Azabicyclo [3. 1. 0] hexane-2-ketone compound as well as preparation method and application thereof

Abstract

The invention provides a method for preparing an azabicyclo [3.1. 0] hexane-2-ketone compound, and belongs to the technical field of organic synthesis. Specifically, under the mediation effect of alkali, beta-oxoacrylamide and vinyl sulfonium salt serve as raw materials, and the azabicyclo [3.1. 0] hexane-2-ketone compound is synthesized through a one-step method. The azabicyclo [3.1. 0] hexane-2-ketone compound is synthesized by taking simple and easily available beta-oxoacrylamide and vinyl sulfonium salt as starting raw materials and carrying out serial [3 + 2] / [2 + 1] cycloaddition reaction under mediation of an alkali reagent, the method is simple and convenient to operate and mild in reaction condition, a metal catalyst is not used, the used reagents and raw materials are economical and easily available, and the method is suitable for industrial production. The target product yield is high, and the substrate application range is wide; the compound is applied to preparation of anti-tumor drugs and has a good application prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to an azabicyclo[3.1.0]hexan-2-one compound, a preparation method thereof, and an application thereof. Background Art

[0002] Azabicyclo[3.1.0]hexan-2-one compounds are a class of fused bicyclic structures containing pyrrolidone and cyclopropane functional groups, which are widely present in natural products, agrochemicals, and bioactive pharmaceutical molecules, and have various pharmacological activities such as bactericidal, antibacterial, antitumor, and antiviral activities. For example, procymidone is a dicarboximide fungicide that can effectively control gray mold and sclerotinia rot on various crops; Duocarmycin A is an antitumor antibiotic that can effectively alkylate the N3 of adenine at the 3' end of AT-rich sequences in DNA, thereby exerting its antitumor effect; Amitifadine (DOV-21947) is an antidepressant candidate compound that can be used as a triple reuptake inhibitor; Nirmatrelvir is a small molecule novel coronavirus treatment drug, mainly used for the treatment of novel coronavirus infection. Therefore, the development of an efficient synthesis strategy for azabicyclo[3.1.0]hexan-2-one compounds will provide key technical support for drug discovery and development.

[0003] The Mandour research group reported the Ru(II)-catalyzed asymmetric intramolecular cyclopropanation of N-allyl diazo Weinreb amides, and a series of optically pure azabicyclo[3.1.0]hexane-2-ones were synthesized in excellent yields and enantioselectivities (Hamada S. A. Mandour, et al. Beilstein J. Org. Chem. 2019,15, 357). The Zhang research group reported the intramolecular amidation of vinylcyclopropanecarboxamides catalyzed by Pd(PPh3)2Cl2. The reaction requires the use of oxygen and an equivalent amount of base reagent, and a series of azabicyclo[3.1.0]hexane-2-ones can be prepared in moderate yields (Zhiguo Zhang, Guisheng Zhang, Jingya Li. CN 115536573 A). The Aïssa research group developed the chiral Ir(I)-catalyzed asymmetric intramolecular cyclopropanation of α-carbonyl sulfoxonium ylides, in which the in-situ generated iridocarbene is the key reaction intermediate, and chiral azabicyclo[3.1.0]hexane-2-one derivatives were obtained in good yields and excellent enantioselectivities (Christophe Aïssa, et al. Org. Lett. 2022, 24, 8503). Other methods include the atom transfer radical cyclization reaction of N-allyl iodoacetamide initiated by tetrahydroxy diboron, the C-H oxidation reaction of azabicyclo[3.1.0]hexane catalyzed by metal Ru or Co, and the tandem acetylation / [3+2] cyclization / pyrolysis reaction of N-allylbenzylamine and diazoacyl compounds, etc.

[0004] Although certain progress has been made in the synthesis research of azabicyclo[3.1.0]hexane-2-ones, the existing systems still have deficiencies such as the use of precious metal catalysts, the use of excessive oxidants, cumbersome steps, and narrow substrate expansion ranges. Therefore, developing new methods for the efficient and green synthesis of azabicyclo[3.1.0]hexane-2-ones has important application values. Summary of the Invention

[0005] Aiming at the problems existing in the prior art, the present invention provides an azabicyclo[3.1.0]hexane-2-one compound, its preparation method and application. This method uses easily available β-oxoacrylamide and vinyl sulfonium salt as starting materials, and undergoes a [3+2] / [2+1] cycloaddition reaction under the action of a base reagent to synthesize azabicyclo[3.1.0]hexane-2-one compounds.

[0006] The present invention is realized through the following technical solutions: The present invention provides a kind of azabicyclo[3.1.0]hexan-2-one compound, and the structural formula of the azabicyclo[3.1.0]hexan-2-one compound is as follows: ; wherein, R 1 is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-chlorophenyl, 2-methylphenyl, 2-fluorophenyl, 2-bromophenyl, 2-naphthyl, 2-thienyl, methyl, tert-butyl, benzyl; R 2 is one of C1-C5 alkyl, C3-C12 cycloalkyl, allyl, propargyl, benzyl, 4-methylbenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-trifluorobenzyl, 2-naphthylmethyl; Ar is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-chlorophenyl, 2-methylphenyl, 2-fluorophenyl, 2-naphthyl, 2-thienyl.

[0007] In the present invention, a preparation method of the azabicyclo[3.1.0]hexan-2-one compound is also provided. Under the action of a base, using β-oxoacrylamide and vinyl sulfonium salt as raw materials, the azabicyclo[3.1.0]hexan-2-one compound is synthesized by a one-step method.

[0008] Furthermore, the structural formula of the β-oxoacrylamide is as follows: ; The structural formula of the vinyl sulfonium salt is as follows: ; R 3 is one of C1-C6 alkyl, C3-C6 cycloalkyl; X is tetrafluoroborate, trisubstituted methanesulfonate or halogen.

[0009] Furthermore, the molar ratio of β-oxoacrylamide, vinyl sulfonium salt and base reagent is 1:1.0-1.5:1.2-2.

[0010] Furthermore, the molar ratio of β-oxoacrylamide, vinyl sulfonium salt and base reagent is 1:1.2:2.

[0011] Further, the base reagent is one or more of triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 4-dimethylaminopyridine, pyridine, cesium carbonate, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide; the solvent for the one-step synthesis of azabicyclo[3.1.0]hexan-2-one compounds is one of dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, acetone, toluene, p-xylene, tetrahydrofuran, and ethyl acetate; the reaction temperature for the one-step synthesis of azabicyclo[3.1.0]hexan-2-one compounds is 0~40 °C, and the reaction time is 6~12 h.

[0012] Further, the base reagent is 1,8-diazabicyclo[5.4.0]undec-7-ene; the solvent for the one-step synthesis of azabicyclo[3.1.0]hexan-2-one compounds is dichloromethane.

[0013] Further, after the reaction for the one-step synthesis of azabicyclo[3.1.0]hexan-2-one compounds is completed, the reaction solution is concentrated under vacuum, and the residue is passed through a silica gel column chromatography with 200 meshes to obtain azabicyclo[3.1.0]hexan-2-one compounds.

[0014] Further, the silica gel column chromatography uses a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1~3:1 as the eluent.

[0015] In the present invention, the application of the azabicyclo[3.1.0]hexan-2-one compounds in the preparation of anti-tumor drugs is also provided.

[0016] The beneficial effects achieved by the present invention are as follows: By using easily available β-oxoacrylamide and vinyl sulfonium salt as starting materials, the present invention synthesizes azabicyclo[3.1.0]hexan-2-one compounds through a tandem [3+2] / [2+1] cycloaddition reaction catalyzed by a base reagent. This method is simple to operate, has mild reaction conditions, does not use metal catalysts, the reagents and raw materials used are economically available, the target product has a high yield, and the substrate scope is relatively wide; when applied to the preparation of anti-tumor drugs, it has good application prospects. Description of the Drawings

[0017] Figure 1 For the HNMR spectrum of azabicyclo[3.1.0]hexan-2-one compound 3aa in Example 1 1 HNMR spectrum; Figure 2 For the azabicyclo[3.1.0]hexan-2-one compound 3aa in Example 113 CNMR spectrum; Figure 3 For the 1 HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ba in Example 2; Figure 4 For the 13 CNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ba in Example 2; Figure 5 For the 1 HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ca in Example 3; Figure 6 For the 13 CNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ca in Example 3; Figure 7 For the 1 HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3da in Example 4; Figure 8 For the 13 CNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3da in Example 4; Figure 9 For the 1 HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ea in Example 5; Figure 10 For the 13 CNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ea in Example 5; Figure 11 For the 1 HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3fa in Example 6; Figure 12 For the 13 CNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3fa in Example 6; Figure 13 For the 1 HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ga in Example 7; Figure 14 For the 13 CNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ga in Example 7; Figure 15For the HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ha in Example 8 1 HNMR spectrum; Figure 16 For the HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ha in Example 8 13 CNMR spectrum; Figure 17 For the HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ia in Example 9 1 HNMR spectrum; Figure 18 For the HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ia in Example 9 13 CNMR spectrum; Figure 19 For the HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ja in Example 10 1 HNMR spectrum; Figure 20 For the HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ja in Example 10 13 CNMR spectrum; Figure 21 For the HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ka in Example 11 1 HNMR spectrum; Figure 22 For the HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ka in Example 11 13 CNMR spectrum; Figure 23 For the HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3la in Example 12 1 HNMR spectrum; Figure 24 For the HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3la in Example 12 13 CNMR spectrum; Figure 25 For the HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ab in Example 13 1 HNMR spectrum; Figure 26 For the HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ab in Example 13 13 CNMR spectrum; Figure 27 For the HNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ac in Example 14 1 HNMR spectrum; Figure 28 For the 13 13 CNMR spectrum of the azabicyclo[3.1.0]hexan-2-one compound 3ac in Example 14. Detailed implementation mode

[0018] Next, in combination with the embodiments of the present invention, the technical solutions of the present invention will be described clearly and completely. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work shall fall within the protection scope of the present invention.

[0019] In order to enable those skilled in the art to more clearly understand the technical solutions of the present invention, the technical solutions of the present invention will be described in detail below in combination with specific embodiments.

[0020] The structural formula of α-phenyl-vinylsulfonium tetrafluoroborate 2a in the following examples is: ; The structural formula of α-(4-tert-butylphenyl)-vinylsulfonium tetrafluoroborate 2b is: ; The structural formula of α-(3-bromophenyl)-vinylsulfonium tetrafluoroborate 2c is: .

[0021] Example 1 Add β-(4-methylbenzoyl)-N-benzyloxyacrylamide 1a (29.5 mg, 0.1 mmol, 1.0 equiv.) and α-phenyl-vinylsulfonium tetrafluoroborate 2a (72.6 mg, 0.15 mmol, 1.5 equiv.) into a 10 mL reaction test tube, add 1 mL of dry dichloromethane (0.1 M), and stir at room temperature until the solid is completely dissolved; then add 1,8-diazabicyclo[5.4.0]undec-7-ene (30.4 mg, 0.2 mmol, 2.0 equiv.) to the reaction system, stir at room temperature for 8 hours, after the reaction is completed, remove dichloromethane under reduced pressure, and then perform column chromatography (200 mesh silica gel column chromatography) separation (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent) to obtain the product azabicyclo[3.1.0]hexan-2-one compound 3aa, white solid, the separation yield is 36.8 mg, and the yield is 92.7%. The 1 1 HNMR and 13 CNMR spectra are respectively as Figure 1 and Figure 2 shown; 11H NMR (500 MHz, CDCl3) δ 7.61 – 7.54 (m, 2H), 7.40 (dd, J J = 6.7, 3.0 Hz, 2H), 7.38 – 7.33 (m, 3H), 7.16 (s, 2H), 7.12 – 7.06 (m, 3H), 6.98 – 6.91 (m, 2H), 5.00 (d, J J = 11.1 Hz, 1H), 4.91 (d, J J = 11.2 Hz, 1H), 3.58 (dd, J J = 10.2, 1.6 Hz, 1H), 3.52 (d, J J = 10.1 Hz, 1H), 3.09 (dd, J J = 3.3, 1.6 Hz, 1H), 2.82 (d, J J = 3.3 Hz, 1H), 2.33 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 190.81, 167.97, 143.25, 134.15, 133.85, 132.87, 128.88, 128.32, 128.16, 127.69, 127.59, 127.52, 127.12, 127.01, 75.98, 54.98, 36.53, 35.88, 27.99, 20.66;HRMS(ESI) m / z [M+Na] + calcd for C 26 21 23 H NO3Na: 420.1576, Found: 420.1578;The structural formula is as follows:

[0022] Example 2 β-(4-Methoxybenzoyl)-N-benzyloxyacrylamide 1b (31.1 mg, 0.1 mmol, 1.0 equiv.) and α-phenylvinylsulfonium tetrafluoroborate 2a (72.6 mg, 0.15 mmol, 1.5 equiv.) were added into a 10 mL reaction tube, and 1 mL of dry dichloromethane (0.1 M) was added. The mixture was stirred at room temperature until the solids were completely dissolved. Subsequently, 1,8-diazabicyclo[5.4.0]undec-7-ene (30.4 mg, 0.2 mmol, 2.0 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 11 h. After the reaction was completed, dichloromethane was removed under reduced pressure, and then column chromatography (200-mesh silica gel column chromatography) was performed for separation (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent) to obtain the product azabicyclo[3.1.0]hexan-2-one compound 3ba, a white solid. The isolated yield was 36.3 mg, and the yield was 88%. The 1 1H NMR and 13 13C NMR spectra are shown in Figure 3 and Figure 4 respectively; 1 1H NMR (500 MHz, CDCl3) δ 7.70 – 7.62 (m, 2H), 7.43 – 7.38 (m,2H), 7.36 (dt, J J = 5.0, 1.7 Hz, 3H), 7.13 – 7.06 (m, 3H), 6.98 – 6.91 (m, 2H),6.87 – 6.79 (m, 2H), 5.01 (d, J J = 11.1 Hz, 1H), 4.92 (d, J J = 11.1 Hz, 1H), 3.79(s, 3H), 3.59 (dd, J J = 10.1, 1.7 Hz, 1H), 3.52 (d, J J = 10.2 Hz, 1H), 3.09 (dd, J J =3.3, 1.6 Hz, 1H), 2.80 (d, J J = 3.3 Hz, 1H). 1313C NMR (126 MHz, CDCl3) δ 189.57, 168.08, 162.71, 134.19, 132.99, 129.45, 129.32, 128.87, 128.14, 127.69, 127.58, 127.52, 126.99, 112.82, 76.00, 55.01, 54.51, 36.36, 35.62, 27.89; HRMS(ESI) m / z [M+Na] + calcd for C 26 H 23 NO4Na: 436.1525, Found: 436.1526; The structural formula of 3ba is as follows: 。

[0023] Example 3 Add β-(4-fluorobenzoyl)-N-benzyloxyacrylamide 1c (30 mg, 0.1 mmol, 1.0 equiv.) and α-phenyl-vinylsulfonium tetrafluoroborate 2a (72.6 mg, 0.15 mmol, 1.5 equiv.) into a 10 mL reaction tube, add 1 mL of dry dichloromethane (0.1 M), and stir at room temperature until the solid is completely dissolved; then add 1,8-diazabicyclo[5.4.0]undec-7-ene (30.4 mg, 0.2 mmol, 2.0 equiv.) into the reaction system, and stir at room temperature for 9 hours; after the reaction is completed, remove dichloromethane under reduced pressure, and then perform column chromatography (200-mesh silica gel column chromatography) separation (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent) to obtain the product azabicyclo[3.1.0]hexan-2-one compound 3ca, a white solid, with a separation yield of 36.1 mg and a yield of 90%. The 1 1H NMR and 13 13C NMR spectra are respectively as Figure 5 and Figure 6 shown; 1 1H NMR (500 MHz, CDCl3) δ 7.81 – 7.73 (m, 2H), 7.51 – 7.45 (m, 2H), 7.45 – 7.39 (m, 3H), 7.22 – 7.15 (m, 3H), 7.14 – 7.07 (m, 2H), 7.05 – 6.98 (m, 2H), 5.09 (d, J = 11.0 Hz, 1H), 4.99 (d, J= 11.2 Hz, 1H), 3.70 (dd, J =10.3, 1.8 Hz, 1H), 3.62 (d, J = 10.2 Hz, 1H), 3.19 (dd, J = 3.3, 1.6 Hz, 1H),2.87 (d, J = 3.3 Hz, 1H). 13 C NMR (126 MHz, CDCl3) δ 190.79, 168.72, 165.87 (d, J =255.9 Hz), 135.18, 133.75 (d, J = 3.0 Hz), 133.66, 130.68 (d, J = 9.4 Hz),129.91, 129.20, 128.73, 128.63, 128.56, 128.19, 115.85 (d, J = 21.8 Hz), 77.03,55.92, 37.54, 37.10, 29.16;HRMS (ESI) m / z [M+Na] + calcd for C 25 H 20 FNO3Na:424.1325, Found: 424.1327;3ca structural formula is as follows: 。

[0024] Example 4 Add β-(4-chlorobenzoyl)-N-benzyloxyacrylamide 1d (31.6 mg, 0.1 mmol, 1.0 equiv.) and α-phenyl-vinylsulfonium tetrafluoroborate 2a (72.6 mg, 0.15 mmol, 1.5 equiv.) into a 10 mL reaction test tube, add 1 mL of dry dichloromethane (0.1 M), and stir at room temperature until the solid is completely dissolved; then add 1,8-diazabicyclo[5.4.0]undec-7-ene (30.4 mg, 0.2 mmol, 2.0 equiv.) into the reaction system, and stir at room temperature for 10 hours; after the reaction is completed, remove dichloromethane under reduced pressure, and then carry out column chromatography (200-mesh silica gel column chromatography) separation (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent) to obtain the product azabicyclo[3.1.0]hexan-2-one compound 3da, white solid, the separated yield is 37.0 mg, and the yield is 89%. The 1 1H NMR and13 The CNMR spectra are shown respectively as Figure 7 and Figure 8 shown; 1 H NMR (500 MHz, CDCl3) δ 7.63 – 7.57 (m, 2H), 7.44 – 7.32 (m,7H), 7.15 – 7.09 (m, 3H), 6.97 – 6.90 (m, 2H), 5.02 (d, J = 11.2 Hz, 1H), 4.92(d, J = 11.2 Hz, 1H), 3.60 (dd, J = 10.3, 1.6 Hz, 1H), 3.54 (d, J = 10.3 Hz, 1H),3.11 (dd, J = 3.3, 1.5 Hz, 1H), 2.77 (d, J = 3.2 Hz, 1H). 13 C NMR (126 MHz, CDCl3)δ 190.12, 167.61, 138.90, 134.53, 134.13, 132.50, 128.90, 128.37, 128.20,127.99, 127.70, 127.62, 127.52, 127.20, 76.00, 54.90, 36.51, 36.24, 28.18;HRMS (ESI) m / z [M+Na] + calcd for C 25 H 20 ClNO3Na: 440.1029, Found: 440.1030;The 3D structural formula is shown as follows: .

[0025] Example 5 β-(4-Bromobenzoyl)-N-benzyloxyacrylamide 1e (35.9 mg, 0.1 mmol, 1.0 equiv.) and α-phenylvinylsulfonium tetrafluoroborate 2a (72.6 mg, 0.15 mmol, 1.5 equiv.) were added into a 10 mL reaction tube, and 1 mL of dry dichloromethane (0.1 M) was added. The mixture was stirred at room temperature until the solids were completely dissolved. Subsequently, 1,8-diazabicyclo[5.4.0]undec-7-ene (30.4 mg, 0.2 mmol, 2.0 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, dichloromethane was removed under reduced pressure, and then column chromatography (200-mesh silica gel column chromatography) was performed for separation (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent) to obtain the product azabicyclo[3.1.0]hexan-2-one compound 3ea, a white solid. The isolated yield was 39.2 mg, and the yield was 85%. The 1 1H NMR and 13 13C NMR spectra are shown in Figure 9 and Figure 10 respectively; 1 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J J = 1.2 Hz, 4H), 7.40 (dd, J J = 6.8, 3.1 Hz, 2H), 7.36 (dt, J J = 4.2, 2.3 Hz, 3H), 7.14 – 7.07 (m, 3H), 6.93 (dt, J J = 6.2, 3.4 Hz, 2H), 5.02 (d, J J = 11.1 Hz, 1H), 4.92 (d, J J = 11.2 Hz, 1H), 3.60 (dd, J J = 10.4, 1.6 Hz, 1H), 3.54 (d, J J = 10.3 Hz, 1H), 3.11 (dd, J J = 3.4, 1.5 Hz, 1H), 2.76 (d, J J = 3.3 Hz, 1H). 1313C NMR (126 MHz, CDCl3) δ 190.32, 167.58, 134.91, 134.11, 132.48, 130.98, 128.90, 128.46, 128.20, 127.70, 127.64, 127.61, 127.51, 127.20, 75.99, 54.87, 36.47, 36.26, 28.17; HRMS (ESI) m / z [M+Na] + calcd for C 25 H 20 NNaO3Br: 484.0524, Found: 484.0525; The structural formula of 3ea is as follows: 。

[0026] Example 6 Add β-(4-phenylbenzoyl)-N-benzyloxyacrylamide 1f (35.8 mg, 0.1 mmol, 1.0 equiv.) and α-phenyl-vinylsulfonium tetrafluoroborate 2a (72.6 mg, 0.15 mmol, 1.5 equiv.) into a 10 mL reaction test tube, add 1 mL of dry dichloromethane (0.1 M), and stir at room temperature until the solid is completely dissolved; then add 1,8-diazabicyclo[5.4.0]undec-7-ene (30.4 mg, 0.2 mmol, 2.0 equiv.) into the reaction system, and stir at room temperature for 9 hours; after the reaction is completed, remove dichloromethane under reduced pressure, and then perform column chromatography (200-mesh silica gel column chromatography) separation (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent) to obtain the product azabicyclo[3.1.0]hexan-2-one compound 3fa, white solid, the separated yield is 39.6 mg, and the yield is 86%. The 1 1H NMR and 13 13C NMR spectra are respectively as Figure 11 and Figure 12 shown; 1 1H NMR (500 MHz, CDCl3) δ 7.74 (dd, J J = 8.3, 1.5 Hz, 2H), 7.59 –7.51 (m, 4H), 7.44 – 7.30 (m, 8H), 7.10 (dd, J J = 5.3, 1.9 Hz, 3H), 6.97 (dt, J J =6.6, 1.5 Hz, 2H), 5.02 (d, J= 11.1 Hz, 1H), 4.92 (d, J = 11.1 Hz, 1H), 3.63(ddd, J = 10.2, 3.8, 1.7 Hz, 1H), 3.54 (d, J = 10.2 Hz, 1H), 3.13 (dt, J = 3.3, 1.8Hz, 1H), 2.88 (t, J = 2.9 Hz, 1H). 13 C NMR (126 MHz, CDCl3) δ 191.91, 168.93,146.10, 139.65, 136.02, 135.22, 133.86, 129.96, 129.26, 129.06, 128.78,128.69, 128.68, 128.64, 128.46, 128.16, 127.32, 127.31, 77.07, 56.04, 37.71,37.18, 29.23; HRMS (ESI) m / z [M+Na] + calcd for C 31 H 25 NO3Na: 482.1732, Found:482.1735; 3fa structure is as follows: .

[0027] Example 7 β-(3-methoxybenzoyl)-N-benzyloxyacrylamide 1g (31.1 mg, 0.1 mmol, 1.0 equiv.) and α-phenyl-vinyl tetrafluoroborate sulfonium salt 2a (72.6 mg, 0.15 mmol, 1.5 equiv.) were added to a 10 mL reaction tube, and 1 mL of dry dichloromethane (0.1 M) was added and stirred at room temperature until the solid was completely dissolved. Subsequently, 1,8-diazabicyclo[5.4.0]undec-7-ene (30.4 mg, 0.2 mmol, 2.0 equiv.) was added to the reaction system and stirred at room temperature for 10 hours. After the reaction was completed, dichloromethane was removed under reduced pressure, and the product was separated by column chromatography (200 mesh silica gel column chromatography) using a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 as the eluent to obtain the product azabicyclo[3.1. 0] Hexane-2-one compound 3ga, white solid, isolated yield 35.1 mg, yield 85%, 3ga 1 HNMR and 13 CNMR spectra are as followsFigure 13 and Figure 14 as shown; 1 H NMR (500 MHz, CDCl3) δ 7.42 – 7.33 (m, 5H), 7.31 – 7.25 (m,2H), 7.17 (dd, J J = 3.5, 2.0 Hz, 1H), 7.10 (dd, J J = 4.9, 1.9 Hz, 3H), 7.02 (dt, J J =7.0, 2.5 Hz, 1H), 6.99 – 6.92 (m, 2H), 5.00 (d, J J = 11.1 Hz, 1H), 4.91 (d, J J =11.1 Hz, 1H), 3.75 – 3.68 (m, 3H), 3.59 (dd, J J = 10.3, 1.6 Hz, 1H), 3.52 (d, J J =10.2 Hz, 1H), 3.10 (dd, J J = 3.3, 1.6 Hz, 1H), 2.83 (d, J J = 3.3 Hz, 1H). 13 C NMR(126 MHz, CDCl3) δ 191.16, 167.82, 158.83, 137.62, 134.08, 132.76, 128.86,128.60, 128.25, 127.�2, 127.61, 127.56, 127.08, 119.57, 118.56, 111.55,76.01, 54.94, 54.42, 36.71, 36.17, 28.19;HRMS (ESI) m / z [M+Na] + calcd forC 26 H 23 NO4Na: 436.1525, Found: 436.1526;The structural formula of 3ga is as shown below: .

[0028] Example 8 β-(3-chlorobenzoyl)-N-benzyloxyacrylamide 1h (31.6 mg, 0.1 mmol, 1.0 equiv.) and α-phenylvinylsulfonium tetrafluoroborate 2a (72.6 mg, 0.15 mmol, 1.5 equiv.) were added into a 10 mL reaction tube, and 1 mL of dry dichloromethane (0.1 M) was added. The mixture was stirred at room temperature until the solids were completely dissolved. Subsequently, 1,8-diazabicyclo[5.4.0]undec-7-ene (30.4 mg, 0.2 mmol, 2.0 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 10 hours. After the reaction was completed, dichloromethane was removed under reduced pressure, and then column chromatography (200-mesh silica gel column chromatography) was carried out (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent) to obtain the product azabicyclo[3.1.0]hexan-2-one compound 3ha, a white solid. The isolated yield was 34.6 mg, and the yield was 83%. The 1 1H NMR and 13 13C NMR spectra are shown in Figure 15 and Figure 16 respectively; 1 1H NMR (500 MHz, CDCl3) δ 7.60 (t, J J = 1.9 Hz, 1H), 7.53 (dt, J J = 7.8, 1.4 Hz, 1H), 7.46 (ddd, J J = 8.0, 2.2, 1.1 Hz, 1H), 7.40 (q, J J = 5.4, 4.9 Hz, 5H), 7.30 (t, J J = 7.8 Hz, 1H), 7.15 – 7.07 (m, 3H), 6.97 – 6.90 (m, 2H), 5.03 (d, J J = 11.1 Hz, 1H), 4.91 (d, J J = 11.1 Hz, 1H), 3.59 – 3.50 (m, 2H), 3.10 (dd, J J = 3.3, 1.2 Hz, 1H), 2.71 (d, J J = 3.3 Hz, 1H). 1313C NMR (126 MHz, CDCl3) δ 191.20, 168.46, 138.74, 135.10, 134.99, 133.46, 133.34, 130.09, 130.03, 129.47, 128.79, 128.66, 128.60, 128.26, 128.07, 126.12, 77.00, 55.93, 37.59, 37.57, 29.39; HRMS (ESI) m / z [M+Na] + calcd for C 25 H 20 ClNO3Na: 440.1029, Found: 440.1030; The structural formula of 3ha is as follows: 。

[0029] Example 9 β-Naphthoyl-N-benzyloxyacrylamide 1i (33.1 mg, 0.1 mmol, 1.0 equiv.) and α-phenyl-vinylsulfonium tetrafluoroborate 2a (72.6 mg, 0.15 mmol, 1.5 equiv.) were added into a 10 mL reaction tube, and then 1 mL of dry dichloromethane (0.1 M) was added. The mixture was stirred at room temperature until the solid was completely dissolved. Subsequently, 1,8-diazabicyclo[5.4.0]undec-7-ene (30.4 mg, 0.2 mmol, 2.0 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 11 h. After the reaction was completed, dichloromethane was removed under reduced pressure, and then column chromatography (silica gel column chromatography with 200 mesh) was carried out for separation (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent) to obtain the product azabicyclo[3.1.0]hexan-2-one compound 3ia, a white solid. The isolated yield was 37.2 mg and the yield was 86%. The 1 1H NMR and 13 13C NMR spectra are shown as Figure 17 and Figure 18 shown below; 1 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J J = 1.7 Hz, 1H), 7.92 – 7.86 (m, 1H), 7.83 – 7.74 (m, 2H), 7.70 (dd, J= 8.6, 1.8 Hz, 1H), 7.57 – 7.48 (m, 2H), 7.47– 7.33 (m, 5H), 7.13 – 7.03 (m, 3H), 7.01 – 6.93 (m, 2H), 5.05 (d, J = 11.1 Hz,1H), 4.94 (d, J = 11.2 Hz, 1H), 3.65 (dd, J = 10.3, 1.6 Hz, 1H), 3.56 (d, J = 10.2Hz, 1H), 3.17 (dd, J = 3.3, 1.6 Hz, 1H), 2.98 (d, J = 3.3 Hz, 1H). 13 C NMR (126MHz, CDCl3) δ 191.12, 167.87, 134.62, 134.19, 133.67, 132.79, 131.37, 128.98,128.63, 128.45, 128.26, 127.73, 127.63, 127.60, 127.56, 127.08, 126.86,126.01, 122.67, 75.99, 55.07, 36.68, 36.16, 28.20;HRMS (ESI) m / z [M+Na] + calcdfor C 29 H 23 NO3Na: 456.1576, Found: 456.1578;3ia structural formula is as follows: 。

[0030] Example 10 β-(4-Methylbenzoyl)-N-ethoxyacrylamide 1j (23.3 mg, 0.1 mmol, 1.0 equiv.) and α-phenylvinylsulfonium tetrafluoroborate 2a (72.6 mg, 0.15 mmol, 1.5 equiv.) were added into a 10 mL reaction tube, and 1 mL of dry dichloromethane (0.1 M) was added. The mixture was stirred at room temperature until the solids were completely dissolved. Subsequently, 1,8-diazabicyclo[5.4.0]undec-7-ene (30.4 mg, 0.2 mmol, 2.0 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 10 hours. After the reaction was completed, dichloromethane was removed under reduced pressure, and then column chromatography (silica gel column chromatography with 200 mesh) was carried out (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent) to obtain the product azabicyclo[3.1.0]hexan-2-one compound 3ja, a white solid. The isolated yield was 29.5 mg, and the yield was 88%. The 1 1H NMR and 13 13C NMR spectra are shown in Figure 19 and Figure 20 respectively; 1 1H NMR (500 MHz, CDCl3) δ 7.74 – 7.65 (m, 2H), 7.19 – 7.11 (m,5H), 7.10 – 7.03 (m, 2H), 4.07 (dt, J J = 10.2, 1.7 Hz, 1H), 3.98 (qd, J J = 7.1, 2.6Hz, 2H), 3.83 (d, J J = 10.1 Hz, 1H), 3.17 (dd, J J = 3.3, 1.7 Hz, 1H), 3.13 (d, J J =3.3 Hz, 1H), 2.32 (s, 3H), 1.23 (t, J J = 7.1 Hz, 3H). 13 13C NMR (126 MHz, CDCl3) δ190.83, 168.22, 143.25, 133.97, 133.04, 128.40, 127.65, 127.62, 127.13,127.08, 69.76, 54.29, 36.59, 35.72, 28.18, 20.65, 12.70; HRMS (ESI) m / z [M+Na] + calcd for C 21 H 21NO3Na: 358.1419, Found: 358.1420; The structural formula of 3ja is as follows: 。

[0031] Example 11 Add β-(4-methylbenzoyl)-N-dodecyloxyacrylamide 1k (35.9 mg, 0.1 mmol, 1.0 equiv.) and α-phenyl-vinylsulfonium tetrafluoroborate 2a (72.6 mg, 0.15 mmol, 1.5 equiv.) into a 10 mL reaction tube, add 1 mL of dry dichloromethane (0.1 M), and stir at room temperature until the solid completely dissolves; then add 1,8-diazabicyclo[5.4.0]undec-7-ene (30.4 mg, 0.2 mmol, 2.0 equiv.) into the reaction system, and stir at room temperature for 10 hours; after the reaction is completed, remove dichloromethane under reduced pressure, and then perform column chromatography (200-mesh silica gel column chromatography) separation (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent) to obtain the product azabicyclo[3.1.0]hexan-2-one compound 3ka, white solid, the separation yield is 37.8 mg, and the yield is 80%. The 1 1H NMR and 13 13C NMR spectra are respectively as Figure 21 and Figure 22 shown; 1 1H NMR (500 MHz, CDCl3) δ 7.69 (d, J J = 8.1 Hz, 2H), 7.15 (q, J J = 7.5 Hz, 5H), 7.08 (dd, J J = 7.7, 1.9 Hz, 2H), 4.07 (ddd, J J = 22.3, 8.6, 2.2 Hz, 2H), 3.83 (d, J J = 10.2 Hz, 1H), 3.17 (dd, J J = 3.3, 1.6 Hz, 1H), 3.12 (d, J J = 3.3 Hz, 1H), 2.32 (s, 3H), 1.71 – 1.62 (m, 2H), 1.53 (dddd, J J = 28.9, 14.1, 6.8, 4.7 Hz, 2H), 1.42 (dq, J J = 11.5, 6.1, �.0 Hz, 2H), 1.36 – 1.22 (m, 16H).13 13C NMR (126 MHz, CDCl3) δ 190.90, 169.02, 143.21, 134.04, 133.17, 128.40, 127.72, 127.61, 127.11, 127.05, 82.21, 55.76, 36.42, 35.88, 28.59, 27.48, 27.37, 23.46, 23.43, 22.83, 22.42, 22.32, 22.29, 22.20, 20.64, 20.00, 19.99; HRMS (ESI) m / z [M+Na] + calcd for C 31 H 39 NO3Na: 496.2828, Found: 496.2830; The structural formula of 3ka is as follows: 。

[0032] Example 12 Add β-(4-methylbenzoyl)-N-allyloxyacrylamide 1l (35.9 mg, 0.1 mmol, 1.0 equiv.) and α-phenyl-vinylsulfonium tetrafluoroborate 2a (72.6 mg, 0.15 mmol, 1.5 equiv.) into a 10 mL reaction test tube, add 1 mL of dry dichloromethane (0.1 M), and stir at room temperature until the solid is completely dissolved; then add 1,8-diazabicyclo[5.4.0]undec-7-ene (30.4 mg, 0.2 mmol, 2.0 equiv.) into the reaction system, and stir at room temperature for 13 hours; after the reaction is completed, remove dichloromethane under reduced pressure, and then perform column chromatography (silica gel column chromatography with 200 mesh) separation (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent) to obtain the product azabicyclo[3.1.0]hexan-2-one compound 3la, white solid, the separated yield is 26.0 mg, and the yield is 75%. The 1 1H NMR and 13 13C NMR spectra are respectively as Figure 23 and Figure 24 shown; 1 1H NMR (500 MHz, CDCl3) δ 7.73 – 7.65 (m, 2H), 7.20 – 7.12 (m, 5H), 7.09 – 7.03 (m, 2H), 5.97 (ddt, J= 16.9, 10.2, 6.5 Hz, 1H), 5.37 – 5.27(m, 2H), 4.48 – 4.38 (m, 2H), 4.07 (dt, J = 10.2, 1.2 Hz, 1H), 3.81 (d, J = 10.1Hz, 1H), 3.16 (dd, J = 3.3, 1.6 Hz, 1H), 3.13 (d, J = 3.3 Hz, 1H), 2.33 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 191.88, 169.21, 144.30, 135.00, 134.04, 132.45, 129.45, 128.69, 128.66, 128.13, 121.23, 76.30, 55.74, 37.54, 36.91, 29.20, 21.68;HRMS (ESI) m / z [M+Na] + calcd for C 22 H 21 NO3Na: 370.1419, Found: 370.1420;The structural formula of 3la is as follows: 。

[0033] Example 13 Add β-(4-methylbenzoyl)-N-benzyloxyacrylamide 1a (29.5 mg, 0.1 mmol, 1.0 equiv.) and α-(4-tert-butylphenyl)-vinylsulfonium tetrafluoroborate 2b (81 mg, 0.15 mmol, 1.5 equiv.) into a 10 mL reaction tube, add 1 mL of dry dichloromethane (0.1 M), and stir at room temperature until the solid is completely dissolved; then add 1,8-diazabicyclo[5.4.0]undec-7-ene (30.4 mg, 0.2 mmol, 2.0 equiv.) into the reaction system, and stir at room temperature for 12 hours; after the reaction is completed, remove dichloromethane under reduced pressure, and then perform column chromatography (200-mesh silica gel column chromatography) separation (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent) to obtain the product azabicyclo[3.1.0]hexan-2-one compound 3ab, white solid, the isolated yield is 36.2 mg, and the yield is 80%. The 1 HNMR and 13 CNMR spectra are shown in Figure 25 and Figure 26as shown; 1 H NMR (500 MHz, CDCl3) δ 7.61 – 7.56 (m, 2H), 7.39 (dd, J J = 6.7, 3.1 Hz, 2H), 7.37 – 7.33 (m, 3H), 7.16 (d, J J = 8.0 Hz, 2H), 7.12 – 7.07(m, 2H), 6.89 – 6.84 (m, 2H), 4.99 (d, J J = 11.1 Hz, 1H), 4.90 (d, J J = 11.2 Hz,1H), 3.58 (dd, J J = 10.2, 1.6 Hz, 1H), 3.53 (d, J J = 10.2 Hz, 1H), 3.07 (dd, J J = 3.3,1.5 Hz, 1H), 2.80 (d, J J = 3.4 Hz, 1H), 2.33 (s, 3H), 1.12 (s, 9H). 13 C NMR (126MHz, CDCl3) δ 192.01, 169.17, 150.85, 144.19, 135.24, 135.07, 130.86, 129.87,129.35, 129.16, 128.71, 128.31, 128.19, 125.50, 77.01, 56.26, 37.72, 36.74,34.48, 31.19, 29.18, 26.93, 21.69; HRMS (ESI) m / z [M+Na] + calcd for C 30 H 31 NO3Na:476.2202, Found: 476.2205; The structural formula of 3ab is as follows: .

[0034] Example 14 β-(4-Methylbenzoyl)-N-benzyloxyacrylamide 1a (29.5 mg, 0.1 mmol, 1.0 equiv.) and α-(3-bromophenyl)-vinylsulfonium tetrafluoroborate 2c (84.5 mg, 0.15 mmol, 1.5 equiv.) were added into a 10 mL reaction tube. 1 mL of dry dichloromethane (0.1 M) was added, and the mixture was stirred at room temperature until the solids were completely dissolved. Subsequently, 1,8-diazabicyclo[5.4.0]undec-7-ene (30.4 mg, 0.2 mmol, 2.0 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 10 hours. After the reaction was completed, dichloromethane was removed under reduced pressure, and then column chromatography (silica gel column chromatography with 200 mesh) was carried out (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent) to obtain the product azabicyclo[3.1.0]hexan-2-one compound 3ac, a white solid. The isolated yield was 40.9 g, and the yield was 86%. The 1 1H NMR and 13 13C NMR spectra are shown in Figure 27 and Figure 28 respectively; 1 1H NMR (500 MHz, CDCl3) δ 7.59 – 7.53 (m, 2H), 7.43 –7.31 (m, 5H), 7.20 (ddd, J J = 8.0, 2.0, 1.0 Hz, 1H), 7.16 (d, J J = 8.0 Hz, 2H),7.10 (t, J J = 1.9 Hz, 1H), 6.94 (t, J J = 7.9 Hz, 1H), 6.85 (dt, J J = 7.7, 1.3 Hz, 1H),4.99 (d, J J = 11.1 Hz, 1H), 4.91 (d, J J = 11.1 Hz, 1H), 3.55 (dd, J J = 10.2, 1.7 Hz,1H), 3.46 (d, J J = 10.2 Hz, 1H), 3.04 (dd, J J = 3.3, 1.6 Hz, 1H), 2.82 (d, J J = 3.3Hz, 1H), 2.32 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 191.71, 168.49, 144.55, 136.28, 135.11, 134.78, 131.79, 131.28, 130.06, 129.94, 129.46, 129.28, 128.77, 128.17, 127.38, 122.52, 77.04, 55.73, 37.29, 36.20, 29.27, 21.71; HRMS(ESI) m / z [M+Na] + calcd for C 26 H 22 BrNO3Na: 498.0681, Found: 498.0684; The structural formula of 3ac is as follows: 。

[0035] Examples 15 - 24 According to the corresponding relationship shown in Table 1, taking Example 1 as an example, 1,8 - diazabicyclo[5.4.0]undec - 7 - ene was replaced with other base reagents in the same molar amount, and other operations were the same. The yields of the obtained products are shown in Table 1.

[0036] Table 1 Yields of products with different base reagents As can be seen from Table 1, using different base reagents can all obtain the target product. Among them, cesium carbonate and potassium carbonate have better reaction effects, second only to the product yield of the optimal base reagent 1,8 - diazabicyclo[5.4.0]undec - 7 - ene.

[0037] Examples 25 - 33 According to the corresponding relationship shown in Table 2, taking Example 1 as an example, the solvent dichloromethane in Example 1 was replaced with other solvents in the same volume, and other operations were the same. The yields of the obtained products are shown in Table 2.

[0038] Table 2 Yields of products with different solvents As can be seen from Table 2, the solvent has a certain influence on the final result. Among them, acetonitrile, toluene or ethyl acetate show better effects, second only to the product yield of the optimal solvent dichloromethane, and the yields of other solvents all decrease to varying degrees.

[0039] Examples 34 - 36 According to the corresponding relationship shown in Table 3, taking Example 1 as an example, the reaction temperature in Example 1 was replaced with other reaction temperatures, and other operations were the same. The yields of the obtained products are shown in Table 3.

[0040] Table 3. Product yields at different reaction temperatures As can be seen from Table 3 in combination with Example 1, the reaction temperature has a certain influence on the product yield. Among them, room temperature is the optimal reaction temperature. Increasing or decreasing the temperature will both reduce the reaction yield.

[0041] In summary, it can be clearly seen from all the above examples that when the method of the present invention is adopted, the compounds of formula (I) and formula (II) can react smoothly, so as to obtain the target product of formula (III) with good to excellent yields and simple post-treatment. The achievement of these results depends on the combined synergistic effects of multiple factors such as base reagents, solvents and temperature.

[0042] Application Example: Antitumor Activity Test Human breast cancer cells (Michigan Cancer Foundation-7, MCF-7) and human liver cancer cells (Human Liver Cancer Cells, HepG2) were selected as the research objects (Table 1) to evaluate the in vitro antitumor activity of azabicyclo[3.1.0]hexan-2-one compounds.

[0043] The counted MCF-7 or HepG2 cell suspension was added dropwise to a 96-well plate, seeded at 3000 - 5000 cells per well, and the liquid in each well was added to 100 μL, then 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 h. 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 h. The culture was terminated and the culture medium in the wells was aspirated. 100 μL of dimethyl sulfoxide was added to each well, and the plate was placed on a shaker and shaken at low speed for 30 min to fully dissolve the crystals; the absorbance of each well was measured at 490 nm on an enzyme-linked immunosorbent assay detector, and the inhibition rate was calculated. The results are shown in Table 4 below: Table 4 In vitro antitumor activity of azabicyclo[3.1.0]hexan-2-one compounds (inhibition rate %) As can be seen from Table 1, azabicyclo[3.1.0]hexan-2-one compounds show good cytotoxicity against human breast cancer cells and human liver cancer cell lines, and their highest inhibition rates are 94.26% and 98.21% (3ca), respectively.

[0044] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. An azabicyclo[3.1.0]hexan-2-one compound, characterized in that, The structural formula of the azabicyclo[3.1.0]hexan-2-one compounds is as follows: ; Among them, R 1 is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-chlorophenyl, 2-methylphenyl, 2-fluorophenyl, 2-bromophenyl, 2-naphthyl, 2-thienyl, methyl, tert-butyl, benzyl; R 2 is one of C1-C5 alkyl, C3-C12 cycloalkyl, allyl, propargyl, benzyl, 4-methylbenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-trifluorobenzyl, 2-naphthylmethyl; Ar is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-chlorophenyl, 2-methylphenyl, 2-fluorophenyl, 2-naphthyl, 2-thienyl.

2. A method for preparing the azabicyclo[3.1.0]hexan-2-one compound according to claim 1, characterized in that, Under the action of a base, β-oxoacrylamide and vinyl sulfonium salt are used as raw materials to synthesize azabicyclo[3.1.0]hexan-2-one compounds in one step.

3. The preparation method of the azabicyclo[3.1.0]hexan-2-one compound according to claim 2, characterized in that, The structural formula of the β-oxopropenamide is as follows: ; The structural formula of the vinyl sulfonium salt described above is: ; R 3 is one of C1-C6 alkyl or C3-C6 cycloalkyl; X is tetrafluoroborate, trisubstituted methanesulfonate or halogen.

4. The preparation method of the azabicyclo[3.1.0]hexan-2-one compound according to claim 2, characterized in that, The molar ratio of β-oxoacrylamide, vinyl sulfonium salt, and base reagent is 1:1.0 - 1.5:1.2 - 2.

5. The preparation method of the azabicyclo[3.1.0]hexan-2-one compound according to claim 4, characterized in that, The molar ratio of β-oxoacrylamide, vinyl sulfonium salt, and base reagent is 1:1.2:

2.

6. The preparation method of the azabicyclo[3.1.0]hexan-2-one compound according to claim 2, wherein, The base reagent is one or more of triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 4-dimethylaminopyridine, pyridine, cesium carbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide; the solvent for the one-step synthesis of azabicyclo[3.1.0]hexan-2-one compounds is one of dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, acetone, toluene, p-xylene, tetrahydrofuran, ethyl acetate; the reaction temperature for the one-step synthesis of azabicyclo[3.1.0]hexan-2-one compounds is 0 - 40 °C, and the reaction time is 6 - 12 h.

7. The preparation method of the azabicyclo[3.1.0]hexan-2-one compound according to claim 6, characterized in that, The base reagent is 1,8-diazabicyclo[5.4.0]undec-7-ene; the solvent for the one-step synthesis of azabicyclo[3.1.0]hexan-2-one compounds is dichloromethane.

8. The preparation method of the azabicyclo[3.1.0]hexane-2-one compound according to claim 2, wherein, After the reaction for the one-step synthesis of azabicyclo[3.1.0]hexan-2-one compounds is completed, the reaction solution is concentrated under vacuum, and the residue is passed through a silica gel column chromatography with 200 mesh to obtain azabicyclo[3.1.0]hexan-2-one compounds.

9. The preparation method of the azabicyclo[3.1.0]hexan-2-one compound according to claim 8, characterized in that, The silica gel column chromatography uses a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 - 3:1 as the eluent.

10. Use of the azabicyclo[3.1.0]hexan-2-one compound described in claim 1 or the azabicyclo[3.1.0]hexan-2-one compound prepared by the method described in any one of claims 2 - 9 in the preparation of anti-tumor drugs.

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