Preparation method of biaryl compound

Abstract

The invention discloses a preparation method of a biaryl compound (formula I or formula II), which shortens the synthetic route by designing a specific coupling reaction positioning and guiding group. Meanwhile, a reaction path is effectively controlled through reaction conditions, so that an arylation substitution product and an arylation cyclization product are selectively obtained. In addition, the atom utilization rate of the guiding group is high, by-products are reduced, products of various structure types can be formed through further derivatization of the guiding group, and the method can be used as an effective synthesis strategy of biaryl cyclopeptide molecules. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a method for preparing a biaryl compound, and particularly to a method for preparing a biaryl compound as a pharmaceutical intermediate. Background Art

[0002] Natural cyclic peptides containing biaryl groups widely exist in nature, and most of them exhibit remarkable biological properties, including antibacterial activity, cytotoxicity, proteasome inhibition and other biological properties. For example, vancomycin is isolated from the fermentation broth of actinomycetes. Its main structure is a biaryl and diaryl ether system formed by cross-linking the aryl side chains of corresponding amino acids. It is the first glycopeptide antibiotic, used for infections allergic to β-lactam antibiotics, treating methicillin-resistant Staphylococcus aureus, and is the last resort for treating infections caused by drug-resistant strains.

[0003]

[0004] Biphenylcyclopeptide natural products

[0005] From the perspective of the structure of such cyclic peptide molecules, their preparation process includes a coupling reaction for constructing a biphenyl group. For example, an intramolecular Suzuki-Miyaura cross-coupling reaction is used in the total synthesis of the natural product Arylomycin. Although a closed ring can be formed through the coupling reaction, when the conventional coupling reaction is applied to the structure construction of macrocyclic peptide molecules, the product yield is not high, and it is easy to form proto-dearylated by-products; the substrate needs to be pre-activated, and usually an additional borate group needs to be introduced, resulting in an increase in the synthesis route; and the borate group removed after coupling cannot be reused, forming toxic by-products, with low atom economic efficiency, and also causing environmental pollution.

[0006] In addition, conventional metal coupling reactions also face the same problems. Their raw materials are generally haloarenes and other highly reactive reagents (such as borate esters, amines, Grignard reagents, olefins, alkynes, etc.). In the case where the target molecule to be synthesized is relatively complex, these reagents cannot be directly obtained, increasing the length of the reaction synthesis route and reducing the synthesis efficiency. Summary of the Invention

[0007] Object of the Invention: The present invention aims to provide a method for preparing a biaryl compound with high atomic utilization.

[0008] Technical Solution: The method for preparing a biaryl compound having the structure of Formula I according to the present invention,

[0009]

[0010] In Formula I, the definitions of R and R' satisfy any one of the following cases:

[0011] (1) When R is selected from halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or halogenated phenyl substituted at the 2- or 6-position, it is mono-substituted at the 2- or 6-position, and R' is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 acyl, or C1-C4 ester group substituted at the para- or meta-position;

[0012] (2) When R is selected from halogen, C1-C4 alkyl, or C1-C4 haloalkyl substituted at the 3- or 5-position, it is mono- or di-substituted at the 2- and / or 6-position, and the definition of R' is the same as described above;

[0013] (3) When R is selected from hydrogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 alkyl C1-C4 carboxylate group substituted at the 4-position, it is di-substituted at the 2- and 6-positions, and the definition of R' is the same as described above;

[0014] The preparation method described above includes the following steps:

[0015] (1) Preparation of a compound containing a regioselective directing group

[0016]

[0017] Compound 2-11 is subjected to acylation, alkylation, condensation, and deamination protection reactions to obtain compound 2-13;

[0018] (2) Introduction of a regioselective directing group

[0019]

[0020] Compound 2-13 and compound 2-14 are subjected to an acylation reaction to obtain compound 2-15;

[0021] (3) Preparation of a biaryl compound

[0022]

[0023] Compound 2-15 and an iodinated compound are subjected to a coupling reaction to obtain the compound of formula I.

[0024] The preparation method of the biaryl compound having the structure of formula II according to the present invention,

[0025]

[0026] The definitions of R and R' in formula II are the same as described above;

[0027]

[0028] Compound 2-15 and the iodo compound are subjected to a coupling cyclization reaction to obtain the compound of Formula II.

[0029] In the preparation method designed by the present invention, on the one hand, by introducing a specific coupling reaction orientation guiding group and adopting a carbon-hydrogen bond activation reaction, the functional group transformation of the inert carbon-hydrogen bond is directly carried out, without the need to synthesize the coupling fragment molecule before using the traditional metal coupling reaction, reducing the reaction cost. At the same time, under the spatial fixation of the transition metal by the orientation guiding group containing a coordination atom in this reaction system, the ortho-carbon-hydrogen bond of the aryl group can be selectively activated and finally the arylation reaction is completed, with high reaction activity and ortho-regional selectivity. In addition, the guiding group will not be removed after the coupling reaction, and its methoxyoxime structure can undergo various reactions, and in combination with the ortho-carbon-hydrogen arylation reaction, the construction of various active molecular structures can be completed. On the other hand, by coordinating different reaction conditions, the reaction path is effectively controlled, so as to selectively obtain the arylation substitution product and the arylation cyclization product.

[0030]

[0031] Preferably, in the preparation method, the definition of R satisfies any of the following situations:

[0032] (1) When R is a 2-position or 6-position substituent, R is selected from nitro, fluorine, chlorine, bromine, methyl, methoxy, 4-chlorophenyl, 4-fluorophenyl;

[0033] (2) When R is a 3-position or 5-position substituent, R is selected from fluorine, chlorine, bromine, methoxy;

[0034] (3) When R is a 4-position substituent, R is selected from hydrogen, cyano, trifluoromethyl, methyl formate, tert-butyl, methyl, methoxy.

[0035] More preferably, in the preparation method, is selected from any of the following groups:

[0036]

[0037] More preferably, in the preparation method, is selected from any of the following groups:

[0038] where is the coupling site with the benzene ring, is the cyclization site with -C(O)-NH-.

[0039] Preferably, the molar ratio of the compound 2-15 to 4-iodoanisole is 1:3 to 1:5.

[0040] Preferably, the catalyst for the coupling reaction or the coupling cyclization reaction comprises Component 1, Component 2, and Component 3, wherein Component 1 is selected from Pd(OAc)2, Pd(TFA)2, Pd(OPiv)2, PdCl2, PdBr2, PdI2, Component 2 is selected from Ag2CO3, AgOAc, AgTFA, AgOPiv, Ag2O, and Component 3 is selected from Na2CO3, K2CO3.

[0041] More preferably, the molar ratio among Component 1, Component 2, and Component 3 of the catalyst is 0.1:(1.2 - 2.5):(2 - 4).

[0042] Preferably, the reaction solvent for the coupling reaction or the coupling cyclization reaction is selected from 1,2-dichloroethane, toluene, o-xylene, m-xylene, p-xylene, hexafluoroisopropanol.

[0043] More preferably, the reaction solvent for the coupling reaction is selected from 1,2-dichloroethane, and the reaction solvent for the coupling cyclization reaction is selected from hexafluoroisopropanol.

[0044] Preferably, the reaction temperature of the coupling reaction is 115 - 125 °C, and the reaction temperature of the coupling cyclization reaction is 125 - 135 °C.

[0045] More preferably, the reaction temperature of the coupling reaction is 120 ± 2 °C, and the reaction temperature of the coupling cyclization reaction is 130 ± 2 °C.

[0046] Preferably, the coupling reaction or the coupling cyclization reaction is carried out in an oxygen-free and water-free environment.

[0047] Beneficial effects: Compared with the prior art, the present invention has the following remarkable advantages:

[0048] By designing a specific coupling reaction positioning and guiding group, the present invention shortens the synthesis route. Meanwhile, the reaction path is effectively controlled through reaction conditions, thereby achieving selective acquisition of arylated substitution products and arylated cyclization products. In addition, the atom utilization rate of the guiding group is relatively high, reducing by-products. Moreover, various structural types of products can be further derived through the guiding group, which can be used as an effective synthesis strategy for diarylcyclopeptide molecules. Specific embodiments

[0049] The technical solution of the present invention will be further described below in conjunction with examples.

[0050] Example 1: Preparation of a compound containing a positioning and guiding group

[0051]

[0052] Using 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid 2-11 (5 g, 24.6 mmol, 1.0 equiv.) and dimethylhydroxylamine hydrochloride 2-12 (3.58 g, 36.9 mmol, 1.5 equiv.) as reaction raw materials, 30 ml of dichloromethane was added to the reaction system as the reaction solvent. Then DMAP (4.5 g, 36.9 mmol, 1.5 equiv.) and EDCI (7.07 g, 36.9 mmol, 1.5 equiv.) were added to the system. After 5 h, the reaction was stopped, the pH of the reaction system was adjusted to 5 - 6 with 1 mol / L HCl, and then the reaction system was extracted with water three times. The organic phase was dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and purified by column chromatography to obtain Weinreb amide 2-19 (4.5 g, 75%).

[0053] 2-19 (5 g, 20.3 mmol, 1.0 equiv.) was dissolved in 40 ml of ultra-dry tetrahydrofuran. At 0 °C, methylmagnesium bromide (3 M in THF, 16.9 ml, 50.8 mmol, 2.5 equiv.) was slowly added dropwise to the system. After reacting for 4 h, saturated ammonium chloride solution was slowly added to the system for quenching while maintaining the system at 0 °C throughout the process. After quenching, the tetrahydrofuran in the system was removed by distillation under reduced pressure, and then the aqueous phase was extracted three times with ethyl acetate, the organic phase was washed three times with saturated sodium chloride, then dried over anhydrous sodium sulfate and concentrated, and finally purified by column chromatography to obtain methyl ketone 2-21 (2.7 g, 65%).

[0054] 2-21 (1 g, 5.0 mmol, 1.0 equiv.) was dissolved in 10 ml of methanol in a high-pressure resistant glass sealed tube. Subsequently, pyridine (1.19 g, 15.0 mmol, 3.0 equiv.) and methylamine hydrochloride 2-22 (675.2 mg, 10.0 mmol, 2.0 equiv.) were added to the system, and argon was introduced for protection. Then the system was reacted overnight at 65 °C. The methanol in the system was removed by distillation under reduced pressure, and after extracting three times with ethyl acetate and water, the organic phase was washed three times with saturated sodium chloride, then dried over anhydrous sodium sulfate and concentrated, and finally purified by column chromatography to obtain methoxyoxime 2-23 (725.0 mg, 63%).

[0055] 2-23 (1 g, 4.3 mmol, 1.0 equiv.) was dissolved in a 3:7 solution (10 ml) of trifluoroacetic acid and dichloromethane at room temperature. After reacting for 3 h, the pH was adjusted to 9 with saturated sodium carbonate solution at 0 °C. Subsequently, the system was extracted three times with ether and water, the organic phase was washed three times with saturated sodium chloride, then dried over anhydrous sodium sulfate and concentrated, and the crude product 2-13 (374.8 mg, 67%) was directly obtained without column chromatography purification and used for subsequent reactions.

[0056] 2 - 13: Yellow liquid; R f = 0.5; DCM:MeOH = 10:1; 1 H NMR (400 MHz, CDCl3) δ = 5.24 (s, 1H), 2.15 (s, 3H), 1.39 (s, 9H), 1.36 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ = 209.39, 154.68, 79.74, 60.72, 28.38, 24.03, 23.54. HRMS (ESI) m / z calcd. for C6H 15 N2O + [M + H + : 131.1985, found: 131.1987.

[0057] Example 2: Introduction of the positioning - guiding group

[0058]

[0059] Add a DCM solution containing the guiding group 2 - 13 (0.75 g, 5.8 mmol, 1.0 equiv.) to a 100 - mL round - bottom flask. Then add the corresponding benzoyl chloride 2 - 14 (17.3 mmol, 3.0 equiv.) into the round - bottom flask. Immediately inject triethylamine (1.8 g, 17.3 mmol, 3.0 equiv.) into the round - bottom flask with a syringe. After about 3 h, the raw materials are completely reacted. Then use 1M HCl to adjust the pH value of the reaction system to 4 - 5. After that, extract the organic phase with water three times, 20 mL of water each time. After combining the organic phases, extract the organic phase with saturated sodium carbonate aqueous solution once. Then add anhydrous sodium sulfate to dry the organic phase and concentrate it with a rotary evaporator. Subsequently, perform column chromatography purification to obtain the substrate required for the C - H activation reaction after purification.

[0060] Compound 2 - 15: White solid (62%); R f = 0.43, PE:EA = 3:1; IR (KBr): 3267, 2933, 1633, 1047 cm -1 ; 1 HNMR (400 MHz, CDCl3) δ = 7.80 - 7.77 (m, 3H), 7.50 - 7.40 (m, 3H), 3.91 (s, 3H), 1.88 (s, 3H), 1.65 (s, 6H); 1313C NMR (100 MHz, CDCl3) δ = 166.0, 159.4, 135.8, 131.3, 128.6, 126.9, 62.0, 56.9, 24.4, 10.1; HRMS (ESI) m / z calcd. for C 13 H 19 N2O2 + [M + H + : 235.1441, found: 235.1438.

[0061] Referring to the preparation method of Example 2, the following compounds were prepared:

[0062]

[0063] Compound 2 - 28a: White solid (47%); R f = 0.27, PE:EA = 3:1; IR (KBr): 3279, 2933, 1652, 1531, 1342, 1047 cm -1 ; 1 1H NMR (400 MHz, CDCl3) δ = 8.01 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.57 - 7.52 (m, 2H), 7.32 (s, 1H), 3.81 (s, 3H), 1.88 (s, 3H), 1.67 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 165.0, 158.7, 146.7, 133.8, 133.7, 130.3, 128.8, 124.6, 61.9, 57.6, 2.06, 10.2; HRMS (ESI) m / z calcd. for C 13 H 18 N3O4 + [M + H + : 280.1292, found: 280.1293.

[0064]

[0065] Compound 2 - 28b: White solid (87%); R f = 0.31, PE:EA = 3:1; IR (KBr): 3283, 2940, 1652, 1053 cm -1 ; 11H NMR (400 MHz, CDCl3) δ = 7.68 (d, J = 7.2 Hz, 1H), 7.60 - 7.49 (m, 3H), 7.28 (s, 1H), 3.81 (s, 3H), 1.87 (s, 3H), 1.65 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 166.6, 158.6, 137.1 (q, J = 2.0 Hz), 132.1, 129.6, 128.8, 127.2 (q, J = 32.0 Hz), 126.4 (q, J = 5.0 Hz), 123.8 (q, J = 272.0 Hz), 61.9, 57.5, 24.0, 10.1; HRMS (ESI) m / z calcd. for C 14 H 18 F3N2O2 + [M + H + : 303.1315, found: 303.1319.

[0066]

[0067] Compound 2 - 28c: White solid (76%); R f = 0.47, PE:EA = 3:1; IR (KBr): 3302, 2930, 1643, 1047 cm -1 ; 1 1H NMR (400 MHz, CDCl3) δ = 8.18 (d, J = 12.8 Hz, 1H), 8.06 (td, J = 8.0, 2.0 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.26 - 7.22 (m, 1H), 7.11 (ddd, J = 12.0, 8.4, 0.8 Hz, 1H), 3.91 (s, 3H), 1.87 (s, 3H), 1.65 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 161.8 (d, J = 4.0 Hz), 160.7 (d, J = 246.0 Hz), 158.8 (d, J = 1.0 Hz), 133.0 (d, J = 9.0 Hz), 131.9 (d, J = 3.0 Hz), 124.7 (d, J = 3.0 Hz), 122.2 (d, J = 12.0 Hz), 116.1 (d, J = 25.0 Hz), 61.9, 57.4, 24.6, 10.1; HRMS (ESI) m / z calcd. for C 13 H 18 FN2O2 + [M + H +: 253.1347, found: 253.1345.

[0068]

[0069] Compound 2-24: White solid (84%); R f = 0.38, PE:EA = 3:1; IR(KBr): 3270, 2933, 1643, 1047 cm -1 ; 1 1H NMR(400 MHz, CDCl3) δ = 7.62(dd, J = 6.8, 1.6 Hz, 1H), 7.51(s, 1H), 7.39 - 7.27(m, 3H), 3.85(s, 3H), 1.88(s, 3H), 1.65(s, 6H); 13 13C NMR(100 MHz, CDCl3) δ = 165.3, 158.8, 136.2, 131.1, 130.8, 130.3, 130.1, 127.1, 61.9, 57.6, 24.5, 10.2; HRMS(ESI) m / z calcd. for C 13 1 18 7 + lN2O2 + [M + H

[0070]

[0071] Compound 2-28d: White solid (66%); R f = 0.32, PE:EA = 3:1; IR(KBr): 3276, 2930, 1646, 1050 cm -1 ; 1 1H NMR(400 MHz, CDCl3) δ = 7.49(d, J = 8.0 Hz, 1H), 7.43(dd, J = 7.6, 1.2 Hz, 1H), 7.28 - 7.24(m, 2H), 7.19 - 7.14(m, 1H), 3.77(s, 3H), 1.81(s, 3H), 1.59(s, 6H); 13 13C NMR(100 MHz, CDCl3) δ = 166.5, 158.8, 138.8, 133.4, 131.0, 129.6, 127.6, 119.4, 61.9, 57.5, 24.5, 10.2; HRMS(ESI) m / z calcd. for C 13 1 18 1 + [M + H +: 313.0546, found: 313.0551.

[0072]

[0073] Compound 2-28e: White solid (63%); R f = 0.47, DCM:CH3OH = 8:1; IR (KBr): 3286, 2933, 1643, 1047 cm -1 ; 1 1H NMR (400 MHz, CDCl3) δ = 7.47 (d, J = 7.6 Hz, 1H), 7.36 (q, J = 7.6 Hz, 1H), 7.29 (d, J = 7.2 Hz, 2H), 7.20 (s, 1H), 3.92 (s, 3H), 2.54 (s, 3H), 1.96 (s, 3H), 1.74 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 169.0, 159.1, 137.6, 135.9, 131.9, 129.7, 127.0, 125.9, 61.9, 57.1, 24.7, 20.0, 10.2; HRMS (ESI) m / z calcd. for C 14 19 21 N2O2 + [M+H + : 249.1598, found: 249.1593.

[0074]

[0075] Compound 2-28f: Yellow oily liquid (58%); R f = 0.27, DCM:CH3OH = 8:1; IR (KBr): 3340, 2933, 1656, 1233, 1053 cm -1 ; 1 1H NMR (400 MHz, CDCl3) δ = 8.96 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 1.86 (s, 3H), 1.63 (s, 6H); 1313C NMR (100 MHz, CDCl3) δ = 163.9, 160.1, 157.6, 132.6, 132.2, 122.6, 121.3, 111.4, 61.7, 57.0, 55.9, 24.8, 10.4; HRMS (ESI) m / z calcd. for C 14 H 21 N2O3 + [M + H + : 265.1547, found: 265.1550.

[0076]

[0077] Compound 2 - 30a: white solid (52%); R f = 0.55, PE:EA = 3:1; IR (KBr): 3279, 2933, 1636, 1047 cm -1 ; 1 1H NMR (400 MHz, CDCl3) δ = 7.86 (s, 1H), 7.54 - 7.48 (m, 2H), 7.39 (td, J = 8.0, 5.6 Hz, 1H), 7.17 (tdd, J = 8.4, 2.8, 0.8 Hz, 1H), 3.92 (s, 3H), 1.88 (s, 3H), 1.65 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 164.6 (d, J = 2.0 Hz), 162.9 (d, J = 246.0 Hz), 159.2, 138.2 (d, J = 7.0 Hz), 130.3 (d, J = 8.0 Hz), 122.3 (d, J = 3.0 Hz), 118.3 (d, J = 21.0 Hz), 114.4 (d, J = 22.0 Hz), 62.1, 57.0, 24.3, 10.2; HRMS (ESI) m / z calcd. for C 13 H 18 FN2O2 + [M + H + : 253.1347, found: 235.1342.

[0078]

[0079] Compound 2 - 30b: white solid (38%); R f = 0.40, PE:EA = 3:1; IR (KBr): 3299, 2921, 1636, 1050 cm -1 ; 11H NMR (400 MHz, CDCl3) δ = 7.83 (s, 1H), 7.77 (t, J = 2.0 Hz, 1H), 7.63 (dt, J = 8.0, 1.2 Hz, 1H), 7.44 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 3.92 (s, 3H), 1.88 (s, 3H), 1.64 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 164.6, 159.2, 137.6, 134.8, 131.3, 129.9, 127.5, 124.9, 62.0, 57.1, 24.3, 10.2; HRMS (ESI) m / z calcd. for C 13 H 18 ClN2O2 + [M+H + : 269.1051, found: 269.1045.

[0080]

[0081] Compound 2 - 30c: White solid (53%); R f = 0.44, PE:EA = 3:1; IR (KBr): 3305, 2933, 1640, 1047 cm -1 ; 1 1H NMR (400 MHz, CDCl3) δ = 7.93 (t, J = 2.0 Hz, 1H), 7.83 (s, 1H), 7.65 (dt, J = 7.6, 0.8 Hz, 1H), 7.60 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 3.92 (s, 3H), 1.88 (s, 3H), 1.65 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 164.5, 159.1, 137.8, 134.3, 130.4, 130.2, 125.4, 122.9, 62.1, 57.1, 24.3, 10.2; HRMS (ESI) m / z calcd. for C 13 H 18 BrN2O2 + [M+H + : 313.0546, found: 313.0549.

[0082]

[0083] Compound 2 - 30d: Yellow solid (64%); Rf = 0.47, PE:EA = 3:1; IR(KBr): 3286, 2921, 1636, 1053 cm -1 ; 1 H NMR(400 MHz, CDCl3) δ = 7.69(s, 1H), 7.56(s, 1H), 7.48(d, J = 6.4 Hz, 1H), 7.23(d, J = 6.8 Hz, 2H), 3.85(s, 3H), 2.32(s, 3H), 1.81(s, 3H), 1.58(s, 6H); 13 C NMR(100 MHz, CDCl3) δ = 166.2, 159.4, 138.4, 135.7, 132.0, 128.5, 127.8, 123.8, 61.9, 56.9, 24.4, 21.5, 10.1; HRMS(ESI) m / z calcd. for C 14 H 21 N2O2 + [M + H + : 249.1598, found: 249.1596.

[0084]

[0085] Compound 2 - 30e: yellow oily liquid (43%); R f = 0.34, PE:EA = 3:1; IR(KBr): 3279, 2930, 1643, 1137, 1053 cm -1 ; 1 H NMR(400 MHz, CDCl3) δ = 7.73(s, 1H), 7.31 - 7.30(m, 1H), 7.24 - 7.18(m, 2H), 6.95 - 6.92(m, 1H), 3.83(s, 3H), 3.76(s, 3H), 1.80(s, 3H), 1.57(s, 6H); 13 C NMR(100 MHz, CDCl3) δ = 165.8, 159.9, 159.3, 137.2, 129.6, 118.7, 117.8, 112.1, 62.0, 56.9, 55.5, 24.4, 10.1; HRMS(ESI) m / z calcd. for C 14 H 21 N2O3 + [M + H + : 265.1547, found: 265.1547.

[0086]

[0087] Compound 2-32a: white solid (68%); R f = 0.52, PE:EA = 3:1; IR(KBr): 3273, 2927, 1646, 1050 cm -1 ; 1 H NMR(400 MHz, CDCl3) δ = 7.97(s, 1H), 7.88(d, J = 8.4 Hz, 2H), 7.70(d, J = 8.0 Hz, 2H), 3.92(s, 3H), 1.89(s, 3H), 1.67(s, 6H); 13 C NMR(100 MHz, CDCl3) δ = 164.7, 159.1, 139.2, 133.0(q, J = 32.0 Hz), 127.4, 125.7(q, J = 4.0 Hz), 123.9(q, J = 4.0 Hz), 62.1, 57.2, 24.2, 10.2; HRMS(ESI) m / z calcd. for C 14 H 18 F3N2O2 + [M + H + : 303.1315, found: 303.1318.

[0088]

[0089] Compound 2-32b: white solid (66%); R f = 0.25, PE:EA = 3:1; IR(KBr): 3286, 2917, 2229, 1640, 1057 cm -1 ; 1 H NMR(400 MHz, CDCl3) δ = 8.00(s, 1H), 7.88 - 7.86(m, 2H), 7.74 - 7.72(m, 2H), 3.92(s, 3H), 1.89(s, 3H), 1.66(s, 6H); 13 C NMR(100 MHz, CDCl3) δ = 164.0, 159.0, 139.8, 132.6, 127.6, 118.3, 114.9, 62.1, 57.2, 24.1, 10.2; HRMS(ESI) m / z calcd. for C 14 H 18 N3O2 + [M + H + : 260.1394, found: 260.1397.

[0090]

[0091] Compound 2-32c: white solid (67%); R f = 0.33, PE:EA = 3:1; IR(KBr): 3314, 2924, 1726, 1646, 1284, 1053 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ = 8.07 (d, J = 8.0 Hz, 2H), 7.92 (s, 1H), 7.81 (d, J = 8.0 Hz, 2H), 3.90 (d, J = 4.4 Hz, 6H), 1.87 (s, 3H), 1.64 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ = 166.5, 165.0, 159.1, 139.7, 132.5, 129.9, 126.9, 62.0, 57.1, 52.4, 24.2, 10.1; HRMS(ESI) m / z calcd. for C 15 H 21 N2O4 + [M+H + : 293.1496, found: 293.1498.

[0092]

[0093] Compound 2-32d: white solid (64%); R f = 0.26, PE:EA = 3:1; IR(KBr): 3276, 2930, 1633, 1050 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ = 7.73 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 3.91 (s, 3H), 2.38 (s, 3H), 1.87 (s, 3H), 1.64 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ = 166.0, 159.4, 141.6, 133.0, 129.3, 126.9, 61.9, 56.8, 24.4, 21.5, 10.1; HRMS(ESI) m / z calcd. for C 14 H 21 N2O2 + [M+H + : 249.1598, found: 249.1551.

[0094]

[0095] Compound 2-32e: white solid (87%); R f = 0.60, PE:EA = 3:1; IR (KBr): 3305, 2962, 1636, 1050 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ = 7.77 (s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 3.91 (s, 3H), 1.87 (s, 3H), 1.64 (s, 6H), 1.32 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ = 165.9, 159.4, 154.7, 132.9, 126.7, 125.5, 61.9, 56.8, 34.9, 31.3, 24.4, 10.1; HRMS (ESI) m / z calcd. for C 17 H 27 N2O2 + [M+H + : 291.2067, found: 291.2069.

[0096]

[0097] Compound 2-32f: white solid (71%); R f = 0.26, PE:EA = 3:1; IR (KBr): 3251, 2927, 1630, 1255, 1047 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ = 7.74 (d, J = 8.8 Hz, 2H), 7.69 (s, 1H), 6.92 (d, J = 8.4 Hz, 2H), 3.92 (s, 3H), 3.84 (s, 3H), 1.87 (s, 3H), 1.64 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ = 165.6, 162.1, 159.6, 128.7, 128.1, 113.8, 62.0, 56.8, 55.5, 24.5, 10.2; HRMS (ESI) m / z calcd. for C 14 H 21 N2O3 + [M+H + : 265.1547, found: 265.1542.

[0098] Example 3: Coupling substitution reaction

[0099] Coupling substitution reaction conditions: Weigh compound 2-15 (0.20 mmol, 1.0 equiv.), p-methoxyphenyl iodide (234.0 mg, 1.00 mmol, 5.0 equiv.), Pd(OAc)2 (4.5 mg, 0.02 mmol, 0.1 equiv.), Ag2O (92.7 mg, 0.40 mmol, 2.0 equiv.), and Na2CO3 (42.2 mg, 0.40 mmol, 2.0 equiv.) and add them to a 15 mL high-pressure resistant glass sealed tube. Then add 2.0 mL of a mixed solution of 1,2-dichloroethane:acetic acid = 3:1 as the solvent. Subsequently, insert a soft rubber tube connected to an argon gas cylinder into the sealed tube, and slowly blow air with a suitable air flow for half a minute. Do this three times in total. Immediately tighten the stopper of the sealed tube while taking out the rubber tube. Place the sealed tube vertically into a metal bath and heat the metal bath to 120 °C for 48 h. After the reaction is completed, wait for the sealed tube to cool to room temperature, then pour the reaction system into a sintered funnel filled with diatomaceous earth, filter the reaction system by suction, and rinse with dichloromethane until no product remains in the diatomaceous earth. Then concentrate the system under reduced pressure using a rotary evaporator and purify it by column chromatography to finally obtain the ortho-aryl substituted product without carbon-nitrogen ring closure product.

[0100]

[0101] Compound 2-17: Yellow solid (89%); 1 H NMR (400 MHz, CDCl3) δ = 7.44 - 7.39 (m, 5H), 7.29 (d, J = 7.6 Hz, 2H), 6.91 - 6.88 (m, 4H), 6.57 (s, 1H), 3.82 (s, 6H), 3.73 (s, 3H), 1.50 (s, 3H), 1.16 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ = 167.7, 159.2, 158.8, 139.9, 137.0, 133.2, 130.3, 129.0, 128.6, 113.6, 61.7, 56.9, 55.4, 23.7, 9.7; HRMS (ESI) m / z calcd. for C 27 H 31 N2O4 + [M + H + : 447.2278, found: 447.2284.

[0102] Referring to the preparation method of Example 3, the following compounds were prepared:

[0103]

[0104] Compound 2-33a: Yellow solid (90%); 1 H NMR (400 MHz, CDCl3) δ = 8.01 (dd, J = 8.0, 1.2 Hz, 1H), 7.61 - 7.52 (m, 2H), 7.37 - 7.33 (m, 2H), 6.98 (s, 1H), 6.94 - 6.90 (m, 2H), 3.83 (s, 3H), 3.73 (s, 3H), 1.70 (s, 3H), 1.40 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ = 163.9, 159.8, 158.3, 147.2, 141.6, 135.6, 132.5, 130.6, 130.3, 129.2, 123.1, 113.9, 61.8, 57.3, 55.5, 23.4, 9.9; HRMS (ESI) m / z calcd. for C 20 H 24 N3O5 + [M + H + : 386.1710, found: 386.1714.

[0105]

[0106] Compound 2-33b: Yellow solid (86%); 1 H NMR (400 MHz, CDCl3) δ = 7.68 - 7.64 (m, 1H), 7.50 (d, J = 4.0 Hz, 2H), 7.37 - 7.33 (m, 2H), 6.92 - 6.88 (m, 3H), 3.82 (s, 3H), 3.74 (s, 3H), 1.68 (s, 3H), 1.36 (s, 6H).; 13 C NMR (100 MHz, CDCl3) δ = 165.3, 159.6, 158.4, 141.1, 135.8 (d, J = 2.0 Hz), 134.0, 131.8, 130.3, 128.8, 127.8 (q, J = 32.0 Hz), 125.0 (q, J = 5.0 Hz), 124.0 (q, J = 273.0 Hz), 113.7, 61.8, 57.3, 55.4, 23.4, 9.9; HRMS (ESI) m / z calcd. for C 21 H 24 F3N2O3 + [M + H + : 409.1734, found: 409.1739.

[0107]

[0108] Compound 2-33c: Yellow solid (67%); 1 H NMR (400 MHz, CDCl3) δ = 7.40 - 7.33 (m, 3H), 7.13 (dd, J = 7.6, 0.8 Hz, 1H), 7.08 - 7.03 (m, 1H), 6.92 - 6.88 (m, 2H), 6.78 (s, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 1.73 (s, 3H), 1.42 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ = 163.8, 159.7 (d, J = 247.0 Hz), 159.6, 158.7, 141.6 (d, J = 4.0 Hz), 131.7 (d, J = 2.0 Hz), 130.3 (d, J = 9.0 Hz), 130.0, 125.8, 125.6 (d, J = 2.0 Hz), 114.3 (d, J = 21.0 Hz), 113.9, 61.8, 57.2, 55.4, 24.2, 10.0; HRMS (ESI) m / z calcd. for C 20 H 24 FN2O3 + [M+H + : 359.1765, found: 359.1769.

[0109]

[0110] Compound 2-25: Yellow solid (87%); 1 H NMR (400 MHz, CDCl3) δ = 7.33 - 7.16 (m, 5H), 6.84 (d, J = 8.8 Hz, 2H), 6.62 (s, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 1.66 (s, 3H), 1.33 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ = 165.5, 159.5, 158.8, 141.2, 136.7, 131.9, 131.7, 130.1, 129.7, 128.5128.5, 113.8, 61.8, 57.2, 55.5, 24.1, 10.1; HRMS (ESI) m / z calcd. for C 20 H 24 ClN2O3 + [M+H + : 375.1470, found: 375.1472.

[0111]

[0112] Compound 2-33e: white solid (45%); 1 HNMR (400 MHz, CDCl3) δ = 7.32 (d, J = 8.4 Hz, 2H), 7.24 - 7.21 (m, 1H), 7.14 - 7.09 (m, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.47 (s, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 2.38 (s, 3H), 1.63 (s, 3H), 1.30 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ = 168.6, 159.2, 158.7, 139.0, 137.5, 135.7, 133.3, 130.2, 129.1, 128.6, 127.5, 113.7, 61.8, 56.9, 55.5, 24.1, 19.6, 10.1; HRMS (ESI) m / z calcd. for C 21 H 27 N2O3 + [M + H + : 355.2016, found: 355.2017.

[0113]

[0114] Compound 2-33f: yellow solid (25%); 1 H NMR (400 MHz, CDCl3) δ = 7.41 - 7.32 (m, 3H), 6.93 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 8.4 Hz, 3H), 6.46 (s, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 1.73 (s, 3H), 1.37 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ = 166.4, 159.4, 159.2, 156.7, 140.8, 132.7, 130.1, 129.7, 127.2, 122.3, 113.7, 109.8, 61.7, 57.0, 56.1, 55.4, 24.5, 10.0; HRMS (ESI) m / z calcd. for C 21 H 27 lN2O4 + [M + H + : 371.1965, found: 371.1968.

[0115]

[0116] Compound 2 - 36a: Yellow solid (85%); 1 H NMR (400 MHz, CDCl3) δ = 7.37 - 7.32 (m, 4H), 7.25 - 7.23 (m, 1H), 7.14 (t, J = 8.8 Hz, 1H), 6.91 - 6.84 (m, 4H), 6.58 (s, 1H), 3.79 (d, J = 2.0 Hz, 6H), 3.73 (s, 3H), 1.48 (s, 3H), 1.08 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ = 166.2 (d, J = 3.0 Hz), 159.5, 159.1 (q, J = 89.0 Hz), 139.46 (d, J = 1.0 Hz), 135.6 (d, J = 4.0 Hz), 132.3, 131.3, 130.6 (d, J = 8.0 Hz), 130.3, 127.2 (d, J = 17.0 Hz), 125.7, 115.9 (d, J = 23.0 Hz), 113.6 (d, J = 3.0 Hz), 61.8, 56.9, 55.4 (d, J = 3.0 Hz), 23.6, 9.7; HRMS (ESI) m / z calcd. for C 27 H 30 FN2O4 + [M + H + : 465.2184, found: 465.2182.

[0117]

[0118] Compound 2 - 35b: Yellow solid (62%); 1 H NMR (400 MHz, CDCl3) δ = 7.64 (d, J = 2.4 Hz, 1H), 7.40 (dd, J = 8.0, 2.0 Hz, 1H), 7.34 - 7.31 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H), 6.94 - 6.90 (m, 2H), 6.65 (s, 1H), 3.83 (s, 3H), 3.72 (s, 3H), 1.69 (s, 3H), 1.40 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ = 167.0, 159.7, 158.4, 138.3, 137.6, 133.4, 131.7 (d, J = 4.0 Hz), 130.2, 129.9, 128.9, 114.1, 61.8, 57.0, 55.5, 24.0, 10.0; HRMS (ESI) m / z calcd. for C 20 H 24ClN2O3 + [M+H + :375.1470,found:375.1475.

[0119] Compound 2-36b: yellow oily liquid (11%); 1 1H NMR (400 MHz, CDCl3) δ = 7.51 (d, J = 8.4 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.30 (s, 1H), 7.28 (d, J = 2.8 Hz, 2H), 6.94 - 6.88 (m, 4H), 6.61 (s, 1H), 3.83 (d, J = 2.8 Hz, 6H), 3.78 (s, 3H), 1.51 (s, 3H), 1.06 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 166.4, 159.4 (d, J = 6.0 Hz), 158.7, 139.7, 138.1 (d, J = 4.0 Hz), 133.1, 132.1, 131.2, 130.3 (d, J = 7.0 Hz), 129.6 (d, J = 3.0 Hz), 113.7, 113.4, 61.8, 56.9, 55.4 (d, J = 5.0 Hz), 23.5, 9.7; HRMS (ESI) m / z calcd. for C 27 H 30 ClN2O4 + [M+H + :481.1889,found:481.1892.

[0120]

[0121] Compound 2-35c: yellow oily liquid (88%); 1 1H NMR (400 MHz, CDCl3) δ = 7.78 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 8.0, 2.0H), 7.34 - 7.30 (m, 2H), 7.19 (d, J = 8.4 Hz, 1H), 6.94 - 6.10 (m, 2H), 6.66 (s, 1H), 3.83 (s, 3H), 3.72 (s, 3H), 1.69 (s, 3H), 1.40 (s, 6H); 1313C NMR (100 MHz, CDCl3) δ = 166.8, 159.7, 158.4, 138.5, 138.1, 132.9, 131.9, 131.8, 131.6, 130.2, 121.3, 114.1, 61.8, 57.0, 55.5, 23.9, 10.0; HRMS (ESI) m / z calcd. for C 20 H 24 BrN2O3 + [M + H + : 419.0965, found: 419.0968.

[0122]

[0123] Compound 2-35d: Yellow solid (92%); 1 1H NMR (400 MHz, CDCl3) δ = 7.55 (s, 1H), 7.41 - 7.38 (m, 2H), 7.32 - 7.28 (m, 2H), 6.99 - 6.96 (m, 2H), 6.57 (s, 1H), 3.88 (s, 3H), 3.78 (s, 3H), 2.45 (s, 3H), 1.75 (s, 3H), 1.45 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 168.5, 159.3, 158.7, 137.2, 136.7, 136.4, 132.8, 130.6, 130.3, 129.5, 114.0, 61.7, 56.8, 55.5, 24.1, 21.1, 10.0; HRMS (ESI) m / z calcd. for C 21 H 27 N2O3 + [M + H + : 355.2016, found: 355.2018.

[0124]

[0125] Compound 2-36e: Yellow oily liquid (88%); 1 1H NMR (400 MHz, CDCl3) δ = 7.41 - 7.37 (m, 2H), 7.29 (dd, J = 8.8, 6.8 Hz, 3H), 7.01 (d, J = 8.8 Hz, 1H), 6.89 (t, J = 9.2 Hz, 4H), 6.54 (s, 1H), 3.81 (s, 6H), 3.78 (s, 3H), 3.76 (s, 3H), 1.48 (s, 3H), 1.07 (s, 6H); 1313C NMR (100 MHz, CDCl3) δ = 167.1, 158.89 (d, J = 3.0 Hz), 156.1, 139.2, 133.0, 132.0, 131.5, 130.3, 130.1, 128.4, 128.2, 113.5, 113.3, 111.2, 61.7, 56.8, 56.1, 55.4 (d, J = 7.0 Hz), 23.6, 9.7; HRMS (ESI) m / z calcd. for C 28 H 33 N2O5 + [M + H + : 477.2384, found: 477.2389.

[0126]

[0127] Compound 2 - 38a: White solid (85%); 1 1H NMR (400 MHz, CDCl3) δ = 7.55 (s, 2H), 7.42 (d, J = 8.8 Hz, 4H), 6.92 (d, J = 8.8 Hz, 4H), 6.70 (s, 1H), 3.83 (s, 6H), 3.74 (s, 3H), 1.54 (s, 3H), 1.17 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 166.5, 159.6, 158.5, 140.8, 140.0, 131.8, 130.7 (q, J = 32.0 Hz), 130.3, 125.6 (q, J = 4.0 Hz), 120.62 (q, J = 271.0 Hz), 113.8, 61.8, 57.1, 55.5, 23.5, 9.7; HRMS (ESI) m / z calcd. for C 28 H 30 F3N2O4 + [M + H + : 515.2152, found: 515.2153.

[0128]

[0129] Compound 2 - 38b: Yellow solid (87%); 1 1H NMR (400 MHz, CDCl3) δ = 7.57 (s, 2H), 7.38 (d, J = 8.4 Hz, 4H), 6.91 (d, J = 8.4 Hz, 4H), 6.74 (s, 1H), 3.82 (s, 6H), 3.73 (s, 3H), 1.54 (s, 3H), 1.16 (s, 6H); 1313C NMR (100 MHz, CDCl3) δ = 166.0, 159.8, 158.4, 141.2, 140.8, 132.2, 130.9, 130.2, 118.4, 113.9, 112.6, 61.8, 57.1, 55.5, 23.5, 9.7; HRMS (ESI) m / z calcd. for C 28 H 30 N3O4 + [M + H + : 472.2231, found: 472.2235.

[0130]

[0131] Compound 2 - 38c: Yellow solid (92%); 1 1H NMR (400 MHz, CDCl3) δ = 7.96 (s, 2H), 7.43 - 7.40 (m, 4H), 6.92 - 6.88 (m, 4H), 6.68 (s, 1H), 3.90 (s, 3H), 3.81 (s, 6H), 3.72 (s, 3H), 1.51 (s, 3H), 1.16 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 166.9, 166.7, 159.4, 158.5, 140.7, 140.2, 132.1, 130.3, 130.1, 129.9, 113.6, 61.7, 56.9, 55.4, 52.3, 23.5, 9.6; HRMS (ESI) m / z calcd. for C 29 H 33 N2O6 + [M + H + : 505.2333, found: 505.2338.

[0132]

[0133] Compound 2 - 38d: Yellow solid (86%); 1 1H NMR (400 MHz, CDCl3) δ = 7.41 (d, J = 8.8 Hz, 4H), 7.12 (s, 2H), 6.90 (d, J = 8.4 Hz, 4H), 6.54 (s, 1H), 3.82 (s, 6H), 3.74 (s, 3H), 2.42 (s, 3H), 1.51 (s, 3H), 1.16 (s, 6H); 1313C NMR (100 MHz, CDCl3) δ = 167.9, 159.1, 158.9, 139.9, 138.3, 134.5, 133.3, 130.3, 129.6, 113.5, 61.7, 56.8, 55.4, 23.7, 21.3, 9.7; HRMS (ESI) m / z calcd. for C 28 H 33 N2O4 + [M + H + : 461.2435, found: 461.2431.

[0134]

[0135] Compound 2 - 38e: White solid (93%); R f = 0.45, PE:EA = 3:1; IR (KBr): 3382, 2953, 1652, 1607, 1246, 1050 cm -1 ; 1 1H NMR (400 MHz, CDCl3) δ = 7.44 (d, J = 8.8 Hz, 4H), 7.32 (s, 2H), 6.92 (d, J = 8.8 Hz, 4H), 6.53 (s, 1H), 3.83 (s, 6H), 3.76 (s, 3H), 1.51 (s, 3H), 1.38 (s, 9H), 1.18 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 168.0, 159.1, 158.9, 151.5, 139.5, 134.4, 133.7, 130.3, 126.1, 113.6, 61.7, 56.8, 55.4, 34.9, 31.4, 23.8, 9.7; HRMS (ESI) m / z calcd. for C 31 H 39 N2O4 + [M + H + : 503.2904, found: 503.2906.

[0136]

[0137] Compound 2 - 38f: Yellow solid (93%); 11H NMR (400 MHz, CDCl3) δ = 7.41 (d, J = 8.4 Hz, 4H), 6.91 - 6.88 (m, 4H), 6.82 (s, 2H), 6.54 (s, 1H), 3.85 (s, 3H), 3.82 (s, 6H), 3.74 (s, 3H), 1.50 (s, 3H), 1.16 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 167.8, 159.2, 159.0, 158.8, 141.5, 133.2, 130.2, 130.1, 114.2, 113.5, 61.6, 56.7, 55.5, 55.4, 23.6, 9.7; HRMS (ESI) m / z calcd. for C 28 H 33 N2O5 + [M + H + : 477.2384, found: 477.2388.

[0138]

[0139] Compound 3 - 1: White solid (86%); 1 1H NMR (400 MHz, CDCl3) δ = 7.43 - 7.31 (m, 4H). 7.22 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 8.0 Hz, 2H), 6.76 (s, 1H), 3.76 (s, 3H), 1.71 (s, 3H), 1.37 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 165.2, 162.7 (d, J = 246.0 Hz) 158.6, 140.5, 136.7, 135.4 (d, J = 30.0 Hz), 131.7, 130.7 (d, J = 80.0 Hz), 129.7, 128.8, 128.4, 115.2 (d, J = 8.4 Hz), 61.8, 57.2, 23.9, 10.1; HRMS (ESI) m / z calcd. for C 19 H 21 ClFN2O2 + [M + H + : 363.1270, found: 363.1274.

[0140]

[0141] Compound 3 - 2: White solid (84%); 11H NMR (400 MHz, CDCl3) δ = 7.40 - 7.33 (m, 6H), 7.22 (d, J = 7.6 Hz, 1H), 6.80 (s, 1H), 6.77 (s, 3H), 1.72 (s, 3H), 1.39 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 165.1, 158.6, 140.3, 137.8, 136.7, 134.2, 131.8, 130.3, 129.8, 128.9, 128.5, 128.3, 61.8, 57.3, 23.9, 10.1; HRMS (ESI) m / z calcd. for C 19 H 21 Cl2N2O2 + [M + H + : 379.0975, found: 379.0977.

[0142]

[0143] Compound 3 - 3: Pale yellow solid (88%); 1 1H NMR (400 MHz, CDCl3) δ = 7.34 - 7.22 (m, 4H), 7.21 (t, J = 6.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.63 (s, 1H), 3.73 (s, 3H), 2.32 (s, 3H), 1.67 (s, 3H), 1.32 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 165.4, 168.8, 141.6, 137.7, 136.6, 136.5, 131.6, 129.6, 129.0, 128.8, 128.4, 128.3, 61.7, 57.2, 24.0, 21.3, 10.0; HRMS (ESI) m / z calcd. for C 210 H 24 ClN2O2 + [M + H + : 359.1521, found: 359.1527.

[0144]

[0145] Compound 3 - 4: Yellow solid (81%); 11H NMR (400 MHz, CDCl3) δ = 7.95 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.44 - 7.35 (m, 2H), 7.25 (d, J = 6.8 Hz, 1H), 6.85 (s, 1H), 3.76 (s, 3H), 2.61 (s, 3H), 1.69 (s, 3H), 1.36 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 197.9, 164.9, 158.5, 144.2, 140.4, 136.6, 136.5, 131.9, 129.9, 129.4, 129.3, 128.4, 128.2, 61.8, 57.3, 26.8, 23.9, 10.1; HRMS (ESI) m / z calcd. for C 21 H 24 ClN2O3 + [M + H + : 387.7410, found: 387.7404.

[0146]

[0147] Compound 3 - 5: Yellow solid (76%); 1 1H NMR (400 MHz, CDCl3), δ = 8.03 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.44 - 7.34 (m, 2H), 7.25 (d, J = 6.0 Hz, 1H), 6.82 (s, 1H), 3.92 (s, 3H), 3.75 (s, 3H), 1.69 (s, 3H), 1.36 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 166.9, 164.9, 158.6, 144.0, 140.5, 136.7, 131.9, 129.9, 129.6, 129.3, 129.1, 128.3, 61.8, 57.3, 52.4, 23.9, 10.1; HRMS (ESI) m / z calcd. for C 21 H 24 ClN2O4 + [M + H + : 403.1419, found: 403.1424.

[0148]

[0149] Compound 3 - 6: White solid (83%); 11H NMR (400 MHz, CDCl3) δ = 8.24 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.49 - 7.39 (m, 2H), 7.27 (d, J = 6.0 Hz, 1H), 6.99 (s, 1H), 3.77 (s, 3H), 1.73 (s, 3H), 1.40 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 164.6, 158.5, 147.6, 146.0, 139.2, 136.6, 132.0, 130.1, 130.0, 129.9, 128.1, 123.5, 61.9, 57.4, 23.8, 10.1; HRMS (ESI) m / z calcd. for C 19 H 21 ClN3O4 + [M + H + : 390.1215, found: 390.1219.

[0150]

[0151] Compound 3 - 7: Yellow solid (80%); 1 1H NMR (400 MHz, CDCl3) δ = 7.50 (d, J = 8.4 Hz, 2H), 7.42 - 7.31 (m, 4H), 7.21 (dd, J = 7.6, 1.2 Hz, 1H), 6.8 (s, 1H), 3.77 (s, 3H), 1.72 (s, 3H), 1.39 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 165.0, 158.6, 140.3, 138.3, 136.6, 131.8, 131.5, 130.6, 129.8, 129.0, 128.2, 122.4, 61.8, 57.3, 23.9, 10.1; HRMS (ESI) m / z calcd. for C 19 H 21 ClBrN2O2 + [M + H + : 423.0469, found: 423.0471.

[0152]

[0153] Compound 3 - 8: Yellow solid (81%); 11H NMR (400 MHz, CDCl3) δ = 7.44 - 7.34 (m, 4H), 7.26 - 7.21 (m, 3H), 6.81 (s, 1H), 3.76 (s, 3H), 1.69 (s, 3H), 1.36 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 164.9, 158.5, 149.1, 141.4, 139.9, 136.7, 131.8, 129.9, 129.8, 129.3, 128.2, 127.6, 121.5, 120.6 (q, J = 255.7 Hz), 120.3, 61.8, 57.3, 23.8, 9.9; HRMS (ESI) m / z calcd. for C 20 H 21 ClF3N2O3 + [M + H + : 429.1187, found: 429.1195.

[0154]

[0155] Compound 3 - 9: Yellow solid (84%); 1 1H NMR (400 MHz, CDCl3) δ = 7.32 - 7.18 (m, 3H), 6.99 (s, 2H), 6.92 (s, 1H), 6.63 (s, 1H), 3.72 (s, 3H), 2.26 (s, 6H), 1.66 (s, 3H), 1.31 (s, 6H); 13 13C NMR (100 MHz, CDCl3) δ = 165.4, 158.7, 141.8, 139.3, 137.8, 136.5, 131.7, 129.6, 129.5, 128.5, 128.3, 126.7, 61.7, 57.1, 23.9, 21.4, 9.9; HRMS (ESI) m / z calcd. for C 21 H 26 ClN2O2 + [M + H + : 373.1677, found: 373.1685.

[0156] Example 4: Coupling cyclization reaction

[0157] Coupling cyclization reaction conditions: Weigh compound 2-15 (0.10 mmol, 1.0 equiv.), p-methoxyphenyl iodide (70.2 mg, 0.30 mmol, 3.0 equiv.), Pd(OAc)2 (2.2 mg, 0.01 mmol, 0.1 equiv.), Ag2CO3 (33.1 mg, 0.12 mmol, 1.2 equiv.), and Na2CO3 (21.2 mg, 0.20 mmol, 2.0 equiv.) and add them to a 15 mL high-pressure resistant glass sealed tube. Then add 2.5 mL of hexafluoroisopropanol as the solvent. Subsequently, insert the soft rubber tube connected to the argon gas cylinder into the sealed tube, and slowly blow air with a suitable air flow for half a minute. Blow air three times in total. Immediately tighten the stopper of the sealed tube while taking out the rubber tube. Vertically place the sealed tube in a metal bath and heat the metal bath to 130 °C for 18 h. After the reaction is completed, wait for the sealed tube to cool to room temperature, then pour the reaction system into a sand core funnel containing diatomaceous earth, filter the reaction system by suction, and wash it with dichloromethane until no product remains in the diatomaceous earth. Then concentrate the system under reduced pressure using a rotary evaporator and purify it by column chromatography. Finally, obtain the carbon-nitrogen cyclized product and no separate substitution product remains.

[0158]

[0159] Compound 2-18: Yellow solid (68%); 1 1H NMR (400 MHz, CDCl3) δ = 8.05 (d, J = 8.8 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 7.25 - 7.23 (m, 3H), 6.95 (d, J = 8.8 Hz, 2H), 6.78 (dd, J = 9.2, 2.4 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.81 (s, 3H), 1.93 (s, 6H), 1.52 (s, 3H).; 13 13C NMR (100 MHz, CDCl3) δ = 165.9, 163.1, 160.0, 158.6, 143.1, 140.1, 135.5, 131.1, 130.5, 129.4, 125.5, 125.3, 120.5, 113.9, 113.3, 110.1, 100.9, 66.4, 61.9, 55.5, 55.3, 25.6, 11.9; HRMS (ESI) m / z calcd. for C 27 H 29 N2O4 + [M + H + : 445.2122, found: 445.2123.

[0160] Referring to the preparation method of Example 4, the following compounds were prepared:

[0161]

[0162] Compound 2-34a: yellow solid (72%); 1 1H NMR (400 MHz, CDCl3) δ = 8.16 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.27 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 1.98 (s, 6H), 1.44 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ = 162.1, 161.7, 160.9, 150.2, 140.1, 136.1, 132.1, 125.4, 123.8, 120.7, 118.5, 112.4, 111.3, 101.5, 67.4, 61.9, 55.6, 25.6, 11.9; HRMS (ESI) m / z calcd. for C 20 H 22 N3O5 + [M + H + : 384.1554, found: 384.1555.

[0163]

[0164] Compound 2-34b: yellow solid (71%); 1 1H NMR (400 MHz, CDCl3) δ = 8.23 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 2.4 Hz, 1H), 6.78 (dd, J = 8.9, 2.4 Hz, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 2.01 (s, 6H), 1.46 (s, 3H); 13CNMR (100 MHz, CDCl3) δ = 164.3, 162.5, 160.7, 140.0, 136.3, 131.0, 129.2 (q, J = 32.0 Hz), 126.2 (q, J = 7.0 Hz), 125.6, 125.5, 125.3, 124.1 (q, J = 27.0 Hz), 112.8, 110.5, 100.7, 66.6, 61.9, 55.5, 25.4, 11.7; HRMS (ESI) m / z calcd. for C 21 H 22 F3N2O3 + [M + H + : 407.1577, found: 407.1573.

[0165]

[0166] Compound 2-26: Yellow solid (65%); 1 HNMR (400 MHz, CDCl3) δ = 7.94 (d, J = 8.4 Hz, 2H), 7.54 - 7.47 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 6.4, 2.4 Hz, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 2.02 (s, 6H), 1.46 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ = 163.8, 162.7, 160.4, 139.9, 137.0, 134.4, 131.8, 129.9, 125.5, 122.5, 120.4, 114.7, 110.5, 101.1, 66.7, 61.9, 55.8, 55.5, 11.8; HRMS (ESI) m / z calcd. for C 20 H 22 ClN2O3 + [M + H + : 373.1313, found: 373,1318.

[0167]

[0168] Compound 2-34d: Yellow solid (38%); 11H NMR (400 MHz, CDCl3) δ = 8.06 (d, J = 8.4 Hz, 2H), 7.64 (t, J = 8.0 Hz, 1H), 7.18 - 7.15 (m, 2H), 6.79 (dd, J = 8.8, 2.4 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 1.74 (d, J = 4.7 Hz, 6H), 1.43 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ = 165.3, 159.7, 144.8, 139.8, 134.4, 130.8, 127.9, 125.4, 120.7, 120.3, 116.5, 114.7, 110.1, 101.2, 66.3, 61.8, 55.5, 19.3, 11.9; HRMS (ESI) m / z calcd. for C 20 H 22 BrN2O3 + [M + H + : 417.0808, found: 417.0811.

[0169]

[0170] Compound 2 - 34f: white solid (63%); 1 1H NMR (400 MHz, CDCl3) δ = 7.94 (d, J = 8.8 Hz, 1H), 7.62 - 7.55 (m, 2H), 7.21 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 6.74 (dd, J = 8.8, 2.0 Hz, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 3.80 (s, 3H), 2.02 (s, 6H), 1.45 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ = 164.0, 160.3, 160.0, 140.0, 136.9, 132.8, 125.6, 116.6, 114.0, 113.5, 110.2, 109.2, 101.0, 66.5, 61.8, 56.5, 55.5, 25.9, 11.9; HRMS (ESI) m / z calcd. for C 21 H 25 N2O4 + [M + H + : 369.1809, found: 369.1814.

[0171]

[0172] Compound 2-37a: yellow solid (72%); 1 H NMR (400 MHz, CDCl3) δ = 8.45 (dd, J = 9.2, 1.6 Hz, 1H), 7.37 (dd, J = 12.8, 8.4 Hz, 1H), 7.23 - 7.17 (m, 4H), 6.94 (d, J = 8.8 Hz, 2H), 6.79 - 6.76 (m, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.81 (s, 3H), 1.90 (s, 6H), 1.52 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ = 165.1 (d, J = 4.0 Hz), 162.6, 159.8 (d, J = 3.0 Hz), 159.3, 158.5, 156.8, 140.0, 139.0 (d, J = 4.0 Hz), 135.0, 130.7 (d, J = 8.0 Hz), 129.4 (d, J = 22.0 Hz), 129.3, 127.7 (d, J = 3.0 Hz), 123.5 (d, J = 10.0 Hz), 118.2 (d, J = 24.0 Hz), 113.3, 111.2 (d, J = 5.0 Hz), 109.9 (d, J = 2.0 Hz), 100.8, 66.5, 61.9, 55.4 (d, J = 11.0 Hz), 25.2, 11.9; HRMS (ESI) m / z calcd. for C 27 H 28 FN2O4 + [M + H + : 463.2028, found: 463.2034.

[0173]

[0174] Compound 2-37b: white solid (73%); 1 H NMR (400 MHz, CDCl3) δ = 7.97 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.78 (dd, J = 9.2, 2.4 Hz, 1H), 3.90 (d, J = 7.6 Hz, 6H), 3.89 (s, 3H), 3.80 (s, 3H), 1.84 (s, 6H), 1.48 (s, 3H); 1313C NMR (100 MHz, CDCl3) δ = 165.1, 162.6, 160.3, 158.7, 140.3, 139.9, 133.9, 133.8, 132.6, 132.0, 129.6, 127.7, 125.2, 122.0, 113.4, 113.0, 110.3, 100.8, 66.4, 61.9, 55.5, 55.2, 25.4, 11.7; HRMS (ESI) m / z calcd. for C 27 H 28 ClN2O4 + [M + H + : 479.1732, found: 479.1737.

[0175]

[0176] Compound 2 - 37c: Clear oily liquid (67%); 1 1H NMR (400 MHz, CDCl3) δ = 7.99 (d, J = 8.8 Hz, 1H), 7.90 (s, 2H), 7.18 (d, J = 2.4 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.77 (dd, J = 8.8, 2.4 Hz, 1H), 3.89 (d, J = 4.8 Hz, 6H), 3.79 (s, 3H), 1.81 (s, 6H), 1.46 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ = 165.0, 162.6, 160.4, 158.7, 142.2, 140.0, 135.6, 134.3, 134.2, 129.5, 128.0, 125.2, 124.8, 122.3, 113.4, 113.1, 110.3, 100.8, 66.4, 61.9, 55.5, 55.2, 25.5, 11.8; HRMS (ESI) m / z calcd. for C 27 H 28 BrN2O4 + [M + H + : 523.1227, found: 523.1232.

[0177]

[0178] Compound 2 - 37d: Yellow solid (72%); 11H NMR (400 MHz, CDCl3) δ = 8.01 - 7.94 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.76 (dd, J = 8.8, 2.4 Hz, 1H), 3.89 (d, J = 7.2 Hz, 6H), 3.80 (s, 3H), 2.13 (s, 3H), 1.83 (s, 6H), 1.47 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ = 166.1, 162.9, 159.7, 158.1, 141.4, 139.7, 138.3, 136.6, 134.2, 133.5, 132.9, 129.1, 126.5, 124.9, 120.4, 116.5, 113.3, 113.6, 109.9, 100.7, 66.1, 61.8, 55.4, 55.2, 25.5, 21.0, 11.7; HRMS (ESI) m / z calcd. for C 28 H 31 N2O4 + [M + H + : 459.2278, found: 459.2275.

[0179]

[0180] Compound 2 - 37e: Yellow solid (73%); 1 1H NMR (400 MHz, CDCl3) δ = 8.04 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.20 - 7.17 (m, 3H), 6.99 (d, J = 8.4 Hz, 2H), 6.76 (dd, J = 8.8, 2.4 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.80 (s, 6H), 1.87 (s, 6H), 1.50 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ = 165.9, 163.0, 159.3, 158.3, 156.4, 139.1, 130.2, 130.1 (d, J = 2.0 Hz), 128.2, 127.5, 124.4, 122.0, 115.9, 113.8, 113.3, 109.9, 100.8, 66.1, 61.8, 56.6, 55.4, 55.2, 25.5, 11.7; HRMS (ESI) m / z calcd. for C28 H 31 N2O5 + [M+H + :475.2227, found:475.2230.

[0181]

[0182] Compound 2-39a: yellow solid (66%); 1 H NMR (400 MHz, CDCl3) δ = 8.31 (s, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 0.8 Hz, 1H), 7.29 - 7.28 (m, 3H),, 7.00 (d, J = 8.8 Hz, 2H), 6.84 (dd, J = 9.2, 2.4 Hz, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 3.84 (s, 3H), 1.95 (s, 6H), 1.55 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ = 165.0, 162.5, 160.7, 159.1, 144.3, 140.4, 135.7, 134.1, 133.2 (q, J = 33.0 Hz), 129.4, 127.5, 126.3 (q, J = 3.0 Hz), 125.5, 123.9 (q, J = 271.0 Hz), 113.5, 113.0, 110.6, 101.1, 66.7, 61.9, 55.5, 55.4, 25.5, 11.8; HRMS (ESI) m / z calcd. for C 28 H 28 F3N2O4 + [M+H + :513.1996, found:513.1999.

[0183]

[0184] Compound 2-39b: yellow solid (66%); 1 H NMR (400 MHz, CDCl3) δ = 8.08 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.02 (s, 2H), 6.97 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 6.59 (dd, J = 8.8, 2.0 Hz, 1H), 3.68 (s, 3H), 3.63 (s, 3H), 3.58 (s, 3H), 1.67 (s, 6H), 1.28 (s, 3H); 1313C NMR (100 MHz, CDCl3) δ = 164.6, 162.3, 161.0, 159.3, 144.5, 140.5, 135.9, 133.2, 132.0, 129.3, 127.9, 125.5, 124.8, 118.4, 114.7, 113.6, 112.2, 110.8, 101.1, 66.8, 62.0, 55.6, 55.4, 25.4, 11.8; HRMS (ESI) m / z calcd. for C 28 H 28 N3O4 + [M + H + : 470.2074, found: 470.2072.

[0185]

[0186] Compound 2 - 39c: Yellow solid (68%); 1 1H NMR (400 MHz, CDCl3) δ = 8.74 (d, J = 0.8 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.27 - 7.25 (m, 3H), 6.97 (d, J = 8.4 Hz, 2H), 6.82 (dd, J = 9.2, 2.4 Hz, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 3.88 (s, 3H), 3.81 (s, 3H), 1.93 (s, 6H), 1.53 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ = 166.6, 165.3, 162.6, 160.4, 158.8, 143.5, 140.2, 135.4, 134.6, 131.9, 130.4, 129.4, 128.1, 125.6, 122.1, 113.4, 110.4, 100.9, 66.6, 61.9, 55.5, 55.3, 52.6, 25.4, 11.8; HRMS (ESI) m / z calcd. for C 29 H 31 N2O6 + [M + H + : 503.2177, found: 503.2173.

[0187]

[0188] Compound 2 - 39d: Yellow solid (74%); 11H NMR (400 MHz, CDCl3) δ = 8.07 (d, J = 8.8 Hz, 1H), 7.88 (s, 1H), 7.29 (s, 1H), 7.26 (d, J = 2.4 Hz, 2H), 7.15 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.80 (dd, J = 8.8, 2.4 Hz, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 3.84 (s, 3H), 2.55 (s, 3H), 1.97 (s, 6H), 1.55 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ = 165.8, 163.0, 159.9, 158.5, 143.1, 141.2, 140.2, 135.5, 135.3, 131.9, 129.4, 125.2, 123.2, 120.6, 113.9, 113.2, 110.0, 100.8, 66.3, 61.8, 55.4, 55.3, 25.6, 22.0, 11.8; HRMS (ESI) m / z calcd. for C 28 H 31 N2O4 + [M + H + : 459.2278, found: 459.2273.

[0189]

[0190] Compound 2 - 39e: Yellow solid (69%); 1 1H NMR (400 MHz, CDCl3) δ = 8.11 - 8.06 (m, 2H), 7.34 (s, 1H), 7.29 - 7.25 (m, 3H), 6.98 (d, J = 8.0 Hz, 2H), 6.80 (dd, J = 9.2, 2.0 Hz, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.82 (s, 3H), 1.95 (s, 6H), 1.54 (s, 3H), 1.45 (s, 9H); 13 13C NMR (100 MHz, CDCl3) δ = 165.7, 163.1, 159.8, 158.5, 154.1, 142.8, 140.2, 135.9, 134.9, 129.5, 128.5, 125.2, 123.2, 116.8, 114.3, 113.2, 110.0, 100.85, 66.2, 61.8, 55.4, 55.3, 35.4, 31.3, 25.5, 11.9; HRMS (ESI) m / z calcd. for C 31 H 37 N2O4+ [M+H + :501.2748,found:501.2751.

[0191]

[0192] Compound 2-39f: yellow solid (73%); 1 1H NMR (400 MHz, CDCl3) δ = 7.98 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.25 - 7.21 (m, 3H), 6.95 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 8.8, 2.0 Hz, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.87 (s, 3H), 3.81 (s, 3H), 1.92 (s, 6H), 1.51 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ = 165.4, 161.2, 160.1, 158.7, 145.5, 140.4, 137.3, 135.4, 129.3, 125.4, 119.4, 117.9, 113.8, 113.3, 110.0, 103.8, 100.9, 66.7, 61.8, 55.6, 55.5, 55.3, 25.6, 11.9; HRMS (ESI) m / z calcd. for C 28 H 31 N2O5 + [M+H + :475.2227,found:475.2226.

[0193]

[0194] Compound 1: yellow solid (82%; 1 1H NMR (400 MHz, (CD3)2SO) δ = 8.40 - 8.36 (m, 1H), 8.33 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 3.86 (s, 3H), 1.88 (s, 6H), 1.40 (s, 3H); 1313C NMR (100 MHz, (CD3)2SO) δ = 162.5, 162.1 (d, J = 244.0 Hz), 161.3, 138.9 (d, J = 11.0 Hz), 135.8, 132.9, 132.8, 130.9, 127.5 (d, J = 10.0 Hz), 123.8, 122.0, 116.4 (d, J = 2.0 Hz), 109.8 (d, J = 22.0 Hz), 103.7 (d, J = 27.0 Hz), 66.0, 61.7, 25.3, 11.4; HRMS (ESI) m / z calcd. for C 19 H 19 ClFN2O2 + [M+H + : 361.1114, found: 361.1118.

[0195]

[0196] Compound 2: Pale yellow solid (75%); 1 1H NMR (400 MHz, (CD3)2SO) δ = 8.35 - 8.31 (m, 2H), 7.76 - 7.60 (m, 3H), 7.29 (dd, J = 8.8, 2.0 Hz, 1H), 3.88 (s, 3H), 1.88 (s, 6H), 1.36 (s, 3H); 13 13C NMR (100 MHz, (CD3)2SO) δ = 162.2, 161.2, 1138.3, 135.5, 133.6, 132.9, 131.3, 126.7, 124.1, 122.6, 122.0, 118.5, 116.4, 65.9, 61.6, 25.3, 11.3; HRMS (ESI) m / z calcd. for C 19 H 19 Cl2N2O2 + [M+H + : 377.0818, found: 377.0825.

[0197]

[0198] Compound 3: Pale yellow solid (81%); 1 1H NMR (400 MHz, (CD3)2SO) δ = 8.52 - 8.41 (m, 2H), 7.90 (s, 1H), 7.79 - 7.71 (m, 2H), 7.53 (d, J = 9.2 Hz, 1H), 3.86 (s, 3H), 1.89 (s, 6H), 1.30 (s, 3H); 1313C NMR(100MHz,(CD3)2SO)δ=161.9,160.7,137.5,134.9,132.9,132.1,128.9(q,J=32Hz),126.2,124.8,123.9(q,J=270.9Hz),122.8,122.6,118.2(q,J=3.7Hz),113.3(q,J=4.3Hz),66.1,61.5,25.2,11.2;HRMS(ESI)m / z calcd.for C 20 H 19 ClF3N2O2 + [M+H + :411.1082,found:411.1084.

[0199]

[0200] Compound 4: Pale yellow solid (84%); 1 1H NMR(400MHz,(CD3)2SO)δ=8.31(d,J=8.0Hz,1H),8.17(d,J=8.0Hz,1H),7.70(t,J=8.0Hz,1H),7.60(d,J=7.6Hz,1H),7.43(s,1H),7.07(d,J=8.4Hz,1H),3.87(s,3H),2.35(s,3H),1.88(s,6H),1.33(s,3H); 13 13C NMR(100MHz,(CD3)2SO)δ=162.5,161.5,139.9,137.5,136.4,132.8,132.6,130.5,124.8,123.8 123.3,121.6,117.1,65.6,61.5,25.4,21.5,11.4;HRMS(ESI)m / z calcd.forC 20 H 22 ClN2O2 + [M+H + :357.1364,found:357.1369。

[0201]

[0202] Compound 5: White solid (75%); 11H NMR (400 MHz, (CD3)2SO) δ = 8.43 (d, J = 7.2 Hz, 2H), 8.18 (s, 1H), 7.79 - 7.71 (m, 3H), 3.88 (s, 3H), 2.58 (s, 3H), 1.91 (s, 6H), 1.33 (s, 3H); 13 13C NMR (100 MHz, (CD3)2SO) δ = 196.9, 162.2, 161.1, 137.4, 136.4, 135.3, 132.9, 132.8, 132.0, 125.4, 124.9, 123.2, 122.7, 121.5, 116.6, 65.9, 61.5, 26.6, 25.5, 11.4; HRMS (ESI) m / z calcd. for C 21 H 22 ClN2O3 + [M + H + : 385.1313, found: 385.1309.

[0203]

[0204] Compound 6: White solid (80%); 1 1H NMR (400 MHz, (CD3)2SO) δ = 8.39 (d, J = 8.0 Hz, 2H), 8.27 (s, 1H), 7.77 - 7.69 (m, 3H), 3.89 (s, 6H), 1.89 (s, 6H), 1.31 (s, 3H); 13 13C NMR (100 MHz, (CD3)2SO) δ = 165.6, 162.1, 160.6, 137.3, 135.2, 132.8, 132.0, 129.5, 127.3, 125.3, 124.8, 123.3, 122.6, 122.2, 117.6, 65.8, 61.5, 52.5, 25.3, 11.2; HRMS (ESI) m / z calcd. for C 21 H 22 ClN2O4 + [M + H + : 401.1263, found: 401.1269.

[0205]

[0206] Compound 7: Pale yellow solid (72%); 11H NMR (400 MHz, (CD3)2SO) δ = 8.38 - 8.37 (m, 2H), 7.79 - 7.67 (m, 3H), 7.43 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H), 1.88 (s, 6H), 1.36 (s, 3H); 13 13C NMR (100 MHz, (CD3)2SO) δ = 162.2, 161.0, 138.4, 135.6, 132.9, 132.8, 131.4, 126.8, 124.9, 124.2, 122.1, 122.0, 119.3, 118.8, 65.9, 61.6, 25.3, 11.4; HRMS (ESI) m / z calcd. for C 19 H 19 BrN2O2 + [M + H + : 421.0313, found: 421.0308.

[0207]

[0208] Compound 8: Pale yellow solid (88%); 1 1H NMR (400 MHz, CDCl3) δ = 8.04 - 7.99 (m, 1H), 7.61 - 7.52 (m, 4H), 6.97 - 6.94 (m, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 1.99 (s, 6H), 1.44 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ = 163.2, 162.4, 154.6, 136.5, 134.6, 132.7, 131.7, 131.3, 129.5, 128.7, 125.6, 121.2, 121.1, 118.5, 115.7, 108.4, 66.5, 61.9, 55.8, 25.9, 11.8; HRMS (ESI) m / z calcd. for C 20 H 22 ClN2O3 + [M + H + : 373.1313, found: 373.1317.

[0209]

[0210] Compound 9: Pale yellow solid (77%); 11H NMR (400 MHz, (CD3)2SO) δ = 8.42 (d, J = 8.0 Hz, 1H), 8.32 - 8.29 (m, 1H), 7.75 - 7.62 (m, 3H), 7.46 (d, J = 9.6 Hz, 1H), 3.84 (s, 3H), 1.86 (s, 6H), 1.37 (s, 3H); 13 13C NMR (100 MHz, (CD3)2SO) δ = 162.1, 161.0, 143.0, 136.3, 135.2, 132.8, 132.7, 131.7, 124.5, 122.5, 121.8, 121.5, 121.1, 120.2 (q, J = 254.7 Hz), 118.4, 117.8, 65.8, 61.5, 25.4, 11.3; HRMS (ESI) m / z calcd. for C 20 H 19 ClF3N2O3 + [M + H + : 427.1031, found: 427.1026.

[0211] Example 5: Hydrogenation Reaction

[0212] Reaction conditions for the hydrogenation of the substituted product: Weigh compound 2 - 25 (0.27 mmol, 1.0 equiv.), boc anhydride (174.6 mg, 0.80 mmol, 3.0 equiv.), Ni (3.17 mg, 0.05 mmol, 0.2 equiv.), add them to a 15 mL hydrogenation reaction glass tube, then add 1 ml of methanol as the solvent, introduce hydrogen gas, stir at room temperature for 24 h. After the reaction is completed, wait for the sealed tube to cool to room temperature, then pour the reaction system into a sintered funnel filled with diatomaceous earth, filter the reaction system by suction, and rinse with dichloromethane until no product remains in the diatomaceous earth. Then concentrate the system under reduced pressure using a rotary evaporator and purify by column chromatography to finally obtain the hydrogenated product.

[0213]

[0214] White solid (92%); 1 1H NMR (400 MHz, CDCl3) δ = 7.39 - 7.30 (m, 4H), 7.21 (d, J = 6.8 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H), 5.89 (m, 1H), 5.62 (d, J = 8.4 Hz, 1H), 3.83 (s, 3H), 3.57 - 3.53 (m, 1H), 1.39 (s, 9H), 1.15 (d, J = 9.2 Hz, 6H), 0.97 (d, J = 6.8 Hz, 3H);13 C NMR (100 MHz, CDCl3) δ=166.9, 159.6, 156.7, 141.1, 136.7, 131.8, 131.4, 130.2, 129.8, 128.4, 128.2, 113.9, 79.5, 58.6, 55.5, 54.2, 28.5, 23.4, 15.8; HRMS (ESI) m / z calcd. for C 24 H 32 ClN2O4 + [M + H + : 447.2045, found: 447.2048.

[0215] Example 6: Hydrogenation Reaction

[0216] Hydrogenation reaction conditions of the cyclization product: Weigh compound 2-26 (0.27 mmol, 1.0 equiv.), boc anhydride (174.6 mg, 0.80 mmol, 3.0 equiv.), Ni (3.17 mg, 0.05 mmol, 0.2 equiv.), add them into a 15 mL hydrogenation reaction glass tube, then add 1 ml of methanol as the solvent, introduce hydrogen gas, stir at room temperature for 24 h. After the reaction is completed, wait for the sealed tube to cool to room temperature, then pour the reaction system into a sintered funnel filled with diatomaceous earth, filter the reaction system by suction, and rinse it with dichloromethane until no product remains in the diatomaceous earth. Then, concentrate the system under reduced pressure using a rotary evaporator and purify it by column chromatography to finally obtain the cyclized hydrogenated product.

[0217]

[0218] White solid (86%); 1 1H NMR (400 MHz, (CD3)2SO) δ=8.34 - 8.27 (m, 2H), 8.17 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.06 - 6.96 (m, 2H), 3.89 (s, 3H), 1.73 (s, 6H), 1.58 (d, J = 8.0 Hz, 3H), 1.33 (s, 9H), 1.23 (s, 3H); 13 13C NMR (100 MHz, (CD3)2SO) δ=156.5, 154.4, 133.4, 132.3, 127.7, 126.7, 126.5, 123.0, 121.8, 114.6, 109.7, 107.8, 77.5, 72.8, 64.5, 55.9, 28.2, 22.1; HRMS (ESI) m / z calcd. for C24 H 30 ClN2O4 + [M+H + :445.1889,found:445.1893.

Claims

1. A method for preparing a biaryl compound with a structure of formula I, characterized in that in formula I, the definitions of R and R’ satisfy any one of the following cases: (1) When R is selected from halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and halogenated phenyl substituted at the 2- or 6-position, is mono-substituted at the 2- or 6-position, and R' is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 acyl, and C1-C4 ester group substituted at the para- or meta-position; (2) When R is selected from halogen, C1-C4 alkyl, or C1-C4 haloalkyl that is trisubstituted or pentasubstituted, it is mono- / disubstituted at the 2-position or / and 6-position, and R' is defined as described above; (3) When R is selected from 4-position substituted hydrogen, cyano group, C1-C4 alkyl group, C1-C4 haloalkyl group, C1-C4 alkoxy group, C1-C4 alkyl C1-C4 carboxylate group, it is disubstituted at the 2-position and 6-position, and the definition of R' is the same as described above; The said preparation method comprises the following steps: (1) Preparation of a compound containing a directing group Compound 2-11 is subjected to acylation, alkylation, condensation and deamination protection reactions to obtain compound 2-13; (2) Introduction of a directing group Compound 2-13 and compound 2-14 are subjected to an acylation reaction to obtain compound 2-15; (3) Preparation of a biaryl compound Compound 2-15 and an iodo compound are subjected to a coupling reaction to obtain the compound of formula I.

2. A method for preparing a biaryl compound with a structure of formula II, characterized in that in formula II, the definitions of R and R’ are as described in claim 1; Compound 2-15 and an iodo compound are subjected to a coupling cyclization reaction to obtain the compound of formula II.

3. The preparation method according to claim 1 or 2, characterized in that, The definition of R satisfies any one of the following cases: (1) When R is a 2- or 6-position substituent, R is selected from nitro, fluoro, chloro, bromo, methyl, methoxy, 4-chlorophenyl, 4-fluorophenyl; (2) When R is a 3- or 5-position substituent, R is selected from fluoro, chloro, bromo, methoxy; (3) When R is a 4-position substituent, R is selected from hydrogen, cyano, trifluoromethyl, methyl formate, tert-butyl, methyl, methoxy.

4. The preparation method according to claim 1 or 2, characterized in that, Any one of the following groups:

5. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of the said compound 2-15 to 4-iodoanisole is 1:3 to 1:

5.

6. The preparation method according to claim 1 or 2, characterized in that, The catalyst for the said coupling reaction or coupling cyclization reaction comprises component one, component two and component three, wherein component one is selected from Pd(OAc)2, Pd(TFA)2, Pd(OPiv)2, PdCl2, PdBr2, PdI2, component two is selected from Ag2CO3, AgOAc, AgTFA, AgOPiv, Ag2O, and component three is selected from Na2CO3, K2CO3.

7. The preparation method according to claim 6, characterized in that, The molar ratio between component one, component two and component three of the said catalyst is 0.1:(1.2 to 2.5):(2 to 4).

8. The preparation method according to claim 1 or 2, characterized in that, The reaction solvent for the said coupling reaction or coupling cyclization reaction is selected from 1,2-dichloroethane, toluene, o-xylene, m-xylene, p-xylene, hexafluoroisopropanol.

9. The preparation method according to claim 1 or 2, characterized in that The reaction temperature of the said coupling reaction is 115 - 125 °C, and the reaction temperature of the said coupling cyclization reaction is 125 - 135 °C.

10. The preparation method according to claim 1 or 2, characterized in that, The said coupling reaction or coupling cyclization reaction is carried out in an oxygen-free and water-free environment.

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