Method for synthesizing 1, 4-dinitrogen seven-membered heterocyclic compound

Abstract

The invention belongs to the field of organic synthesis, and discloses a method for synthesizing a 1, 4-dinitrogen seven-membered heterocyclic compound. Specifically, the invention relates to a method for preparing a series of 1, 4-dinitrogen seven-membered heterocyclic compounds by catalyzing a cyclobutenone compound and an imidazoline compound to react through a Lewis acid catalyst. The method comprises the following specific operation steps: under the protection of argon, adding a Lewis acid catalyst into a reaction tube, then adding a cyclobutenone compound and an imidazolidine compound, then carrying out a heating reaction, and after the reaction is completed, carrying out quenching purification and separation to obtain the 1, 4-dinitrogen seven-membered heterocyclic compound. The method has the advantages of good substrate applicability, mild reaction conditions and high reaction yield.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for the efficient synthesis of 1,4-diazine seven-membered heterocyclic compounds. Background Technology

[0002] 1,4-Daza seven-membered heterocyclic compounds are an important class of organic compound skeletons, widely found in natural products and bioactive compounds. For example, VU0105737 contains a 1,4-diaza seven-membered heterocyclic skeleton and is a class of G-protein-coupled receptor modulators (see: Cheung, Y.-Y.; Zamorano, R.; Blobaum, AL; Weaver, CD; Conn, PJ; Lindsley, CW; Niswender, CM; Hopkins, CR). ACS Comb. Sci. 2011, 13 , 159–165.). BL-V8 contains a 1,4-heterocyclic ketone backbone and has been shown to possess protein kinase C modulator activity (see: Wei, Z.-L.; Sakamuri, S.; Petukhov, PA; George, C.; Lewin, NE; Blumberg, PM; Kozikowski, AP). Org. Lett. 2002, 4 (2169-2172). Therefore, we speculate that the synthesized product of this patent has potential similar biological activity, providing a synthetic route for experts in related pharmaceutical fields to synthesize similar compounds. However, there are currently few reported methods for synthesizing 1,4-diazolium seven-membered heterocyclic compounds, which are generally obtained from chain compounds as raw materials through intramolecular cyclization reactions. The biggest drawback of such methods is that the synthesized 1,4-diazolium seven-membered heterocyclic compounds have a single structure, limiting product diversity.

[0003]

[0004] Ring-opening-cyclization reactions of cyclic compounds are a common method for synthesizing heterocyclic compounds. We recently discovered that imidazolines are excellent 1,5-synthetic dipoles that can participate in a variety of reactions to generate 1,4-diazepine heterocyclic compounds.

[0005] Therefore, starting from imidazoline starting materials, we developed a more efficient method for constructing 1,4-diazoline seven-membered heterocyclic compounds. Through catalytic system design and condition screening, we achieved Lewis acid-catalyzed cycloaddition reactions between cyclobutenones and imidazoline compounds, yielding a series of indoline-1,4-diazoline eight-membered heterocyclic compounds. This method has advantages such as good substrate applicability and mild reaction conditions. Summary of the Invention

[0006] Given that there are no reported methods for synthesizing 1,4-diazide heptaneous heterocyclic compounds in the literature, this invention provides a method for synthesizing 1,4-diazide heptaneous heterocyclic compounds in high yield and with high efficiency using Lewis acid-catalyzed [5+2] cycloaddition reaction strategies, with readily available cyclobutenone compounds and imidazole compounds as reactants.

[0007] To achieve the objectives of this invention, the technical solution adopted is as follows: A method for synthesizing 1,4-diazazo heptaneous heterocyclic compounds, characterized in that: under the catalysis of a Lewis acid catalyst, cyclobutenone compounds (Formula 1) and imidazoline compounds (Formula 2) undergo [5+2] cycloaddition to prepare a series of 1,4-diazazo heptaneous heterocyclic compounds.

[0008] The specific reaction equation is as follows:

[0009] Reaction equation 1: Synthesis of 1,4-diazepine seven-membered heterocyclic compounds;

[0010] Among them, R 1 It is one of phenyl, 4-ethylbenzene, 4-butylbenzene, 4-methoxybenzene, 4-bromophenyl, naphthyl, thiophene, and cyclopropyl; R 2 It is one of phenyl, 4-methylbenzene, 4-isopropylbenzene, 2-benzyloxybenzene, naphthyl, 4-chlorophenyl, furan, and thiophene.

[0011] Further, the method is carried out according to the following steps: Under argon protection, the Lewis acid catalyst is dissolved in tetrahydrofuran solvent and placed in a sealed tube. Then, cyclobutenone compounds (Formula 1) and imidazoline compounds (Formula 2) are added sequentially to the sealed tube to replace the argon gas. The reaction is then carried out at 20-80 °C for 10-14 h. After the reaction is complete, the reaction is quenched and purified to obtain 1,4-diaza-7-membered heterocyclic compounds.

[0012] Furthermore, the molar ratio of the cyclobutenone compound and the imidazoline compound is 1:1 to 2:1, with a more preferred ratio of 1.5:1, as this molar ratio yields the highest yield. The concentration of the cyclobutenone compound and the imidazoline compound in the solvent is 0.1 M.

[0013] Furthermore, the amount of the Lewis acid catalyst is 10%-50% of the imidazoline compound equivalent. Preferably, the amount of the Lewis acid catalyst is 20% of the imidazoline compound equivalent.

[0014] Furthermore, the Lewis acid catalyst is one of copper trifluoromethanesulfonate, scandium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, aluminum trifluoromethanesulfonate, and nickel trifluoromethanesulfonate; preferably zinc trifluoromethanesulfonate.

[0015] Furthermore, the organic solvent is one of dichloroethane, toluene, 1,4-dioxane, tetrahydrofuran, and acetonitrile; tetrahydrofuran is preferred.

[0016] Furthermore, as a preferred option, the reaction temperature is 80 °C.

[0017] Beneficial effects: This invention provides a method for the high-yield synthesis of 1,4-diazepine seven-membered heterocyclic compounds using a Lewis acid-catalyzed [5+2] cycloaddition strategy and cyclobutenone and imidazoline compounds as reactants. This method offers advantages such as good substrate compatibility, mild reaction conditions, and high yield. Attached Figure Description

[0018] Figure 1 The hydrogen spectrum of compound 3aa; Figure 2 The carbon spectrum of compound 3aa; Figure 3 This is the high-resolution spectrum of compound 3aa. Detailed Implementation

[0019] The present invention will be further described below with reference to embodiments, but is not limited thereto.

[0020] General methods for raw material synthesis: In the following specific embodiments of the present invention, cyclobutenone 1a-1h was prepared according to the following general method:

[0021] Reaction Equation 2: Synthesis of Cyclobutenone Raw Materials

[0022] R 1 Specifically, they are phenyl (1a), 4-ethylbenzene (1b), 4-butylbenzene (1c), 4-methoxybenzene (1d), 4-bromophenyl (1e), naphthyl (1f), thiophene (1g) and cyclopropyl (1h).

[0023] Under argon protection, acetylene compound S-I (20 mmol) and a zinc / copper pair (2.63 g, 40 mmol) were dissolved in 21 mL of diethyl ether. The solution was cooled to 0 °C, and 2,2,2-trichloroacetyl chloride (4.5 mL, 50 mmol) in dimethoxyethane (7 mL) was slowly added dropwise using a syringe. After stirring for 15 minutes, the ice bath was removed, and the reaction was allowed to warm to room temperature. After stirring for 12 hours, the resulting mixture was filtered through diatomaceous earth and eluted with pentane. The combined organic layers were washed with ice-cold 0.5 M HCl (2 x 20 mL), ice-cold 5% NaOH (2 x 20 mL), and brine (2 x 20 mL), dried over Na₂SO₄, filtered, and evaporated under vacuum to give a yellow oily dichlorocyclobutenone S-I'. Subsequently, dichlorocyclobutenone S-Ⅰ' was dissolved in methanol and cooled to 0°C. Ammonium chloride (10.7 g, 200 mmol) was added to the reaction mixture, followed by fractional addition of a zinc / copper pair (7.9 g, 120 mmol). The reaction mixture was stirred at 0°C until TLC analysis showed complete conversion (12 h). The reaction mixture was filtered through diatomaceous earth, the filtrate was evaporated to dryness, quenched with water, and extracted with 50 mL of ethyl acetate. The combined organic layers were washed with saturated NaHCO3 (2 x 20 mL), water (20 mL), and brine (1 x 20 mL); the organic phase was dried over Na2SO4 and evaporated under vacuum. Separation by silica gel column chromatography yielded the target product, cyclobutenone 1 (1a-1h).

[0024] In the following specific examples, imidazoline compounds 2a-2h were prepared using the following general method:

[0025] Reaction Equation 3: Synthesis of Imidazoline Raw Material

[0026] R 2 The compounds are phenyl (2a), 4-methylbenzene (2b), 4-isopropylbenzene (2c), 2-benzyloxybenzene (2d), naphthyl (2e), 4-chlorophenyl (2f), furan (2g), and thiophene (2h).

[0027] SA and formaldehyde (7.5 mmol, 1.5 eq., 36% aqueous solution) were dissolved in MeOH (20.0 mL), and then a solution of acetic acid (10 mol%) in MeOH (4.0 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour until the reaction was complete. The corresponding imidazoline compound 2 (2a-2h) was obtained by concentration and purification by silica gel column chromatography.

[0028] Unless otherwise specified, all other reagents used in this invention were commercially purchased.

[0029] Example 1: Synthesis of (3aa)

[0030] Under argon protection, 1a (21.6 mg, 0.15 mmol, 1.5 eq.), 2a (25.2 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate (7.3 mg, 20 mol%, 0.2 eq.) dissolved in dry tetrahydrofuran (1 mL) were added to the reaction tube. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3aa (29.7 mg, yield: 75%).

[0031] 1 H NMR (300 MHz, CDCl3) δ 7.50 -7.08 (m, 15H), 5.45 (s, 1H), 5.20 (s,1H), 4.66 (s, 1H), 4.50 (d, J = 14.6 Hz, 1H), 4.09 (d, J = 7.7 Hz, 1H), 3.65– 3.28 (m, 4H), 2.95 (d, J = 12.6 Hz, 1H), 2.80 (dd, J = 12.6, 7.8 Hz, 1H), 2.48 (dd, J = 11.0, 6.1 Hz, 1H), 2.26 (dt, J = 12.9, 4.7 Hz, 1H).

[0032] 13 C NMR (75 MHz, CDCl3) δ 174.2, 146.9, 141.7, 138.1, 137.7, 129.0,128.7, 128.5, 128.4, 128.3, 127.6, 127.5, 127.3, 127.0, 115.3, 63.1, 55.8,54.9, 51.9, 48.0.

[0033] HRMS (ESI) m / z calculated for C 27 H 29N2O [M+H] + : 397.2274, found:397.2275.

[0034] Example 2: Synthesis of (3ba):

[0035] Under argon protection, 1b (25.8 mg, 0.15 mmol, 1.5 eq.), 2a (25.2 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate (7.3 mg, 20 mol%, 0.2 eq.) dissolved in dry tetrahydrofuran (1 mL) were added to the reaction tube. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3ba (27.2 mg, yield: 64%).

[0036] 1 H NMR (300 MHz, CDCl3) δ 7.37 -7.13 (m, 14H), 5.43 (s, 1H), 5.17 (s,1H), 4.69 (d, J = 14.6 Hz, 1H), 4.48 (d, J = 14.6 Hz, 1H), 4.09 (d, J = 7.5Hz, 1H), 3.57 – 3.36 (m, 4H), 2.95 (d, J = 13.2 Hz, 1H), 2.86 – 2.75 (m, 1H), 2.65 (q, J = 7.6 Hz, 2H), 2.54 – 2.42 (m, 1H), 2.34 – 2.18 (m, 1H), 1.24 (t, J = 7.6 Hz, 3H).

[0037] 13C NMR (75 MHz, CDCl3) δ 174.3, 146.7, 143.6, 139.0, 138.1, 137.7,129.0, 128.9, 128.65, 128.58, 128.5, 128.4, 127.8, 127.5, 127.3, 126.8,114.6, 63.1, 55.7, 54.9, 51.84, 51.79, 47.9, 28.6, 15.6.

[0038] HRMS (ESI) m / z calculated for C 29 H 33 N2O [M+H] + : 425.2587, found:425.2587.

[0039] Example 3: Synthesis of (3ca):

[0040] Under argon protection, 1c (30.0 mg, 0.15 mmol, 1.5 eq.), 2a (25.2 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate (7.3 mg, 20 mol%, 0.2 eq.) dissolved in dry tetrahydrofuran (1 mL) were added to the reaction tube. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3ca (31.2 mg, yield: 69%).

[0041] 1 H NMR (300 MHz, CDCl3) δ 7.36 -7.11 (m, 14H), 5.44 (s, 1H), 5.16 (s,1H), 4.68 (d, J = 14.6 Hz, 1H), 4.49 (d, J = 14.6 Hz, 1H), 4.08 (d, J = 7.5Hz, 1H), 3.58 – 3.35 (m, 4H), 2.96 (d, J = 12.5 Hz, 1H), 2.80 (dd, J= 12.6,7.9 Hz, 1H), 2.60 (t, 2H), 2.54 – 2.44 (m, 1H), 2.31 – 2.20 (m, 1H), 1.66 –1.54 (m, 2H), 1.42 – 1.29 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0042] 13 C NMR (75 MHz, CDCl3) δ 174.3, 146.7, 142.3, 138.9, 138.1, 137.7,129.0, 128.6, 128.5, 128.38, 128.36, 127.5, 127.3, 126.7, 114.5, 63.1, 55.8,54.9, 51.8, 51.7, 47.9, 35.4, 33.7, 22.5, 14.1.

[0043] HRMS (ESI) m / z calculated for C 31 H 37 N2O [M+H] + : 453.2900, found:453.2903.

[0044] Example 4: Synthesis of (3da):

[0045] Under argon protection, 1d (26.1 mg, 0.15 mmol, 1.5 eq.), 2a (25.2 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate (7.3 mg, 20 mol%, 0.2 eq.) dissolved in dry tetrahydrofuran (1 mL) were added to the reaction tube. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3da (28.1 mg, yield: 66%).

[0046] 1 H NMR (300 MHz, CDCl3) δ 7.38 -7.09 (m, 12H), 6.84 (d, J= 8.8 Hz,2H), 5.38 (s, 1H), 5.14 (s, 1H), 4.69 (d, J = 14.6 Hz, 1H), 4.48 (d, J = 14.6Hz, 1H), 4.06 (d, J = 7.6 Hz, 1H), 3.80 (s, 3H), 3.59 – 3.34 (m, 4H), 2.93(d, J = 11.4 Hz, 1H), 2.87 – 2.73 (m, 1H), 2.54 – 2.43 (m, 1H), 2.33 – 2.22(m, 1H).

[0047] 13 C NMR (75 MHz, CDCl3) δ 174.3, 159.2, 146.2, 138.1, 137.7, 134.1,129.0, 128.7, 128.5, 128.4, 128.1, 127.5, 127.3, 114.0, 113.7, 63.1, 55.6,55.4, 55.0, 52.0, 51.9, 47.9.

[0048] HRMS (ESI) m / z calculated for C 28 H 31 N₂O₂ [M+H] + : 427.2380, found:427.2383.

[0049] Example 5: Synthesis of (3ea):

[0050] Under argon protection, 1e (33.3 mg, 0.15 mmol, 1.5 eq.), 2a (25.2 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate (7.3 mg, 20 mol%, 0.2 eq.) dissolved in dry tetrahydrofuran (1 mL) were added to the reaction tube. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3ea (31.3 mg, yield: 66%).

[0051] 1 H NMR (300 MHz, CDCl3) δ 7.45 – 7.36 (m, 2H), 7.34 – 7.13 (m, 12H), 5.44 (d, J = 9.3 Hz, 1H), 5.21 (s, 1H), 4.68 (d, J = 14.6 Hz, 1H), 4.49 (dd, J = 14.6, 6.2 Hz, 1H), 4.06 (dd, J = 22.5, 7.6 Hz, 1H), 3.59 – 3.34 (m, 4H), 3.00 – 2.72 (m, 2H), 2.55 – 2.43 (m, 1H), 2.34 – 2.22 (m, 1H).

[0052] 13 C NMR (75 MHz, CDCl3) δ 174.2, 174.0, 146.9, 145.9, 141.7, 140.5,138.1, 137.9, 137.7, 137.5, 131.4, 129.0, 128.72, 128.68, 128.50, 128.48,128.44, 128.41, 128.3, 127.62, 127.55, 127.5, 127.4, 127.3, 126.9, 121.6,115.9, 115.3, 63.2, 63.1, 55.8, 55.4, 55.2, 54.9, 51.94, 51.88, 48.0, 47.9.

[0053] HRMS (ESI) m / z calculated for C 27 H 28 BrN2O [M+H] + : 475.1380, found:475.1378.

[0054] Example 6: Synthesis of (3fa):

[0055] Under argon protection, 1f (29.1 mg, 0.15 mmol, 1.5 eq.), 2a (25.2 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate (7.3 mg, 20 mol%, 0.2 eq.) dissolved in dry tetrahydrofuran (1 mL) were added to the reaction tube. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3fa (27.2 mg, yield: 61%).

[0056] 1 H NMR (300 MHz, CDCl3) δ 7.89 – 7.72 (m, 4H), 7.57 (dd, J = 8.5, 1.8Hz, 1H), 7.51 – 7.41 (m, 2H), 7.26 – 7.09 (m, 10H), 5.57 (s, 1H), 5.29 (s,1H), 4.67 (d, J = 14.6 Hz, 1H), 4.53 (d, J = 14.6 Hz, 1H), 4.22 (d, J = 7.5Hz, 1H), 3.58 – 3.32 (m, 4H), 2.97 (d, J = 12.5 Hz, 1H), 2.91 – 2.80 (m, 1H), 2.57 – 2.44 (m, 1H), 2.38 – 2.26 (m, 1H).

[0057] 13 C NMR (75 MHz, CDCl3) δ 174.3, 146.8, 139.1, 138.0, 137.7, 133.4,133.0, 129.0, 128.7, 128.5, 128.35, 128.31, 127.9, 127.7, 127.5, 127.3,126.2, 126.0, 125.6, 125.5, 115.8, 63.2, 55.6, 55.1, 51.9, 48.0.

[0058] HRMS (ESI) m / z calculated for C 31 H 31N2O [M+H] + : 447.2431, found:447.2434.

[0059] Example 7: Synthesis of (3ga):

[0060] Under argon protection, 1 g (22.5 mg, 0.15 mmol, 1.5 eq.), 2a (25.2 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate (7.3 mg, 20 mol%, 0.2 eq.) dissolved in dry tetrahydrofuran (1 mL) were added to the reaction tube. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3ga (26.9 mg, yield: 67%).

[0061] 1 H NMR (300 MHz, CDCl3) δ 7.32 – 7.15 (m, 11H), 7.05 – 6.91 (m, 2H), 5.62 (s, 1H), 5.14 (s, 1H), 4.61 (s, 2H), 4.05 (d, J = 8.5 Hz, 1H), 3.66 –3.54 (m, 2H), 3.46 (d, J = 13.3 Hz, 1H), 3.32 (dd, J = 15.7, 6.5 Hz, 1H), 3.08 (d, J = 12.3 Hz, 1H), 2.84 – 2.70 (m, 1H), 2.71 – 2.57 (m, 1H), 2.26 –2.03 (m, 1H).

[0062] 13 C NMR (75 MHz, CDCl3) δ 173.8, 144.9, 140.5, 138.0, 137.7, 129.0,128.7, 128.51, 128.45, 127.6, 127.3, 124.4, 124.1, 114.1, 63.0, 56.0, 54.9,51.8, 51.5, 48.1.

[0063] HRMS (ESI) m / z calculated for C 25 H 27 N2OS [M+H] + : 403.1839, found: 403.1842.

[0064] Example 8: Synthesis of (3ha):

[0065] Under argon protection, 1h (16.2 mg, 0.15 mmol, 1.5 eq.), 2a (25.2 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate (7.3 mg, 20 mol%, 0.2 eq.) dissolved in dry tetrahydrofuran (1 mL) were added to the reaction tube. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3ha (26.7 mg, yield: 74%).

[0066] 1 H NMR (300 MHz, CDCl3) δ 7.32 – 7.22 (m, 10H), 4.79 (d, J = 8.0 Hz,2H), 4.69 – 4.52 (m, 2H), 3.60 – 3.39 (m, 4H), 2.88 (d, J = 5.0 Hz, 2H), 2.53– 2.41 (m, 1H), 2.34 – 2.22 (m, 1H), 1.52 – 1.39 (m, 1H), 0.77 – 0.44 (m,4H), 0.37 – 0.25 (m, 1H). 13 C NMR (75 MHz, CDCl3) δ 174.8, 148.7, 138.0, 137.8, 129.1, 129.0,128.7, 128.6, 128.5, 128.44, 128.35, 127.5, 127.3, 108.6, 63.2, 55.3, 55.1,53.6, 51.8, 47.9, 15.1, 7.7, 5.4. HRMS (ESI) m / z calculated for C 24 H 29 N2O [M+H] + : 361.2274, found:361.2271.

[0067] Example 9: Synthesis of (3ab):

[0068] Under argon protection, 1a (21.6 mg, 0.15 mmol, 1.5 eq.), 2b (28.0 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate (7.3 mg, 20 mol%, 0.2 eq.) dissolved in dry tetrahydrofuran (1 mL) were added to the reaction tube. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3ab (26.7 mg, yield: 63%).

[0069] 1 H NMR (300 MHz, CDCl3) δ 7.41 – 7.24 (m, 6H), 7.20 – 7.03 (m, 7H), 5.46 (s, 1H), 5.20 (s, 1H), 4.70 (d, J = 14.9 Hz, 1H), 4.54 (d, J = 14.9 Hz, 1H), 4.09 (d, J = 8.4 Hz, 1H), 3.51 (d, J = 13.2 Hz, 1H), 3.44 – 3.29 (m,3H), 2.98 (d, J = 12.4 Hz, 1H), 2.91 – 2.74 (m, 1H), 2.58 – 2.43 (m, 1H), 2.32 – 2.19 (m, 7H). 13C NMR (75 MHz, CDCl3) δ 174.0, 146.9, 141.6, 137.6, 136.9, 136.0,135.1, 130.6, 130.5, 129.9, 129.2, 128.3, 127.6, 127.5, 127.4, 126.9, 126.1,125.7, 115.2, 61.0, 55.9, 54.9, 51.7, 49.3, 47.1, 19.4, 19.3. HRMS (ESI) m / z calculated for C 29 H 33 N2O [M+H] + : 425.2587, found:425.2587.

[0070] Example 10: Synthesis of (3ac):

[0071] Under argon protection, 1a (21.6 mg, 0.15 mmol, 1.5 eq.), 2c (33.6 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate (7.3 mg, 20 mol%, 0.2 eq.) dissolved in dry tetrahydrofuran (1 mL) were added to the reaction tube. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3ac (30.3 mg, yield: 63%).

[0072] 1 H NMR (300 MHz, CDCl3) δ 7.47 – 7.26 (m, 5H), 7.11 (d, J = 3.6 Hz,8H), 5.45 (s, 1H), 5.20 (s, 1H), 4.55 (q, J = 14.7 Hz, 2H), 4.09 (d, J = 6.6Hz, 1H), 3.61 – 3.25 (m, 4H), 3.02 – 2.72 (m, 4H), 2.57 – 2.41 (m, 1H), 2.35 – 2.19 (m, 1H), 1.36 – 1.09 (m, 12H). 13 C NMR (75 MHz, CDCl3) δ 174.2, 148.2, 147.9, 147.0, 141.7, 135.4,135.0, 129.3, 129.0, 128.5, 128.3, 127.5, 126.9, 126.8, 126.7, 126.4, 115.2,62.9, 55.8, 54.8, 51.9, 51.6, 47.9, 33.9, 24.14, 24.11. HRMS (ESI) m / z calculated for C 33 H 41 N2O [M+H] + : 481.3213, found:481.3220.

[0073] Example 11

[0074] Synthesis of (3ad):

[0075] Under argon protection, 1a (21.6 mg, 0.15 mmol, 1.5 eq.), 2d (46.4 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate (7.3 mg, 20 mol%, 0.2 eq.) dissolved in dry tetrahydrofuran (1 mL) were added to the reaction tube. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3ad (35.3 mg, yield: 58%).

[0076] 1 H NMR (300 MHz, CDCl3) δ 7.43 – 7.11 (m, 19H), 6.97 – 6.79 (m, 4H), 5.41 (s, 1H), 5.14 (s, 1H), 5.00 (d, J = 4.2 Hz, 4H), 4.70 (q, 2H), 4.05 (d, J = 7.9 Hz, 1H), 3.72 – 3.36 (m, 4H), 3.00 (d, J= 12.5 Hz, 1H), 2.85 – 2.68 (m, 1H), 2.68 – 2.48 (m, 1H), 2.40 – 2.19 (m, 1H). 13 C NMR (75 MHz, CDCl3) δ 174.4, 157.0, 156.7, 147.1, 141.9, 137.3,137.1, 130.7, 130.2, 128.72, 128.66, 128.5, 128.3, 128.3, 128.1, 128.0,127.5, 127.4, 127.3, 126.9, 126.6, 126.3, 121.2, 120.8, 115.2, 112.0, 111.8,70.2, 70.1, 56.5, 55.8, 55.2, 51.6, 48.6, 46.5. HRMS (ESI) m / z calculated for C 41 H 41 N₂O₃ [M+H] + : 609.3112, found:609.3117.

[0077] Example 12

[0078] Synthesis of (3ae):

[0079] Under argon protection, 1a (21.6 mg, 0.15 mmol, 1.5 eq.), 2e (35.2 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate (7.3 mg, 20 mol%, 0.2 eq.) dissolved in dry tetrahydrofuran (1 mL) were added to the reaction tube. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3ae (29.8 mg, yield: 60%).

[0080] 1 H NMR (400 MHz, CDCl3) δ 7.86 – 7.21 (m, 19H), 5.47 (s, 1H), 5.24 (s,1H), 4.85 (d, J= 14.5 Hz, 1H), 4.65 (d, J = 14.5 Hz, 1H), 4.16 (d, J = 7.7Hz, 1H), 3.65 (d, J = 13.2 Hz, 1H), 3.61 – 3.37 (m, 3H), 3.04 (d, J = 12.6Hz, 1H), 2.87 (dd, J = 12.6, 8.0 Hz, 1H), 2.61 – 2.43 (m, 1H), 2.35 – 2.17(m, 1H). 13 C NMR (75 MHz, CDCl3) δ 174.3, 146.9, 141.7, 135.7, 135.2, 133.4,133.3, 132.9, 128.6, 128.4, 128.1, 127.81, 127.79, 127.76, 127.65, 127.59,127.3, 127.1, 126.9, 126.6, 126.3, 126.1, 126.0, 125.8, 115.3, 63.2, 55.9,55.0, 52.0, 51.9, 47.9. HRMS (ESI) m / z calculated for C 35 H 33 N2O [M+H] + : 497.2587, found:497.2596.

[0081] Example 13

[0082] Synthesis of (3af):

[0083] Under argon protection, 1a (21.6 mg, 0.15 mmol, 1.5 eq.), 2f (32.0 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate (7.3 mg, 20 mol%, 0.2 eq.) dissolved in dry tetrahydrofuran (1 mL) were added to the reaction tube. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3af (31.1 mg, yield: 67%).

[0084] 1 H NMR (300 MHz, CDCl3) δ 7.46 – 7.20 (m, 9H), 7.09 (t, J = 7.9 Hz,4H), 5.44 (s, 1H), 5.17 (s, 1H), 4.66 (d, J = 14.6 Hz, 1H), 4.41 (d, J = 14.7Hz, 1H), 4.07 (d, J = 7.3 Hz, 1H), 3.60 – 3.24 (m, 4H), 2.96 – 2.69 (m, 2H), 2.52 – 2.38 (m, 1H), 2.35 – 2.22 (m, 1H). 13 C NMR (75 MHz, CDCl3) δ 174.2, 146.6, 141.4, 136.5, 136.2, 133.4,133.0, 130.2, 129.8, 128.9, 128.6, 128.4, 127.7, 126.9, 115.3, 62.3, 55.4,55.1, 51.9, 51.4, 48.0. HRMS (ESI) m / z calculated for C 27 H 27 Cl2N2O [M+H] + : 465.1495, found:465.1497.

[0085] Example 14

[0086] Synthesis of (3ag):

[0087] Under argon protection, 1a (21.6 mg, 0.15 mmol, 1.5 eq.), 2g (23.2 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate (7.3 mg, 20 mol%, 0.2 eq.) dissolved in dry tetrahydrofuran (1 mL) were added to the reaction tube. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3ag (26.0 mg, yield: 69%).

[0088] 1 H NMR (300 MHz, CDCl3) δ 7.49 – 7.17 (m, 7H), 6.35 – 6.18 (m, 3H), 6.09 (d, J = 3.2 Hz, 1H), 5.43 (s, 1H), 5.13 (s, 1H), 4.76 (d, J = 15.2 Hz, 1H), 4.38 (d, J = 15.2 Hz, 1H), 4.00 (d, J = 8.6 Hz, 1H), 3.77 – 3.46 (m,4H), 3.03 – 2.86 (m, 1H), 2.79 – 2.58 (m, 2H), 2.33 – 2.17 (m, 1H). 13 C NMR (75 MHz, CDCl3) δ 173.9, 151.4, 151.1, 147.0, 142.33, 142.26,141.7, 128.3, 127.4, 126.9, 115.2, 110.5, 110.2, 109.0, 108.6, 55.3, 55.2,54.9, 51.5, 48.3, 44.6. HRMS (ESI) m / z calculated for C 23 H 25 N₂O₃ [M+H] + : 377.1860, found:377.1867.

[0089] Example 15

[0090] Synthesis of (3ah):

[0091] Under argon protection, 1a (21.6 mg, 0.15 mmol, 1.5 eq.), 2h (26.4 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate (7.3 mg, 20 mol%, 0.2 eq.) dissolved in dry tetrahydrofuran (1 mL) were added to the reaction tube. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3ah (29.0 mg, yield: 71%).

[0092] 1 H NMR (300 MHz, CDCl3) δ 7.45 – 7.17 (m, 7H), 7.01 – 6.83 (m, 3H), 6.79 (d, J = 2.8 Hz, 1H), 5.43 (s, 1H), 5.15 (s, 1H), 4.86 (d, J = 14.9 Hz, 1H), 4.62 (d, J = 15.0 Hz, 1H), 4.02 (d, J = 7.9 Hz, 1H), 3.80 – 3.45 (m,4H), 2.95 (d, J = 12.5 Hz, 1H), 2.83 – 2.67 (m, 1H), 2.67 – 2.51 (m, 1H), 2.40 – 2.24 (m, 1H). 13 C NMR (75 MHz, CDCl3) δ 173.9, 146.9, 141.65, 141.61, 140.2, 128.3,127.5, 127.0, 126.8, 126.7, 126.5, 126.1, 125.7, 125.3, 115.2, 57.4, 55.5,54.8, 51.9, 48.3, 47.0. HRMS (ESI) m / z calculated for C 23 H 25 N2OS2 [M+H] +: 409.1403, found:409.1405.

[0093] The following examples 16-19 are experiments with controlled variables: Example 16: Different catalysts can be used for the reaction: Synthesis of (3aa): Under argon protection, 1a (21.6 mg, 0.15 mmol, 1.5 eq.), 2a (25.2 mg, 0.1 mmol, 1.0 eq.), and copper trifluoromethanesulfonate were added to the reaction tube. (7.2 mg, 20 mol%, 0.2 eq.) was dissolved in dry tetrahydrofuran (1 mL). The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3aa (yield: 65%).

[0094] Compared to the above, the difference lies in the choice of catalyst; all other operations remain the same. When scandium trifluoromethanesulfonate is used as the catalyst, the yield is 43%. When ytterbium trifluoromethanesulfonate is used as the catalyst, the yield is 52%. When aluminum trifluoromethanesulfonate is used as the catalyst, the yield is 70%. When nickel trifluoromethanesulfonate is used as the catalyst, the yield is 67%. Without a catalyst, the yield is 0%.

[0095] Example 17: Different solvents were selected for the reaction: Synthesis of (3aa): Under argon protection, 1a (21.6 mg, 0.15 mmol, 1.5 eq.), 2a (25.2 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate were added to the reaction tube. (7.3 mg, 20 mol%, 0.2 eq.) was dissolved in dry dichloroethane (1 mL). The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the crude product was purified by TLC to give 3aa (yield: 25%).

[0096] Compared to the above, the difference lies in the choice of solvent; all other operations remain the same. When toluene is chosen as the reaction solvent, the yield of 3aa is 37%. When 1,4-dioxane is chosen as the reaction solvent, the yield of 3aa is 24%. When acetonitrile is chosen as the reaction solvent, the yield of 3aa is 41%.

[0097] Example 18: Different molar ratios of 1a and 2a were selected for the reaction: Synthesis of (3aa): Under argon protection, 1a (14.4 mg, 0.1 mmol, 1.0 eq.), 2a (25.2 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate were added to the reaction tube. (7.3 mg, 20 mol%, 0.2 eq.) was dissolved in dry tetrahydrofuran (1.0 mL). The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, 2.0 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3aa (yield: 39%).

[0098] The difference compared to the above is that when the molar ratio of cyclobutenone and imidazole compound is 2:1, the yield of 3aa is 75%.

[0099] Example 19: Different temperatures were selected for the reaction: Synthesis of (3aa): Under argon protection, 1a (14.4 mg, 0.1 mmol, 1.0 eq.), 2a (25.2 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate were added to the reaction tube. (7.3 mg, 20 mol%, 0.2 eq.) was dissolved in dry tetrahydrofuran (1.0 mL). The reaction mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction was quenched with 2.0 mL of water, extracted with ethyl acetate (3 x 2 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3aa (yield: 8%).

[0100] Compared to the above, choosing 50℃ for the reaction resulted in a 35% yield of 3aa. Choosing 100℃... o The reaction proceeds at C, with a yield of 75% for 3aa (compared to the standard reaction conditions of 80°C). o At time C, the yield is the same.

[0101] Example 20: Different amounts of catalyst were selected for the reaction: Synthesis of (3aa): Under argon protection, 1a (14.4 mg, 0.1 mmol, 1.0 eq.), 2a (25.2 mg, 0.1 mmol, 1.0 eq.), and zinc trifluoromethanesulfonate were added to the reaction tube. (3.6 mg, 10 mol%, 0.1 eq.) was dissolved in dry tetrahydrofuran (1.0 mL). The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the reaction was quenched with 2.0 mL of water, extracted with ethyl acetate (3 x 2 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by TLC to give 3aa (yield: 60%).

[0102] The difference compared to the above is that zinc trifluoromethanesulfonate is chosen. The reaction was carried out at (11.0 mg, 30 mol%, 0.3 eq.), and the yield of 3aa was 72%. Increasing the catalyst amount further did not improve the yield.

[0103] 3aa application transformation: Deoxygenation reduction of compound 3aa:

[0104] Compound 3aa (40.0 mg, 0.1 mmol, 1.0 eq.) was dissolved in a dry tetrahydrofuran solution (2.0 mL), then cooled to 0 °C, and lithium aluminum hydride (38.0 mg, 1.0 mmol, 10.0 eq.) was slowly added dropwise. The reaction was then carried out at 80 °C for 12 h. After cooling to room temperature, the reaction solution was quenched with sodium hydroxide solution, extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography to give an oily compound 6 (26.2 mg, 68% yield).

[0105] 1 H NMR (300 MHz, CDCl3) δ 7.34-7.22 (m, 15H), 5.18 (s, 1H), 5.03 (s,1H), 3.70 (s, 4H), 3.16 (s, 1H), 3.07-2.73 (m, 6H), 2.72-2.61 (m, 2H).

[0106] 13 C NMR (151 MHz, CDCl3) δ 129.1, 128.4, 127.7, 127.4, 127.1, 126.5,112.2, 62.5, 60.5, 55.2.

[0107] HRMS (ESI) m / z calculated for C 27 H 31 N2 [M+H] + : 383.2482, found:383.2483.

[0108] Quaternization of compound 3aa:

[0109] Compound 3aa (200.0 mg, 0.5 mmol, 1.0 equivalent), 2-cyanobenzyl bromide (295.0 mg, 1.5 mmol, 3.0 equivalent), and acetonitrile (5 mL) were added to a round-bottom flask. The yellow solution was stirred at room temperature for 20 hours. The reaction mixture was added dropwise to ether (20 mL) under vigorous stirring to induce precipitation of the product. The yellowish-white solid was separated by filtration. The solid was washed with ether and dried under high vacuum to give compound 7 (206.9 mg, 70% yield) as a white solid.

[0110] 1 H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 7.3 Hz, 2H), 7.68-7.52 (m, 5H), 7.44-7.21 (m, 8H), 7.14-7.02 (m, 2H), 7.01 – 6.84 (m, 2H), 6.25 (d, J = 12.6Hz, 1H), 5.92 (d, J = 12.7 Hz, 1H), 5.73 – 5.43 (m, 3H), 5.36 (s, 1H), 5.27(d, J = 10.3 Hz, 1H), 4.98 (d, J = 14.2 Hz, 1H), 4.75- 4.59 (m, 1H), 4.44 (d, J = 12.1 Hz, 1H), 4.06 (d, J = 12.5 Hz, 1H), 3.70 (d, J = 14.3 Hz, 1H), 3.21(d, J = 17.5 Hz, 1H), 2.92 (t, J = 11.8 Hz, 1H), 2.52 (t, J = 12.1 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 170.6, 143.9, 140.3, 136.4, 134.1, 133.7,131.3, 131.2, 129.5, 129.2, 128.9, 128.2, 128.0, 127.1, 125.8, 117.0, 116.8,115.9, 63.9, 62.7, 59.5, 56.2, 51.7, 41.9. HRMS (ESI) m / z calculated for C 27 H 29 N2O [M-M'(2-cyanobenzyl bromide) +H] + : 397.2274, found: 397.2275.

[0111] The embodiments described above are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments. Any obvious improvements, substitutions or modifications that can be made by those skilled in the art without departing from the essence of the present invention shall fall within the protection scope of the present invention.

Claims

1. A method of synthesizing 1, 4-diazepine heterocyclic compounds, characterized by: The reaction of a cyclobutenone compound of formula 1 and an imidazoline compound of formula 2 in the presence of a Lewis acid catalyst produces a 1,4-diazepine compound of formula 3. ； wherein R 1 is one of phenyl, 4-ethylphenyl, 4-butylphenyl, 4-methoxyphenyl, 4-bromophenyl, naphthyl, thiophene and cyclopropyl; R 2 is one of phenyl, 4-methylphenyl, 4-isopropylphenyl, 2-benzyloxyphenyl, naphthyl, 4-chlorophenyl, furan, thiophene.

2. The method for synthesizing 1,4-diazepine seven-membered heterocyclic compounds according to claim 1, characterized in that: The method comprises the following steps: under the protection of argon, a Lewis acid catalyst is added into a reaction device, followed by the addition of a cyclobutenone compound and an imidazoline compound, stirring in a reaction solvent, and then heating to reaction until the reaction is completed, quenching, purification, and separation to obtain a 1,4-diazepine compound.

3. The method of synthesizing 1, 4-diazepine compounds according to claim 1 or 2, characterized in that: The molar ratio of the cyclobutenone compound and the imidazoline compound is 1:1-2:

1.

4. The method of synthesizing 1, 4-diazepine compounds according to claim 2, wherein: The reaction solvent is one of dichloroethane, toluene, 1,4-dioxane, tetrahydrofuran, and acetonitrile.

5. The method of synthesizing 1, 4-diazepine compounds according to claim 1 or 2, characterized in that: The Lewis acid catalyst is one of copper triflate, scandium triflate, ytterbium triflate, zinc triflate, aluminum triflate, and nickel triflate.

6. The method of synthesizing 1, 4-diazepine compounds according to claim 2, wherein: The molar ratio of the cyclobutenone compound and the imidazoline compound is 1.5:1; the reaction solvent is tetrahydrofuran; and the Lewis acid catalyst is zinc triflate.

7. The method of synthesizing 1, 4-diazepine compounds according to claim 1 or 2, characterized in that: The amount of the Lewis acid catalyst is 10%-50% of the equivalent of the imidazoline compound.

8. The method of synthesizing 1, 4-diazepine compounds according to claim 7, wherein: The amount of the Lewis acid catalyst is 20% of the equivalent of the imidazoline compound.

9. The method of synthesizing 1, 4-diazepine compounds according to claim 1 or 2, characterized by: The reaction temperature is 25-80°C.

10. The method of synthesizing 1, 4-diazepine compounds according to claim 2, wherein: The concentration of the cyclobutenone compound and the imidazoline compound in the solvent is 0.1 M. The concentration of the cyclobutenone compound and the imidazoline compound in the solvent is 0.1 M.

Images