Cycloheptatriene oxazepine compound as well as preparation method and application of cycloheptatriene oxazepine compound

Abstract

The invention discloses a cycloheptatriene oxazine compound as well as a preparation method and application thereof, and belongs to the technical field of organic synthesis. The structural formula of the cycloheptatriene oxazine compound is as follows: # imgabs0 #. Under the action of a palladium catalyst, an N-sulfonyl azafulvene compound and an alkenyl ethylene carbonate compound are used as raw materials to react, and the cycloheptatriene oxazepine compound is synthesized. The preparation method of the cycloheptatriene oxazepine compound is simple and convenient to operate and mild in reaction condition, and used reagents and raw materials are economical and easy to obtain; the target product yield is high, the substrate application range is wide, and good anti-tumor activity is achieved.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and in particular relates to a cycloheptatriene oxazocine compound, a preparation method and an application thereof. Background Art

[0002] Cycloheptatriene substrates are important precursors for the synthesis of medium-ring compounds, possessing four conjugated double bonds and eight π electrons. This unique charge distribution allows cycloheptatriene synthons to possess multiple reactive sites, enabling them to participate in [2+n]-, [4+n]-, [6+n]-, or [8+n]-higher-order cycloaddition reactions in various configurations (e.g., 2π, 4π, 6π, and 8π units). [8+n]-higher-order cycloadditions are highly efficient in constructing a diverse range of cycloheptatriene carbocyclic or heterocyclic medium-ring compounds. Numerous reports have reported on [8+1], [8+2], [8+3], and [8+4]-higher-order cycloadditions involving cycloheptatriene compounds, successfully constructing a rich array of four- to seven-membered medium-ring compounds. However, the [8+5]-cycloaddition type remains unreported, primarily due to unfavorable entropic and enthalpic effects associated with the construction of larger ring systems. Therefore, how to achieve the efficient synthesis of cycloheptatriene with eight or more membered middle ring systems remains one of the difficulties in this research field.

[0003] Oxacin is a class of octahedral ring structures containing nitrogen and oxygen heteroatoms, and has a wide range of applications in drug discovery, showing potential anti-inflammatory, anti-Alzheimer's, antifungal, anti-diabetic, and anti-cancer activities. For example, nefopam is a non-narcotic analgesic clinically used for postoperative pain relief and cancer pain; KRP is a neurokinin (NK-1) receptor antagonist; MK-3281 is a non-nucleoside hepatitis C virus (HCV) NS5B polymerase inhibitor, which is effective for EC of the gt1a genotype. 50 The value is 28nM. Furthermore, cycloheptatriene compounds, as important organic molecular skeletons, are also widely present in natural products and active pharmaceutical ingredients. Their unique seven-membered ring conjugated system endows them with diverse biological activities, including antibacterial, antiviral, antitumor, insecticide, anti-inflammatory, and enzyme inhibition. For example, Harringtonolide, isolated from the genus Torreya hainanensis, exhibits antiviral and antitumor activities; Gukulenin-like natural products derived from the sponge Phorbas gukhulensis exhibit potent cytotoxicity against various cancer cell lines; and Welwitindolinones, secondary metabolites of marine cyanobacteria, participate in complex biological metabolic pathways as specific substrates of amide nitrogen methyltransferases. Based on the "pharmacophore fusion" strategy, the two aforementioned pharmacophores were integrated to develop a new synthetic method for cycloheptatriene-8-membered oxazocine compounds. This will not only expand the diversity of cycloheptatriene fused ring systems but also promote the development of new heterocyclic drugs. Summary of the Invention

[0004] In response to the problems existing in the prior art, the present invention provides a cycloheptatriene oxazocine compound and a preparation method and application thereof. The method has mild reaction conditions, economical reagents, simple and efficient steps, and uses easily available N-sulfonylazafulvene and alkenyl ethylene carbonate as starting materials to undergo an [8+5]-high-order cycloaddition reaction under palladium catalysis to synthesize the cycloheptatriene oxazocine compound. The compound has the effect of inhibiting tumor cell proliferation.

[0005] The present invention is achieved through the following technical solutions: The present invention discloses a cycloheptatriene oxazocine compound, the structural formula of the cycloheptatriene oxazocine compound is: R 1 is one of C1-C7 alkyl, C3-C7 cycloalkyl, substituted or unsubstituted phenyl, heteroaryl, and trifluoromethyl; R 2 It is one of 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 3-methoxyphenyl, 3-chlorophenyl, 2-methylphenyl, 2-bromophenyl, 2-naphthyl, 2-thienyl and cyclohexyl.

[0006] The present invention discloses a method for preparing the above-mentioned cycloheptatrienol-oxazocine compounds. Under the action of a palladium catalyst, an N-sulfonylazafulvene compound and an alkenyl ethylene carbonate compound are reacted as raw materials to synthesize the cycloheptatrienol-oxazocine compounds. The reaction formula is shown below: .

[0007] Furthermore, the N-sulfonylazafulvene compound and the alkenyl ethylene carbonate compound are dissolved, a palladium catalyst and a ligand are added, and the reaction is carried out under nitrogen protection to obtain a cycloheptatriene-oxazocine compound.

[0008] Furthermore, the palladium catalyst is one or more of tris(dibenzylideneacetone)dipalladium chloroform complex, tris(dibenzylideneacetone)dipalladium, allylpalladium(II) chloride dimer, tetrakis(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, bis[tri(2-methylphenyl)phosphine]palladium, bistriphenylphosphinepalladium dichloride, (1,5-cyclooctadiene)palladium(II) dichloride, palladium chloride, palladium trifluoroacetate, and palladium acetate.

[0009] Furthermore, the palladium catalyst is tris(dibenzylideneacetone)dipalladium-chloroform complex.

[0010] Furthermore, the reaction conditions are 60-100° C. for 10-24 hours.

[0011] Furthermore, the ligand is one of triphenylphosphine, tricyclohexylphosphine, tri(p-tolyl)phosphine, tri(4-trifluoromethylphenyl)phosphine, tri(2-furyl)phosphine, 2-(diphenylphosphino)-2,6-dimethoxybiphenyl, bis(2-diphenylphosphinophenyl) ether (DPEPhos), 1,5-bis(diphenylphosphino)propane (DPPP), 1,2-bis(diphenylphosphino)ethane (DPPE), bis(diphenylphosphino)methane (DPPM), 1,2-bis(diphenylphosphino)benzene, 1,8-(diphenylphosphino)naphthalene, 4,6-bis(diphenylphosphino)phenazine, and (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (BINAP).

[0012] Furthermore, the solvent for dissolving N-sulfonylazafulvene and alkenyl ethylene carbonate is one of toluene, p-xylene, mesitylene, fluorobenzene, chlorobenzene, bromobenzene, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, and tert-butyl methyl ether.

[0013] Furthermore, the molar ratio of the N-sulfonylazafulvene compound, the alkenyl ethylene carbonate compound, the palladium catalyst, and the ligand is 1:1~1.5:0.05~0.1:0.06~0.12.

[0014] The present invention also discloses the use of the cycloheptatriene oxazocine compound in the preparation of anti-tumor drugs.

[0015] The beneficial effects of the present invention are: The present invention provides a cycloheptatrienol oxazocine compound, a preparation method and application thereof. The preparation method of the cycloheptatrienol oxazocine compound provided is simple to operate, has mild reaction conditions, and uses economical and readily available reagents and raw materials. The target product has a high yield and a wide range of substrate applicability, has good anti-tumor activity, and has good prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 The cycloheptatriene oxazocine compound 3aa prepared in Example 1 1 HNMR spectrum; Figure 2 The cycloheptatriene oxazocine compound 3aa prepared in Example 1 13 CNMR spectrum; Figure 3 The single crystal structure of the cycloheptatriene oxazocine compound 3aa prepared in Example 1; Figure 4 The cycloheptatriene oxazocine compound 3ab prepared in Example 2 1HNMR spectrum; Figure 5 The cycloheptatriene oxazocine compound 3ab prepared in Example 2 13 CNMR spectrum; Figure 6 The cycloheptatriene oxazocine compound 3ac prepared in Example 3 1 HNMR spectrum; Figure 7 The cycloheptatriene oxazocine compound 3ac prepared in Example 3 13 CNMR spectrum; Figure 8 The cycloheptatriene oxazocine compound 3ad prepared in Example 4 1 HNMR spectrum; Figure 9 The cycloheptatriene oxazocine compound 3ad prepared in Example 4 13 CNMR spectrum; Figure 10 The cycloheptatriene oxazocine compound 3ae prepared in Example 5 1 HNMR spectrum; Figure 11 The cycloheptatriene oxazocine compound 3ae prepared in Example 5 13 CNMR spectrum; Figure 12 The cycloheptatriene oxazocine compound 3ba prepared in Example 6 1 HNMR spectrum; Figure 13 The cycloheptatriene oxazocine compound 3ba prepared in Example 6 13 CNMR spectrum; Figure 14 The cycloheptatriene oxazocine compound 3ca prepared in Example 7 13 CNMR spectrum; Figure 15 The cycloheptatriene oxazocine compound 3ca prepared in Example 7 13 CNMR spectrum. DETAILED DESCRIPTION

[0017] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0018] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0019] In the following examples, an N-sulfonylazafulvene compound and an alkenyl ethylene carbonate compound were dissolved, a palladium catalyst and a ligand were added, and the mixture was reacted under nitrogen to obtain a cycloheptatriene-oxazocine compound; the chemical reaction formula is: ; N-sulfonylazafulvene compounds: , derived from the easily available cycloheptatrienone, and the specific preparation method is as follows: Under nitrogen protection, cycloheptatrienone (7.5 mmol, 1.0 equiv.) was added to a solution (0.25 M) of the corresponding sulfonamide (8 mmol, 1.05 equiv.), and the mixture was placed in an ice bath and cooled to 0°C; titanium tetrachloride (8.6 mmol, 1 mL, 1.15 equiv.) was slowly added dropwise to the reaction solution for 5 min, and triethylamine (16.5 mmol, 2.3 mL, 2.2 equiv.) was slowly added dropwise to the reaction system for 10 minutes to obtain a brown reaction mixture; then, under nitrogen protection, heating and reflux were continued for overnight reaction; after completion of the reaction, the reaction was cooled to room temperature, the reaction mixture was diluted with dichloromethane and water, and the insoluble matter was removed by filtration through diatomaceous earth; the filtrate was separated by a separatory funnel, and the aqueous phase was extracted three times with dichloromethane (3×60 mL); the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the concentrate was separated and purified by column chromatography (petroleum ether:ethyl acetate=2:1) ​​to obtain N-sulfonylazafulvene (Manzano, R.; Romaniega, A.; Prieto, L.Org.Lett.,2020,22,4721-4725); the reaction formula is: .

[0020] In the following examples, R 1 and R 2 They are shown in Table 1 below: Table 1 .

[0021] Example 1 To a 1 mL toluene solution of N-sulfonylazafulvene 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and alkenyl ethylene carbonate 2a (22.8 mg, 0.12 mmol, 1.2 equiv.) were added tetrakistriphenylphosphine palladium (11.5 mg, 0.01 mmol, 0.1 equiv.) and 1,2-bis(diphenylphosphino)benzene (5.35 mg, 0.012 mmol, 0.12 equiv.). Under nitrogen, the mixture was stirred at 60°C for 12 h. TLC confirmed the complete reaction and the reaction was terminated. The product was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford cycloheptatriene oxazocine 3aa as a white solid in an isolated yield of 34.4 mg (85%). 1 HNMR spectra and 13 CNMR spectra are as follows Figure 1 and Figure 2 As shown, the single crystal structure is shown in Figure 3 As shown; the characterization data are: 1 HNMR (500 MHz, CDCl3) δ7.46 – 7.38 (m, 2H), 7.25 – 7.17 (m, 5H), 7.17 – 7.12(m, 2H), 6.52 (ddd, J = 25.3, 10.9, 6.2 Hz, 2H), 6.31 (d, J = 6.5 Hz, 1H), 6.17 –6.02 (m, 2H), 4.78 – 4.61 (m, 3H), 4.44 (dd, J = 11.2, 9.0 Hz, 1H), 4.23 (d, J =15.1 Hz, 1H), 3.11 (d, J = 5.8 Hz, 1H), 2.36 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ145.03, 143.50, 140.20, 135.33, 129.50, 129.19, 128.52, 128.23, 128.07,128.04, 126.17, 123.90, 123.55, 122.09, 79.64, 71.25, 45.48, 21.62; the molecular formula is as follows: .

[0022] Example 2 To a 1 mL toluene solution of N-sulfonylazafulvene 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and alkenyl ethylene carbonate 2b (26.4 mg, 0.12 mmol, 1.2 equiv.) was added tris(dibenzylideneacetone)dipalladium-chloroform complex (10.2 mg, 0.01 mmol, 0.1 equiv.) and tri(p-tolyl)phosphine (3.6 mg, 0.012 mmol, 0.12 equiv.). Under nitrogen, the mixture was stirred at 60°C for 12 h. TLC confirmed the complete reaction and the reaction was terminated. The mixture was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford cycloheptatriene oxazocine 3ab as a white solid in an isolated yield of 33.1 mg (76%). 1 HNMR spectra and 13 CNMR spectra are as follows Figure 4 and Figure 5 As shown; the characterization data are: 1 H NMR (500 MHz, CDCl3) δ 7.53 – 7.45 (m, 2H), 7.26 (dt, J = 8.3, 1.4 Hz, 2H), 7.20 –7.15 (m, 2H), 6.85 – 6.80 (m, 2H), 6.64 – 6.53 (m, 2H), 6.40 – 6.35 (m, 1H),6.18 – 6.10 (m, 2H), 4.80 – 4.74 (m, 2H), 4.72 (dd, J = 15.1, 1.9 Hz, 1H), 4.50(dd, J = 11.4, 8.9 Hz, 1H), 4.30 (d, J = 15.1 Hz, 1H), 3.78 (s, 3H), 3.17 (d, J =6.0 Hz, 1H), 2.43 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 159.56, 144.33, 143.47,135.33, 132.53, 129.44, 129.18, 128.25, 128.05, 127.38, 122.33, 122.09,113.88, 79.58, 71.18, 55.34, 45.62, 21.63; the molecular formula is as follows: .

[0023] Example 3 To a solution of N-sulfonylazafulvene 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and alkenyl ethylene carbonate 2c (25.0 mg, 0.12 mmol, 1.2 equiv.) in toluene (1 mL) were added tris(dibenzylideneacetone)dipalladium (9.16 mg, 0.01 mmol, 0.1 equiv.) and bis(2-diphenylphosphinophenyl) ether (6.5 mg, 0.012 mmol, 0.12 equiv.). Under nitrogen, the mixture was stirred at 60°C for 12 h. TLC confirmed the complete reaction and the reaction was terminated. The mixture was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford cycloheptatriene oxazocine 3ac as a white solid in an isolated yield of 33.8 mg (80%). 1 HNMR spectra and 13 CNMR spectra are as follows Figure 6 and Figure 7 As shown; the characterization data are: 1 H NMR (500 MHz, CDCl3) δ 7.53 – 7.46 (m, 2H), 7.26 (d, J = 8.2 Hz, 2H), 7.19 (ddq, J =11.1, 5.8, 2.9 Hz, 2H), 7.01 – 6.95 (m, 2H), 6.64 (dd, J = 10.9, 5.8 Hz, 1H),6.58 (dd, J = 10.9, 6.6 Hz, 1H), 6.39 (d, J = 6.7 Hz, 1H), 6.17 (ddd, J = 10.8,8.6, 6.5 Hz, 2H), 4.81 (dd, J = 9.8, 6.1 Hz, 1H), 4.76 (dd, J = 11.5, 8.9 Hz,1H), 4.69 (dd, J = 15.0, 1.8 Hz, 1H), 4.49 (dd, J = 11.5, 8.9 Hz, 1H), 4.26 (d, J =15.1 Hz, 1H), 3.23 (d, J = 6.1 Hz, 1H), 2.44 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ162.59 (d,J = 247.6 Hz), 143.77 (d, J = 51.7 Hz), 136.31 (d, J = 3.3 Hz), 135.28,129.66, 129.23, 128.14, 128.02, 127.91, 127.85, 126.38, 123.98, 123.17,122.05, 115.51, 115.34, 79.35, 70.95, 45.40, 21.63; the molecular formula is as follows: .

[0024] Example 4 To a solution of N-sulfonylazafulvene 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and alkenyl ethylene carbonate 2d (25.0 mg, 0.12 mmol, 1.2 equiv.) in toluene (1 mL) were added tris(dibenzylideneacetone)dipalladium-chloroform complex (10.2 mg, 0.01 mmol, 0.1 equiv.) and tri(p-tolyl)phosphine (3.6 mg, 0.012 mmol, 0.12 equiv.). Under nitrogen, the mixture was stirred at 60°C for 12 h. TLC confirmed the complete reaction and the reaction was terminated. The mixture was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford cycloheptatriene oxazocine derivative 3ad as a white solid in an isolated yield of 31.73 mg (75%). 1 HNMR spectra and 13 CNMR spectra are as follows Figure 8 and Figure 9 As shown; 1 H NMR (500 MHz, CDCl3) δ 7.52 – 7.46 (m, 2H), 7.28 – 7.22 (m, 3H), 7.13 (td, J = 7.6, 2.0 Hz,1H), 7.07 (td, J = 7.5, 1.2 Hz, 1H), 6.98 (ddd, J = 10.7, 8.2, 1.1 Hz, 1H), 6.66– 6.58 (m, 2H), 6.40 (dd, J = 5.0, 1.8 Hz, 1H), 6.15 (td, J = 9.0, 2.3 Hz, 1H), 6.09 – 6.03 (m, 1H), 4.85 (dd,J = 11.0, 9.3 Hz, 1H), 4.81 (dt, J = 15.4, 2.3 Hz,1H), 4.62 (dd, J = 9.6, 5.6 Hz, 1H), 4.53 (dd, J = 11.0, 8.7 Hz, 1H), 4.17 (dd, J =15.4, 1.1 Hz, 1H), 3.06 – 3.01 (m, 1H), 2.44 (s, 3H); 13 C NMR (126 MHz, CDCl3)δ159.50 (d, J = 247.3 Hz), 143.53, 142.05, 135.03, 129.82, 129.75, 129.71,129.37, 129.15, 128.31, 128.15, 126.80, 125.32, 124.37 (d, J = 3.5 Hz), 122.49,122.14, 121.16, 115.72 (d, J = 22.2 Hz), 80.33, 71.99 (d, J = 4.9 Hz), 45.26,21.63; the molecular formula is as follows: Example 5 To a 1 mL toluene solution of N-sulfonylazafulvene 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and alkenyl ethylene carbonate 2e (28.8 mg, 0.12 mmol, 1.2 equiv.) were added tris(dibenzylideneacetone)dipalladium-chloroform complex (10.2 mg, 0.01 mmol, 0.1 equiv.) and tri(p-tolyl)phosphine (3.6 mg, 0.012 mmol, 0.12 equiv.). Under nitrogen, the mixture was stirred at 60°C for 12 h. TLC confirmed the complete reaction and the reaction was terminated. The mixture was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford cycloheptatriene oxazocine derivative 3ae as a white solid in an isolated yield of 31.9 mg (70%). 1 HNMR spectra and 13 CNMR spectra are as follows Figure 10 and Figure 11 As shown; the characterization data are: 1H NMR (500 MHz, CDCl3) δ 7.80 – 7.75 (m, 3H), 7.67 (d, J = 1.8 Hz, 1H), 7.54 – 7.49(m, 2H), 7.48 – 7.43 (m, 2H), 7.38 (dd, J = 8.6, 1.9 Hz, 1H), 7.27 (d, J = 8.0Hz, 2H), 6.64 (dd, J = 10.9, 5.9 Hz, 1H), 6.58 (dd, J = 11.0, 6.7 Hz, 1H), 6.42(d, J = 6.7 Hz, 1H), 6.35 (td, J = 9.0, 1.8 Hz, 1H), 6.19 (dd, J = 9.8, 5.9 Hz,1H), 4.88 – 4.78 (m, 3H), 4.57 (dd, J = 11.5, 8.9 Hz, 1H), 4.44 (d, J = 14.9 Hz,1H), 3.31 (d, J = 6.1 Hz, 1H), 2.44 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 144.71,143.55, 137.38, 135.36, 133.16, 132.88, 129.64, 129.25, 128.22, 128.21,128.15, 128.06, 127.59, 126.47, 126.32, 125.00, 124.41, 124.21, 123.95,123.15, 122.14, 79.33, 70.86, 45.59, 21.65; the molecular formula is as follows: .

[0025] Example 6 To a solution of N-sulfonylazafulvene 1b (30.0 mg, 0.1 mmol, 1.0 equiv.) and alkenyl ethylene carbonate 2a (22.8 mg, 0.12 mmol, 1.2 equiv.) in toluene (1 mL) were added tris(dibenzylideneacetone)dipalladium-chloroform complex (10.2 mg, 0.01 mmol, 0.1 equiv.) and tri(p-tolyl)phosphine (3.6 mg, 0.012 mmol, 0.12 equiv.). Under nitrogen, the mixture was stirred at 60°C for 12 h. TLC confirmed the complete reaction and the reaction was terminated. The mixture was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford cycloheptatriene oxazocine 3ba as a white solid in an isolated yield of 38.4 mg (86%). 1 HNMR spectra and 13 CNMR spectra are as follows Figure 12 and Figure 13 As shown; 1 H NMR (500 MHz, CDCl3) δ 7.55 – 7.51 (m, 2H), 7.48 – 7.44 (m, 2H), 7.30 – 7.25 (m, 3H), 7.23(dd, J = 7.8, 1.9 Hz, 2H), 6.62 – 6.55 (m, 2H), 6.42 – 6.38 (m, 1H), 6.20 (td, J = 9.0, 1.9 Hz, 1H), 6.09 – 6.04 (m, 1H), 4.84 (dd, J = 11.5, 9.1 Hz, 1H), 4.77(dd, J = 15.1, 2.1 Hz, 1H), 4.64 (dd, J = 9.8, 6.0 Hz, 1H), 4.55 (dd, J = 11.5, 8.9Hz, 1H), 4.31 (d, J = 15.1 Hz, 1H), 3.18 (d, J = 6.0 Hz, 1H), 1.35 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 156.57, 145.00, 140.20, 135.39, 129.35, 128.52, 128.22,128.04, 127.91, 126.17, 125.53, 123.97, 123.46, 122.16, 121.80, 79.72, 71.25,45.48, 35.18, 31.15; the molecular formula is as follows: .

[0026] Example 7 To a solution of N-sulfonylazafulvene 1c (32.2 mg, 0.1 mmol, 1.0 equiv.) and alkenyl ethylene carbonate 2a (22.8 mg, 0.12 mmol, 1.2 equiv.) in toluene (1 mL) were added tris(dibenzylideneacetone)dipalladium-chloroform complex (10.2 mg, 0.01 mmol, 0.1 equiv.) and tri(p-tolyl)phosphine (3.6 mg, 0.012 mmol, 0.12 equiv.). Under nitrogen, the mixture was stirred at 60°C for 12 h. The reaction was complete after TLC analysis. The reaction was then concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 3ca as a white solid in a yield of 34.2 mg (73%). 1 HNMR spectra and 13 CNMR spectra are as follows Figure 14 and Figure 15 As shown; 1 H NMR (500 MHz, CDCl3) δ7.63 (ddd, J =8.1, 2.0, 1.0 Hz, 1H), 7.58 – 7.49 (m, 2H), 7.30 (t, J = 7.9 Hz, 1H), 7.26 –7.18 (m, 3H), 7.17 – 7.11 (m, 2H), 6.58 (dd, J = 10.9, 5.7 Hz, 1H), 6.52 (dd, J =10.9, 6.5 Hz, 1H), 6.32 (d, J = 6.5 Hz, 1H), 6.16 – 6.07 (m, 2H), 4.76 – 4.68(m, 2H), 4.66 (dd, J = 9.7, 5.7 Hz, 1H), 4.46 (dd, J= 11.2, 8.8 Hz, 1H), 4.24(d, J = 15.4 Hz, 1H), 3.02 (d, J = 5.7 Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ 145.56,139.90, 139.53, 135.71, 131.26, 130.20, 129.82, 128.58, 128.36, 128.18,126.22, 126.19, 125.19, 123.31, 123.10, 122.54, 122.47, 122.11, 79.98, 71.73,45.66; the molecular formula is as follows: .

[0027] Application examples: Antitumor activity test Human breast cancer cell line (MCF-7) and human cervical cancer cell line (HeLa) were selected as research subjects (Table 1) to evaluate the in vitro antitumor activity of cycloheptatriene oxazocine compounds.

[0028] The counted MCF-7 or HeLa cell suspension was added dropwise to a 96-well plate, and 3000-5000 cells were seeded per well. The liquid in each well was added to 100 μL, and the plate was placed in a cell culture incubator for culture. Different compounds were added to the wells at a final concentration of 100 μM and incubated in the incubator for 24 hours. After incubation, 10 μL of MTT solution (5 mg / mL, i.e., 0.5% MTT) was added to each well and cultured for another 4 hours. The culture was terminated and the culture medium in the well was aspirated. 100 μL of dimethyl sulfoxide was added to each well, and the plate was shaken at low speed for 30 minutes to fully dissolve the crystals. The absorbance of each well was measured at OD 490 nm using an enzyme-linked immunosorbent assay (ELISA) and the inhibition rate was calculated. The results are shown in Table 2 below: Table 2 In vitro antitumor activity of cycloheptatriene oxazocine compounds (inhibition rate %) As shown in Table 1, cycloheptatriene oxazocine compounds showed good cytotoxicity against human breast cancer cell lines and human cervical cancer cell lines, with the highest inhibition rates being 96.58% and 97.34% (3ba), respectively.

[0029] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A cycloheptatriene oxazocine compound, characterized in that: The structural formula of the cycloheptatriene oxazocine compound is: R 1 is one of C1-C7 alkyl, C3-C7 cycloalkyl, substituted or unsubstituted phenyl, heteroaryl, and trifluoromethyl; R 2 It is one of 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 3-methoxyphenyl, 3-chlorophenyl, 2-methylphenyl, 2-bromophenyl, 2-naphthyl, 2-thienyl and cyclohexyl.

2. A method for preparing the cycloheptatriene oxazocine compound according to claim 1, characterized in that: Under the action of palladium catalyst, N-sulfonylazafulvene compound and alkenyl ethylene carbonate compound are reacted as raw materials to synthesize cycloheptatriene oxazocine compounds; the reaction formula is shown below: 。 3. The method for preparing the cycloheptatriene oxazocine compound according to claim 2, wherein: The N-sulfonylazafulvene compound and the alkenyl ethylene carbonate compound are dissolved, a palladium catalyst and a ligand are added, and the reaction is carried out under nitrogen protection to obtain a cycloheptatriene-oxazocine compound.

4. The method for preparing the cycloheptatriene oxazocine compound according to claim 3, wherein: The palladium catalyst is one or more of tris(dibenzylideneacetone)dipalladium chloroform complex, tris(dibenzylideneacetone)dipalladium, allylpalladium(II) chloride dimer, tetrakis(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, bis[tri(2-methylphenyl)phosphine]palladium, bistriphenylphosphinepalladium dichloride, (1,5-cyclooctadiene)palladium(II) dichloride, palladium chloride, palladium trifluoroacetate, and palladium acetate.

5. The method for preparing the cycloheptatriene oxazocine compound according to claim 4, wherein: The palladium catalyst is tris(dibenzylideneacetone)dipalladium-chloroform complex.

6. The method for preparing the cycloheptatriene oxazocine compound according to claim 3, wherein: The reaction conditions are 60-100° C. for 10-24 hours.

7. The method for preparing the cycloheptatriene oxazocine compound according to claim 3, wherein: The ligand is one of triphenylphosphine, tricyclohexylphosphine, tri(p-tolyl)phosphine, tri(4-trifluoromethylphenyl)phosphine, tri(2-furyl)phosphine, 2-(diphenylphosphino)-2,6-dimethoxybiphenyl, bis(2-diphenylphosphinophenyl) ether (DPEPhos), 1,5-bis(diphenylphosphino)propane (DPPP), 1,2-bis(diphenylphosphino)ethane (DPPE), bis(diphenylphosphino)methane (DPPM), 1,2-bis(diphenylphosphino)benzene, 1,8-(diphenylphosphino)naphthalene, 4,6-bis(diphenylphosphino)phenazine, and (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (BINAP).

8. The method for preparing the cycloheptatriene oxazocine compound according to claim 3, wherein: The solvent for dissolving N-sulfonylazafulvene and alkenyl ethylene carbonate is one of toluene, p-xylene, mesitylene, fluorobenzene, chlorobenzene, bromobenzene, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate and tert-butyl methyl ether.

9. The method for preparing the cycloheptatriene oxazocine compound according to claim 3, wherein: The molar ratio of the N-sulfonylazafulvene compound, the alkenyl ethylene carbonate compound, the palladium catalyst and the ligand is 1:1-1.5:0.05-0.1:0.06-0.

12.

10. Use of the cycloheptatriene oxazocine compound according to claim 1 or the cycloheptatriene oxazocine compound prepared by the preparation method according to any one of claims 2 to 9 in the preparation of antitumor drugs.

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