] 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.

[0218] 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, the reaction solution is cooled to 5°C, potassium tert-butoxide (17.0 g, 150.9 mmol) is added in batches, and the temperature is naturally raised and the reaction is carried out 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, yield 59%).

[0219] 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.

[0220] 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 an o-tert-butylaminobenzamide derivative, characterized in that: include, Compound II, compound III, a palladium catalyst, a monophosphine ligand, a base and a first solvent are mixed and subjected to an amination reaction under an inert atmosphere to obtain an o-tert-butylaminobenzamide derivative represented by formula I. The synthesis route is shown in the following formula: ； in, When R1 represents a hydrogen atom, a methyl group, a phenyl group, a methoxy group, a fluorine atom, a chlorine atom, a trifluoromethyl group, an aldehyde group, a methyl ester group or a cyano group, and R2 and R3 both represent a hydrogen atom, R4 represents a tert-butylamino group; When R1 represents a hydrogen atom, R2 represents a fluorine atom, and R3 represents a hydrogen atom, R4 represents a tert-butylamino group; When R1 represents a hydrogen atom, R2 represents a methyl group or a phenyl group, and R3 represents a hydrogen atom, R4 represents a hydrogen atom; When R1 represents a hydrogen atom, R2 represents a hydrogen atom, R3 represents a methyl group and R4 also represents a methyl group, or R3 represents a fluorine atom and R4 also represents a fluorine atom, or R3 represents a chlorine atom and R4 also represents a chlorine atom; The palladium catalyst is palladium iodide; The base is cesium carbonate; The monophosphine ligand is tris(4-trifluoromethylphenyl)phosphine; The reaction temperature of the amination reaction is 125° C. and the reaction time is 12 h.

2. The method for preparing an o-tert-butylaminobenzamide derivative according to claim 1, characterized in that: The preparation method of compound II is as follows: Compound IV, 8-aminoquinoline, 4-dimethylaminopyridine, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and a second solvent are mixed and reacted to obtain compound II. The synthesis route is shown in the following formula: 。 3. The method for preparing an o-tert-butylaminobenzamide derivative according to claim 1, characterized in that: The first solvent is 1,4-dioxane.

4. The method for preparing an o-tert-butylaminobenzamide derivative according to claim 1, characterized in that: The concentration of the compound II in the mixed solution of the compound II, the compound III, the palladium catalyst, the monophosphine ligand, the base and the first solvent is 0.2 mol / L.

5. The method for preparing an o-tert-butylaminobenzamide derivative according to claim 1, characterized in that: The molar ratio of the compound II, palladium catalyst, monophosphine ligand, base and compound III is 1:(0.06-0.12):(0.12-0.24):(1.25-2.5):(1.1-2.1).

6. The method for preparing an o-tert-butylaminobenzamide derivative according to claim 2, characterized in that: The molar ratio of the compound IV, 8-aminoquinoline, 4-dimethylaminopyridine and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:(0.9-1.0):(1-1.5):(1.3-1.5).

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