2, 3-diazabicyclo [3.1. 1] heptane derivative and synthesis method thereof

Abstract

The invention discloses a 2, 3-diazabicyclo [3.1. 1] heptane derivative and a synthesis method of the 2, 3-diazabicyclo [3.1. 1] heptane derivative. According to the method, bicyclo [1.1. 0] butane is taken as a raw material and is subjected to cycloaddition reaction with hydrazone under the catalysis of Lewis acid, a series of 2, 3-diazabicyclo [3.1. 1] heptane derivatives with various structures are synthesized with excellent chemical selectivity, and the product can be further derivatized. The method has the advantages of easily available raw materials, simple operation, mild reaction conditions, and diversity of functional groups.

Description

Technical Field

[0001] The invention belongs to the field of bicyclo[2.1.1]heptane synthesis, and particularly relates to a method for preparing 2,3-diazabicyclo[3.1.1]heptane derivatives by Lewis acid catalysis. Background Art

[0002] In recent years, the strategy of using three-dimensional bicyclic skeletons as bioisosteres to replace aromatic rings has become a hot topic in the field of drug research (Nat. Rev. Chem. 2024, 8, 605–627). Azabicyclo[3.1.1]heptane is an important bioisostere of ortho- or meta-substituted nitrogen aromatic rings. Its application in drug development is expected to improve the physicochemical properties and pharmacokinetic properties of drug-like molecules. Especially since medicinal chemists discovered that replacing the pyridine group in Rupatadine with 3-azabicyclo[3.1.1]heptane greatly improved the water solubility of the drug, reduced lipophilicity, and significantly improved metabolic stability in human liver microsomes (Angew. Chem. Int. Ed. 2023, 62, e202304246.), this research has attracted more and more attention from medicinal chemists and organic synthetic chemists. For example, the Studer team applied chiral 2-azabicyclo[3.1.1]heptane to the modification of a new type of active molecule with antiproliferative activity against HT-29, HeLa and 16MCF-7 (J.Am.Chem.Soc.2024,146,272045–27212); Li Xiaoxun's team also followed this idea and obtained a derivative of the local anesthetic Bupivacaine containing a 3-azabicyclo[3.1.1]heptane skeleton (J.Am.Chem.Soc.2024,146,21069–21077). These practices provide a novel research idea for drug development. Therefore, the construction of a new azabicyclo[3.1.1]heptane skeleton has important research significance.

[0003] So far, the synthetic reports of azabicyclo[3.1.1]heptane skeletons are extremely limited, and the types are limited to bicyclo[3.1.1]heptane skeletons containing only one nitrogen atom (J.Am.Chem.Soc.2024,146,27204–27212; Angew.Chem.Int.Ed.2024,63,e202402730; J.Am.Chem.Soc.2024,146,18565–18575; J.Am.Chem.Soc.2024,146,210 69–21077; Nat. Catal. 2024, DOI: org / 10.1038 / s41929-024-01239-9; Chem. Commun. 2024, DOI: org / 10.1039 / D4CC04730C; Org. Lett. 2024, DOI: org / 10.1021 / acs.orglett.4c03489), the number of these bioisosteres is difficult to meet the growing demand for bioisosteres in medicinal chemistry. Based on this, we hope to develop a method that can be used for modular construction of diazabicyclo[3.1.1]heptane skeletons with high efficiency and strong substrate universality. The obtained compounds can be used as bioequivalents of nitrogen aromatic rings in the modification of drugs, active molecules and natural products, providing new chemical entities for drug research and development. Summary of the invention

[0004] The purpose of the present invention is to use bicyclo[1.1.0]butane 2 as a raw material to undergo a cycloaddition reaction with a hydrazone 3 to construct 2,3-diazabicyclo[3.1.1]heptane 1. The present invention uses bicyclo[1.1.0]butane as a raw material, and undergoes a cycloaddition reaction with a hydrazone under the catalysis of a Lewis acid to synthesize a series of 2,3-diazabicyclo[3.1.1]heptane derivatives with diverse structures with excellent chemical selectivity, and the products can be further derivatized.

[0005] In order to achieve the above object, the technical solution of the present invention is as follows:

[0006] In one aspect, the present invention provides a 2,3-diazabicyclo[3.1.1]heptane derivative, whose molecular structure 1 is as follows:

[0007]

[0008] R 1 is hydrogen; a C1-C10 straight or branched alkyl group; a substituted or unsubstituted aryl group; a heterocycle having 1 to 4 nitrogen, oxygen or sulfur atoms; and the group can be further substituted, and the substituent is selected from a hydroxyl group, an amino group, a halogen group, a nitro group (-NO2), a cyano group (-CN) or a C1-C4 alkyl group;

[0009] R2 is a C1-C10 straight or branched alkyl group; a substituted or unsubstituted aryl group; a heterocyclic ring having 1 to 4 nitrogen, oxygen or sulfur atoms;

[0010] R 3 is a C1-C10 straight chain or branched alkyl group; a substituted or unsubstituted aryl group; an acyl group or a sulfonyl group;

[0011] R 4 is a C1-C10 straight or branched alkyl group; a substituted or unsubstituted aryl group; a heterocycle having 1 to 4 nitrogen, oxygen or sulfur atoms; and a functional group selected from trifluoromethyl and nitro.

[0012] Another aspect of the present invention provides a method for synthesizing the above-mentioned 2,3-diazabicyclo[3.1.1]heptane derivative, wherein a Lewis acid is used as a catalyst, a solvent is added, and a cycloaddition reaction of bicyclo[1.1.0]butane 2 and hydrazone 3 is carried out at room temperature to generate a 2,3-diazabicyclo[3.1.1]heptane derivative 1 (reaction formula (1)). After the reaction is completed, the product is separated and characterized by a conventional separation and purification method to obtain the target product.

[0013]

[0014] Substituents R in Bicyclo[1.1.0]butane 2 3 , R 4 , the substituent R of hydrazone 3 1 , R 2 Same as above: R 1 is hydrogen; a C1-C10 straight or branched alkyl group; a substituted or unsubstituted aryl group; a heterocycle having 1 to 4 nitrogen, oxygen or sulfur atoms; and the group can be further substituted, and the substituent is selected from a hydroxyl group, an amino group, a halogen group, a nitro group (-NO2), a cyano group (-CN) or a C1-C4 alkyl group;

[0015] R 2 is a C1-C10 straight or branched alkyl group; a substituted or unsubstituted aryl group; a heterocyclic ring having 1 to 4 nitrogen, oxygen or sulfur atoms;

[0016] R 3 is a C1-C10 straight chain or branched alkyl group; a substituted or unsubstituted aryl group; an acyl group or a sulfonyl group;

[0017] R 4 is a C1-C10 straight or branched alkyl group; a substituted or unsubstituted aryl group; a heterocycle having 1 to 4 nitrogen, oxygen or sulfur atoms; and a functional group selected from trifluoromethyl and nitro.

[0018] Based on the above technical scheme, preferably, the catalyst is one of Lu(OTf)3, Eu(OTf)3, Ga(OTf)3 or In(OTf)3; wherein, the reaction is best performed with In(OTf)3 as a catalyst, and the molar ratio of bicyclo[1.1.0]butane 2 to the catalyst is 1:0.01-1:0.5, preferably 13:1.

[0019] Based on the above technical scheme, preferably, the solvent is one or more of 1,4-dioxane, dimethyl sulfoxide, acetonitrile, toluene, methanol, N,N-dimethylformamide or tetrahydrofuran; the reaction effect is best when the reaction solvent is tetrahydrofuran.

[0020] Based on the above technical scheme, the preferred reaction temperature is 25-130°C; the reaction time is 0.5-24 hours; the optimal reaction time is 12 hours; and the optimal reaction temperature is 25°C.

[0021] Based on the above technical solution, preferably, the molar ratio of bicyclo[1.1.0]butane 2 to hydrazone 3 is 5:1-1:5, more preferably 1.3:1.

[0022] The present invention uses bicyclo[1.1.0]butane as a raw material, and reacts with hydrazone under the catalysis of Lewis acid to undergo a cycloaddition reaction, thereby synthesizing a series of 2,3-diazabicyclo[3.1.1]heptane derivatives with diverse structures with excellent chemical selectivity, and the products can be further derivatized. Compared with the existing synthesis method of 2,3-diazabicyclo[3.1.1]heptane, the present invention has easy-to-obtain raw materials, simple operation, and the reaction can efficiently modularly synthesize 2,3-diazabicyclo[3.1.1]heptane derivatives with potential biological activity.

[0023] Beneficial Effects

[0024] 1) Both the synthons bicyclo[1.1.0]butane 2 and hydrazone 3 can be prepared in large quantities and used to synthesize 2,3-diazabicyclo[3.1.1]heptane derivatives 1 of different types and structures.

[0025] 2) Cycloaddition reactions do not require the use of heavy metal reagents.

[0026] 3) The present invention utilizes bicyclo[1.1.0]butane 2 to synthesize structurally diverse 2,3-diazabicyclo[3.1.1]heptane derivatives 1 with excellent chemical selectivity, and the raw materials are readily available, the operation is simple, the yield of the target product is high, and further derivatization is possible. DETAILED DESCRIPTION

[0027] The chemical reagents used were all commercially available and used directly without further treatment; bicyclo[1.1.0]butane 2 and hydrazone 3 were synthesized according to the methods reported in the literature (Angew. Chem. Int. Ed. 2024, 63, e202318476; Angew. Chem. Int. Ed. 2023, 62, e202303271; Nat. Commun. 2021, 12, 6551)

[0028] The present invention uses simple bicyclo[1.1.0]butane 2 and hydrazone 3 as raw materials and carries out a cycloaddition reaction under the action of Lewis acid (reaction formula (1)).

[0029]

[0030] The specific process is as follows: under nitrogen atmosphere, bicyclo[1.1.0]butane 2 (0.26 mmol, 1.3 equiv.) and hydrazone 3 (0.20 mmol, 1.0 equiv.) are added sequentially into a dry Schlenk tube equipped with a magnetic stirrer. The tube is evacuated and filled with nitrogen 5 times. Then, anhydrous THF is added sequentially through a syringe. Then, In(OTf)3 (11.2 mg, 0.02 mmol) is added, and the mixture is stirred at 25°C until hydrazone 3 is completely consumed (monitored by TLC). The reaction solution is quenched with water and extracted with ethyl acetate 3 times. The filtrate is separated. The combined organic phase is dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by column chromatography (petroleum ether / acetone or petroleum ether / ethyl acetate, or toluene) to obtain the target product 1.

[0031] The following examples are helpful to further understand the present invention, but the contents of the present invention are not limited thereto.

[0032] Example 1

[0033]

[0034] The specific process is as follows: under nitrogen atmosphere, bicyclo[1.1.0]butane 2a (60.9 mg, 0.26 mmol) and hydrazone 3a (39.3 mg, 0.20 mmol) were added sequentially to a dry Schlenk tube equipped with a magnetic stirrer. The tube was evacuated and filled with nitrogen 5 times. Then anhydrous THF was added sequentially through a syringe. Then, In(OTf)3 (11.2 mg, 0.02 mmol) was added and the mixture was stirred at 25°C until hydrazone 3 was completely consumed (monitored by TLC). The reaction solution was quenched with water and extracted with ethyl acetate 3 times. The filtrate was separated. The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / acetone or petroleum ether / ethyl acetate, or toluene) to obtain the target product 1a (82.7 mg, yield 96%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0035] Example 2

[0036]

[0037] The reaction steps and operations were the same as those in Example 1, except that the hydrazone added to the reaction system was 3b (42.1 mg, 0.20 mmol). The reaction was stopped and the target product 1b (82.7 mg, 93% yield) was obtained by post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0038] Example 3

[0039]

[0040] The reaction steps and operations were the same as those in Example 1, except that the hydrazone added to the reaction system was 3c (45.3 mg, 0.20 mmol). The reaction was stopped and the target product 1c (88.4 mg, 96% yield) was obtained by post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0041] Example 4

[0042]

[0043] The reaction steps and operations were the same as those in Example 1, except that the hydrazone added to the reaction system was 3d (42.1 mg, 0.20 mmol). The reaction was stopped and the target product 1d (88.0 mg, yield 99%) was obtained by post-treatment as a white solid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0044] Example 5

[0045]

[0046] The reaction steps and operations were the same as those in Example 1, except that the hydrazone added to the reaction system was 3e (42.8 mg, 0.20 mmol). The reaction was stopped and the target product 1e (85.2 mg, 95% yield) was obtained by post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0047] Example 6

[0048]

[0049] The reaction steps and operations were the same as those in Example 1, except that the hydrazone added to the reaction system was 3f (49.3 mg, 0.20 mmol). The reaction was stopped and the target product 1f (86.5 mg, 90% yield) was obtained by post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0050] Example 7

[0051]

[0052] The reaction steps and operations are the same as those in Example 1, except that 3 g (40.5 mg, 0.20 mmol) of hydrazone is added to the reaction system. The reaction is stopped and 1 g (82.9 mg, 95% yield) of the target product as a white solid is obtained by post-treatment. The target product is confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0053] Example 8

[0054]

[0055] The reaction steps and operations were the same as those in Example 1, except that the hydrazone added to the reaction system was 3h (40.5 mg, 0.20 mmol). The reaction was stopped and the target product 1h (76.0 mg, 87% yield) was obtained as a white solid after post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0056] Example 9

[0057]

[0058] The reaction steps and operations were the same as those in Example 1, except that the hydrazone added to the reaction system was 3i (42.1 mg, 0.20 mmol). The reaction was stopped and the target product 1i (84.5 mg, 95% yield) was obtained by post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0059] Example 10

[0060]

[0061] The reaction steps and operations were the same as those in Example 1, except that the hydrazone added to the reaction system was 3j (46.1 mg, 0.20 mmol). The reaction was stopped and the target product 1j (91.1 mg, yield 98%) was obtained by post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0062] Embodiment 11

[0063]

[0064] The reaction steps and operations were the same as those in Example 1, except that the hydrazone added to the reaction system was 3k (42.1 mg, 0.20 mmol). The reaction was stopped and the target product 1k (80.0 mg, 90% yield) was obtained by post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0065] Example 12

[0066]

[0067] The reaction steps and operations were the same as those in Example 1, except that bicyclo[1.1.0]butane 2b (64.6 mg, 0.26 mmol) was added to the reaction system. The reaction was stopped and the target product 11 (81.8 mg, 92% yield) was obtained by post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0068] Embodiment 13

[0069]

[0070] The reaction steps and operations were the same as those in Example 1, except that bicyclo[1.1.0]butane 2c (65.6 mg, 0.26 mmol) was added to the reaction system. The reaction was stopped and the target product 1m (88.8 mg, yield 99%) was obtained by post-treatment as a white solid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0071] Embodiment 14

[0072]

[0073] The reaction steps and operations were the same as those in Example 1, except that bicyclo[1.1.0]butane 2d (68.7 mg, 0.26 mmol) was added to the reaction system. The reaction was stopped and the target product 1n (84.7 mg, 92% yield) was obtained by post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0074] Embodiment 15

[0075]

[0076] The reaction steps and operations were the same as those in Example 1, except that bicyclo[1.1.0]butane 2e (65.6 mg, 0.26 mmol) was added to the reaction system. The reaction was stopped and the target product 1o (87.0 mg, 97% yield) was obtained by post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0077] Example 16

[0078]

[0079] The reaction steps and operations were the same as those in Example 1, except that bicyclo[1.1.0]butane 2f (55.7 mg, 0.26 mmol) was added to the reaction system. The reaction was stopped and the target product 1p (69.0 mg, 84% yield) was obtained by post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0080] Embodiment 17

[0081]

[0082] Under nitrogen atmosphere, 2g (656.0mg, 2.60mmol) of (3,5-dimethyl-1H-pyrazolyl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone and (E)-1-benzylidene-2-phenylhydrazine 3a (392.5mg, 2.00mmol) were added to a dry Schlenk flask equipped with a magnetic stirrer. The flask was evacuated and backfilled with nitrogen 5 times. Then anhydrous THF was added in sequence. Subsequently, In(OTf)3 (56.2mg, 0.1mmol) was added and stirred at 50°C. After the reaction was completed (3h), the reaction was quenched with water and extracted with ethyl acetate 3 times. The filtrate was separated. The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / acetone: 50:1) to obtain the corresponding product 1q (358.9mg, yield 40%).

[0083] The present invention uses bicyclo[1.1.0]butane as a raw material, and reacts with hydrazone under the catalysis of Lewis acid to undergo a cycloaddition reaction, thereby synthesizing a series of 2,3-diazabicyclo[3.1.1]heptane derivatives with diverse structures with excellent chemical selectivity. The products can be further derivatized, for example, reacting with methanol to generate ester 1r, oxidizing to generate primary alcohol 4, and oxidizing to generate 2,3-diazabenzocycloheptene 5.

[0084]

[0085] The specific process is as follows: 2,3-diazabicyclo[3.1.1]heptane derivative 1q (89.7 mg, 0.2 mmol) was dissolved in methanol (2.0 mL), and Et3N (0.4 mmol) was added. The reaction mixture was stirred at 50°C for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate: 40:1) to obtain a white solid product 1r (68.4 mg, yield 89%).

[0086]

[0087] The specific process is as follows: 1q (89.7 mg, 0.2 mmol) was added to a dry Schlenk tube and purged with nitrogen. Anhydrous MeOH (2.0 mL) was added to the reaction tube with a syringe. The mixture was stirred at 0°C (ice bath) for 5.0 minutes. Then, NaBH4 (15.1 mg, 0.4 mmol) was slowly added. The resulting solution was heated to 50°C and stirred for 30 minutes. After the reaction was completed, the reaction mixture was quenched with water and extracted 3 times with CH2Cl2. The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate: 10:1) to give a white solid 4 (69.9 mg, yield 98%).

[0088]

[0089] The specific process is as follows: 1a (86.1 mg, 0.2 mmol) was loaded into a dry Schlenk tube and purged with oxygen. Anhydrous THF was added to the reaction tube via a syringe. The mixture was stirred at 50°C (oil bath) for 10 hours. After the reaction was completed, the reaction solution was quenched with water and extracted with ethyl acetate three times. The resulting filtrate was separated. The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate: 50:1) to obtain the corresponding white solid 5 (83.1 mg, yield 97%).

[0090] The products can be introduced into drug molecules as bioisosteres of nitrogen heteroaromatic rings. For example, primary alcohol 4 was used to synthesize a Rupatadine homologue 7.

[0091]

[0092] The specific process is as follows: 4 (356.5 mg, 1.0 mmol) and PPh3 (262.3 mg, 1.0 mmol) were loaded into a dry Schlenk tube and purged with nitrogen. 10.0 mL of anhydrous DCM was added to the reaction tube via a syringe. The temperature was lowered to 0 ° C (ice-water bath) and NBS (178.0 mg, 1.0 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted three times with DCM. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture 6 was obtained by rapid column chromatography (petroleum ether / ethyl acetate = 50:1). The crude product was directly loaded into a flame-dried Schlenk tube and purged with nitrogen. Anhydrous DMF (10.0 mL) was added to the reaction tube via a syringe. Then desloratadine (310.8 mg, 1.0 mmol) and K2CO3 (138.2 mg, 1.0 mmol) were added in sequence, heated to 50°C, stirred for 8 hours, quenched with water after the reaction was completed, extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol / formic acid = 95:5:1) to give the corresponding compound 7 as a white solid. The total yield was 41% (266.2 mg).

[0093] Further studies have shown that compound 7 exhibits better water solubility than Rupatadine (7: 245 μM vs Rupatadine: 29 μM), and reduced lipophilicity (7: logD = 4.0 vs Rupatadine: logD: > 4.5). We also compared the metabolic stability of compound 7 with Rupatadine. Based on its metabolic stability in human liver microsomes, its half-life is significantly longer than that of Rupatadine (7: t1 / 2 (min) = 29.5 vs Rupatadine: t1 / 2 (min) = 3.2). This fully demonstrates the application prospects of this skeleton in drug development.

[0094] Characterization data of typical compounds

[0095] 2,3-Diazabicyclo[3.1.1]heptane derivative (1a), white solid. 1H NMR (400MHz, CDCl3) δ7.60–7.51(m,2H),7.49–7.36(m,3H),7.38–7.29(m,2 H),7.31–7.19(m,3H),7.20–7.05(m,7H),7.06–6.98(m,2H),6.86–6.77(m, 1H),5.16(d,J=11.3Hz,1H),4.89(d,J=11.3Hz,1H),3.35(d,J=9.6Hz,1H), 3.21(dd,J=11.1,8.4Hz,1H),2.90(t,J=9.0Hz,1H),2.78(d,J=11.1Hz,1H); 13 C NMR(100MHz, CDCl3)δ201.0,148.9,143.5,137.0,136.3,132.8,129.0(2C),128.8(2C),128.6,128.5(0)(2C),128.4(7)(2C) ),128.3(2C),127.6(2C),127.2,124.9(2C),119.9,119.1(2C),66.3,65.2,54.9,42.9,40.6; HRMS(ESI-TOF,m / z):calcdfor C 30 H 26 N2ONa[M+Na] + :453.1938,found:453.1931.

[0096] 2,3-Diazabicyclo[3.1.1]heptane derivative (1b), white solid. 1 H NMR (400MHz, CDCl3) δ7.52–7.44(m,4H),7.40–7.32(m,3H),7.29–7.20(m,4H),7.16–7.09(m,2H),7.09–7.01(m,4H),6.93(dd,J=6.5,2.5Hz,1H),6 .86–6.77(m,1H),5.06(d,J=8.3Hz,1H),4.88(d,J=8.1Hz,1H),3.43(d,J= 9.4Hz,1H),3.22(dd,J=11.1,8.4Hz,1H),2.97–2.82(m,2H),2.12(s,3H); 13C NMR(100MHz, CDCl3)δ201.6,148.9,143.6,137.6,136.8,135.4,132.6,130.6,129.1(2C),128.3(9)(2C),128.3(8)(2C),128.3,1 28.0(2C),127.2,126.5,125.7,124.8(2C),119.7,118.7(2C),65.3,61.3,54.4,43.4,40.6,19.2; HRMS(ESI-TOF,m / z):calcdfor C 31 H 28 N2ONa[M+Na] + :467.2094,found:467.2087.

[0097] 2,3-Diazabicyclo[3.1.1]heptane derivative (1c), white solid. 1 H NMR (400MHz, CDCl3) δ7.63–7.54(m,2H),7.48–7.39(m,3H),7.37–7.21(m,5H),7.16– 7.07(m,2H),7.07–7.00(m,3H),6.87–6.76(m,1H),6.74–6.66(m,2H),6.58–6.54(m, 1H),5.23(d,J=10.5Hz,1H),4.88(d,J=10.1Hz,1H),3.56(s,3H),3.31(d,J=9.6Hz,1 H),3.17(dd,J=11.1,8.4Hz,1H),2.91(dd,J=9.6,8.4Hz,1H),2.78(d,J=11.1Hz,1H); 13 C NMR(100MHz, CDCl3)δ201.0,159.6,148.9,143.5,138.6,136.4,132.8,129.8,129.0(2C),128.5(2)(2C),128.5(1)(2C),128.3 (2C),127.2,124.9(2C),119.9,119.4,119.1(2C),114.3,113.4,66.4,65.2,55.1,54.8,43.0,40.2; HRMS(ESI-TOF,m / z):calcd for C 31 H 28 N2O2Na[M+Na] + :483.2043,found:483.2038.

[0098] 2,3-Diazabicyclo[3.1.1]heptane derivative (1d), white solid. 1 H NMR (400MHz, CDCl3) δ7.65–7.56(m,2H),7.49–7.39(m,3H),7.37–7.21(m,5H),7.15–7.07(m,2H),7.05–6.90(m,6H),6.85–6.77(m,1H) ,5.13(s,1H),4.87(s,1H),3.34(d,J=9.7Hz,1H),3.21(dd,J=11.0,8.3Hz,1H),2.92–2.83(m,1H),2.74(d,J=11.1Hz,1H),2.21(s,3H); 13 CNMR(100MHz, CDCl3)δ200.9,148.9,143.6,138.3,136.2,134.0,132.8,129.4(2C),129.0(2C),128.6(2C),128.5(2C),12 8.3(2C),127.4(2C),127.2,124.9(2C),119.8,119.0(2C),66.0,65.2,54.9,42.8,40.7,21.2; HRMS(ESI-TOF,m / z):calcd for C 31 H 28 N2ONa[M+Na] + :467.2094,found:467.2058.

[0099] 2,3-Diazabicyclo[3.1.1]heptane derivative (1e), white solid. 1 H NMR (400MHz, CDCl3) δ7.62–7.54(m,2H),7.50–7.41(m,3H),7.38–7.22(m,5H),7.17–7.04(m,4H),7.04–6.98(m,2H),6.88–6.76(m,3H) ,5.10(brs,1H),4.88(s,1H),3.37(d,J=9.6Hz,1H),3.18(dd,J=11.1,8.4Hz,1H),2.91(dd,J=9.6,8.4Hz,1H),2.78(d,J=11.1Hz,1H); 13C NMR (100MHz, CDCl3) δ200.9, 162.6 (d, J = 247.4Hz), 148.7, 143.4, 136.2, 133.0, 132.9 (d, J = 3.3Hz), 129.4 (d, J = 8.2Hz) (2C), 129.1 (2 C),128.6(2C),128.4(2C),128.3(2C),127.3,124.9(2C),120.0,119.1(2C),115.7(d,J=21.4Hz)(2C),65.6,65.2,54.8,42.9,40.4; 19 FNMR(376MHz, CDCl3)δ-112.94; HRMS(ESI-TOF, m / z):calcd for C 30 H 25 FN2ONa[M+Na] + :471.1844,found:471.1818.

[0100] 2,3-Diazabicyclo[3.1.1]heptane derivative (1f), white solid. 1 H NMR(400MHz, CDCl3)δ7.76–7.69(m,1H),7.64(d,J=8.2Hz,2H),7.58–7.55(m,3H),7.53 –7.46(m,2H),7.45–7.32(m,5H),7.31–7.19(m,4H),7.19–7.10(m,2H),7.09–7.01(m,2 H),6.90–6.80(m,1H),5.27(d,J=11.3Hz,1H),5.08(d,J=11.2Hz,1H),3.39(d,J=9.6Hz ,1H),3.32(dd,J=11.1,8.4Hz,1H),2.96(dd,J=9.6,8.4Hz,1H),2.85(d,J=11.1Hz,1H); 13 C NMR(100MHz, CDCl3)δ201.0,148.9,143.5,136.2,134.5,133.2(4),133.1(9),132.9,129.1(2C),128.6,128.5(2C),128.5(2C),128.3(2C) ,128.2,127.7,127.2,127.1,126.4,126.3,125.3,124.9(2C),119.9,119.1(2C),66.5,65.3,54.9,43.1,40.6; HRMS(ESI-TOF,m / z):calcd forC34 H 28 N2ONa[M+Na] + :503.2094,found:503.2089.

[0101] 2,3-Diazabicyclo[3.1.1]heptane derivative (1 g), white solid. 1 H NMR (400MHz, CDCl3) δ7.67–7.60(m,2H),7.49–7.42(m,3H),7.39–7.29(m,4H),7.29–7.21( m,1H),7.16–7.06(m,3H),7.04–6.97(m,2H),6.86–6.79(m,1H),6.76(dd,J=5.1,3.5Hz,1H) ,6.68(dd,J=3.6,1.2Hz,1H),5.27(d,J=10.8Hz,1H),5.19(d,J=10.9Hz,1H),3.30(d,J=9. 6Hz,1H),3.15(dd,J=11.2,8.4Hz,1H),2.89(dd,J=9.7,8.4Hz,1H),2.74(d,J=11.3Hz,1H); 13 CNMR(100MHz, CDCl3)δ200.3,148.7,143.3,138.9,136.1,132.9,129.0(2C),128.6(2C),128.5(2C),128.3(2C),1 27.3,126.7,126.3,125.0,124.9(2C),120.0,119.1(2C),65.4,61.5,55.1,42.1,39.8; HRMS(ESI-TOF,m / z):calcd for C 28 H 24 N2OSNa[M+Na] + :459.1502,found:459.1498.

[0102] 2,3-Diazabicyclo[3.1.1]heptane derivative (1h), white solid. 1H NMR (600MHz, CDCl3) δ7.90–7.83(m,2H),7.60–7.52(m,1H),7.48–7.42(m,2H),7.39(d,J=7.8Hz,2H),7.35–7.28 (m,2H),7.24–7.19(m,1H),7.09(dd,J=8.6,7.1Hz,2H),6.97(d,J=8.2Hz,2H),6.83–6.75(m,1H),5.13(d,J=7.8H z,1H),3.80(d,J=7.0Hz,1H),3.09(d,J=9.5Hz,1H),2.81(dd,J=11.0,8.4Hz,1H),2.75–2.63(m,1H),2.54(d,J= 10.9Hz,1H),1.88(d,J=12.2Hz,1H),1.73–1.62(m,2H),1.56–1.41(m,3H),1.35–1.23(m,1H),1.19–0.89(m,4H); 13 C NMR (150MHz, CDCl3) δ201.7,149.3,143.7,135.8,133.2,129.0(2C),128.9(2C),128.8(2C),128.3(2C),127.0,124.8(2C) ),119.4,118.5(2C),66.0,65.4,54.1,43.9,40.6,40.0,31.0,26.7,26.4(1),26.3(8),25.9; HRMS(ESI-TOF,m / z):calcd for C 30 H 32 N2ONa[M+Na] + :459.2407,found:459.2388.

[0103] 2,3-Diazabicyclo[3.1.1]heptane derivative (1i), white solid. 1H NMR (400MHz, CDCl3) δ7.61–7.53(m,2H),7.49–7.42(m,2H),7.45–7.36(m,1H) ,7.37–7.29(m,2H),7.30–7.19(m,3H),7.18–7.04(m,5H),6.95–6.88(m,4H), 5.14(d,J=11.3Hz,1H),4.90(d,J=11.3Hz,1H),3.34(d,J=9.5Hz,1H),3.20(d d,J=11.1,8.4Hz,1H),2.97–2.87(m,1H),2.77(d,J=11.1Hz,1H),2.23(s,3H); 13 C NMR(100MHz, CDCl3)δ201.0,146.4,143.6,137.1,136.3,132.8,129.1,129.0,128.9(2C),128.7(2C),128.5(0)(2C),128.4(6) (2C),128.4(6)(2C),127.6(2C),127.1,124.9(2C),119.1(2C),66.3,65.1,54.9,42.7,40.6,20.6; HRMS(ESI-TOF,m / z):calcd for C 31 H 28 N2ONa[M+Na] + :467.2094,found:467.2086.

[0104] 2,3-Diazabicyclo[3.1.1]heptane derivative (1j), white solid. 1 H NMR (400MHz, CDCl3) δ7.64–7.52(m,2H),7.47–7.39(m,3H),7.39–7.32(m,2H ),7.32–7.24(m,3H),7.20–7.12(m,3H),7.11–7.03(m,4H),7.00–6.90(m,2H) ,5.16(d,J=11.4Hz,1H),4.86(d,J=11.4Hz,1H),3.35(d,J=9.6Hz,1H),3.20 (dd,J=11.2,8.4Hz,1H),2.85(dd,J=9.6,8.4Hz,1H),2.79(d,J=11.2Hz,1H); 13C NMR(100MHz, CDCl3)δ200.8,147.5,143.1,136.8,136.2,132.9,129.2(2C),128.8(2C),128.7,128.6(2C),128.4(2C), 128.2(2C),127.6(2C),127.4,124.9,124.8(2C),120.2(2C),66.3,65.3,54.8,42.8,40.5; HRMS(ESI-TOF,m / z):calcd for C 30 H 25 ClN2ONa[M+Na] + :487.1548,found:487.1542.

[0105] 2,3-Diazabicyclo[3.1.1]heptane derivative (1k), white solid. 1 H NMR(400MHz, CDCl3)δ7.65(d,J=7.6Hz,2H),7.49–7.43(m,3H),7.41–7.31(m,4H),7.30–7.20(m,7H),7.13–7.07(m,4H),5.04(s,1H), 4.49(s,1H),3.97(d,J=13.7Hz,1H),3.54(d,J=13.7Hz,1H),3.10(dd,J=10.5,6.6Hz,1H),3.04–2.94(m,2H),2.73(d,J=10.5Hz,1H); 13 C NMR(100MHz, CDCl3)δ201.6,143.8,140.7,137.9,136.8,132.6,128.7(2C),128.6(2C),128.5(3)(2C),128.5(0)(2C),128.4 (2C),128.3,128.1(2C),127.7(2C),127.5,126.7,126.6(2C),66.1,64.4,55.0,53.6,39.8,38.2; HRMS(ESI-TOF,m / z):calcd for C 31 H 28 N2ONa[M+Na] + :467.2094,found:467.2201.

[0106] 2,3-Diazabicyclo[3.1.1]heptane derivative (1l), white solid. 1H NMR (400MHz, CDCl3) δ7.62–7.52(m,2H),7.45–7.39(m,1H),7.37–7.32(m,2H),7 .30–7.23(m,2H),7.19–7.06(m,9H),7.06–7.00(m,2H),6.86–6.78(m,1H),5.15 (d,J=11.4Hz,1H),4.88(d,J=11.3Hz,1H),3.34(d,J=9.5Hz,1H),3.20(dd,J=11 .1,8.4Hz,1H),2.89(dd,J=9.6,8.4Hz,1H),2.76(d,J=11.1Hz,1H),2.33(s,3H); 13 C NMR (100MHz, CDCl3) δ201.0,149.0,140.7,137.1,136.8,136.3,132.8,129.7(2C),128.8(2C),128.5,128.4(9)(2C),128.4( 8)(2C),128.3(2C),127.6(2C),124.8(2C),119.8,119.1(2C),66.3,65.1,54.9,43.0,40.7,21.2; HRMS(ESI-TOF,m / z):calcd for C 31 H 28 N2ONa[M+Na] + :467.2094,found:467.2092.

[0107] 2,3-Diazabicyclo[3.1.1]heptane derivative (1m), white solid. 1 H NMR (400MHz, CDCl3) δ7.59–7.53(m,2H),7.46–7.38(m,3H),7.31–7.25(m,2H ),7.20–7.11(m,5H),7.10–7.06(m,2H),7.06–6.97(m,4H),6.88–6.80(m,1H) ,5.15(d,J=11.4Hz,1H),4.88(d,J=11.3Hz,1H),3.32(d,J=9.6Hz,1H),3.21 (dd,J=11.1,8.4Hz,1H),2.91(dd,J=9.6,8.4Hz,1H),2.75(d,J=11.1Hz,1H); 13C NMR(100MHz, CDCl3)δ200.8,162.0(d,J=245.9Hz),148.7,139.4(d,J=3.2Hz),136.9,136.2,132.9,128.8(2C),128.6,128.5(3)(2C),12 8.4(6)(2C),128.3(2C),127.6(2C),126.6(d,J=8.0Hz)(2C),120.1,119.2(2C),115.9(d,J=21.4Hz)(2C),66.3,64.7,54.8,43.0,40.7; 19 F NMR(376MHz, CDCl3)δ-115.52; HRMS(ESI-TOF, m / z):calcd for C 30 H 25 FN2ONa[M+Na] + :471.1844,found:471.1840.

[0108] 2,3-Diazabicyclo[3.1.1]heptane derivative (1n), white solid. 1 H NMR (400MHz, CDCl3) δ7.64–7.59(m,2H),7.49–7.42(m,2H),7.38–7.30(m,2H),7.28– 7.20(m,1H),7.18–7.08(m,7H),7.07–7.01(m,2H),6.87–6.79(m,1H),6.80–6.74(m, 2H),5.18(d,J=10.8Hz,1H),4.90(d,J=10.7Hz,1H),3.78(s,3H),3.32(d,J=9.6Hz,1 H),3.21(dd,J=11.1,8.4Hz,1H),2.86(dd,J=9.6,8.4Hz,1H),2.74(d,J=11.1Hz,1H); 13 C NMR(100MHz, CDCl3)δ199.2,163.2,148.9,143.6,137.1,130.9(2C),129.0(2C),129.0,128.7(2C),128.5,128.3(2C),12 7.6(2C),127.1,124.9(2C),119.8,119.0(2C),113.7(2C),66.6,65.2,55.5,54.7,42.8,40.8; HRMS(ESI-TOF,m / z):calcd for C 31 H 28 N2O2Na[M+Na]+ :483.2043,found:483.2042.

[0109] 2,3-Diazabicyclo[3.1.1]heptane derivative (1o), white solid. 1 H NMR (400MHz, CDCl3) δ7.65–7.57(m,2H),7.49–7.42(m,2H),7.38–7.31(m,2H),7. 28–7.22(m,1H),7.20–7.06(m,7H),7.04–7.00(m,2H),6.98–6.91(m,2H),6.87–6. 77(m,1H),5.17(d,J=11.3Hz,1H),4.85(d,J=11.2Hz,1H),3.35(d,J=9.5Hz,1H), 3.22(dd,J=11.1,8.4Hz,1H),2.87(dd,J=9.5,8.4Hz,1H),2.76(d,J=11.1Hz,1H); 13 C NMR (100MHz, CDCl3) δ 199.3, 165.4 (d, J = 254.8Hz), 148.8, 143.4, 136.8, 132.6 (d, J = 3.1Hz), 131.1 (d, J = 9.2Hz) (2C), 129.1 (2C), 128 .8(2C),128.7,128.3(2C),127.6(2C),127.2,124.9(2C),119.9,119.0(2C),115.7(d,J=21.8Hz)(2C),66.4,65.2,54.8,42.8,40.6; 19 F NMR(376MHz, CDCl3)δ-105.00; HRMS(ESI-TOF, m / z):calcd for C 30 H 25 FN2ONa[M+Na] + :471.1844,found:471.1836.

[0110] 2,3-Diazabicyclo[3.1.1]heptane derivative (1p), white solid. 1H NMR (400MHz, CDCl3) δ7.45–7.38(m,2H),7.38–7.28(m,7H),7.28–7.20(m,1H),7.12–7.04(m,2H) ,6.99–6.95(m,2H),6.83–6.76(m,1H),4.90(d,J=11.4Hz,1H),4.70(d,J=11.4Hz,1H),3.11–2.8 1(m,2H),2.63(d,J=11.0Hz,1H),2.54(dd,J=9.4,8.3Hz,1H),2.17(ddd,J=17.5,8.1,6.3Hz,1H) ,1.92(ddd,J=17.5,8.1,6.4Hz,1H),1.36–1.10(m,2H),1.05–0.90(m,2H),0.70(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ210.2,148.9,143.6,137.6,129.2(2C),129.0(2C),128.8,128.2(2C),127.8(2C),127.2, 125.0(2C),120.0,119.2(2C),64.6,64.4,54.6,41.1,38.9,38.0,25.0,22.1,13.8; HRMS(ESI-TOF,m / z):calcd for C 28 H 30 N2ONa[M+Na] + :433.2251,found:433.2245.

[0111] 2,3-Diazabicyclo[3.1.1]heptane derivative (1q), white solid. 1 H NMR (400MHz, CDCl3) δ7.52–7.42(m,2H),7.34(dd,J=8.5,6.9Hz,2H),7.26–7.24(m,1H) ,7.23–7.19(m,3H),7.17–7.06(m,4H),7.02–6.95(m,2H),6.83–6.75(m,1H),5.75(d,J =1.2Hz,1H),5.38–5.07(m,2H),3.36(d,J=10.0Hz,1H),3.19(dd,J=11.0,8.4Hz,1H),2 .98(dd,J=10.0,8.3Hz,1H),2.66(d,J=11.0Hz,1H),2.19(s,3H),2.10(d,J=1.0Hz,3H); 13C NMR (100MHz, CDCl3) δ173.4,152.3,149.0,143.9,143.9,137.6,129.0(2C),128.7(2C),128.5,128.1(2C),127.1(3)(2C) ),127.0(7),125.0(2C),119.6,119.3(2C),110.5,65.5,64.8,52.1,43.0,40.5,14.1,13.8; HRMS(ESI-TOF,m / z):calcd for C 29 H 28 N4ONa[M+Na] + :471.2156,found:471.2155.

[0112] 2,3-Diazabicyclo[3.1.1]heptane derivative (1r), white solid. 1 H NMR (400MHz, CDCl3) δ7.46–7.41(m,2H),7.39–7.22(m,8H),7.10–7.02(m,2H),6.97–6.89(m,2H),6.82–6.75(m,1H),4.99(d ,J=10.8Hz,1H),4.67(d,J=10.7Hz,1H),3.39(s,3H),3.10–2.99(m,2H),2.67(d,J=10.9Hz,1H),2.57(dd,J=9.7,8.4Hz,1H); 13 C NMR (100MHz, CDCl3) δ173.5,149.0,143.6,138.1,129.0(2C),128.9(2C),128.5,128.2(2C),127.4(2C ),127.2,125.1(2C),120.1,119.4(2C),65.2,64.7,51.7,48.1,41.2,39.5; HRMS(ESI-TOF,m / z):calcd forC 25 H 24 N2O2Na[M+Na] + :407.1730,found:407.1725.

[0113] Primary alcohol (4), white solid. 1H NMR (400MHz, CDCl3) δ7.50–7.45(m,2H),7.40–7.29(m,7H),7.27–7.21(m,1H),7.08–7.00(m,2H),6.97–6.86(m,2H),6.75(t t,J=7.4,1.3Hz,1H),5.08(brs,1H),4.43(s,1H),3.28(s,2H),2.92–2.76(m,2H),2.32–2.22(m,1H),2.13(d,J=10.5Hz,1H); 13 C NMR (100MHz, CDCl3) δ149.5,144.6,138.6,129.1(2C),128.9(2C),128.5,128.1(2C),127.7(2C),1 26.9,125.1(2C),119.8,119.5(2C),66.1,66.0,65.9,45.3,38.6,38.4; HRMS(ESI-TOF,m / z):calcd for C 24 H 24 N2O2Na[M+Na] + :379.1781,found:379.1778.

[0114] 2,3-Diazabenzocycloheptene (5), white solid. 1 H NMR (400MHz, CDCl3) δ7.90–7.84(m,2H),7.84–7.77(m,2H),7.50–7.41(m,4H),7.40 –7.31(m,6H),7.31–7.22(m,1H),3.66–3.52(m,2H),3.44–3.33(m,2H),2.63(s,1H); 13 C NMR(100MHz, CDCl3)δ197.8,196.5,145.2,134.6(2C),133.6(9),133.6(7),129.6(2C),129.5(2C),128.8 (1)(2C),128.7(9)(2C),128.6(2C),127.6,125.0(2C),73.3,57.6,44.9(2C); HRMS(ESI-TOF,m / z):calcd for C 24 H 20 N2ONa[M+Na] + :375.1468,found:375.1422.

[0115] Rupatadine homologue (7), white solid. 1 H NMR(400MHz, CDCl3)δ8.42(dd,J=4.4,2.2Hz,1H),7.68(dd,J=7.9,2.2Hz,1H),7.38–7.33(m,3H),7.33–7.22(m ,11H),7.17(d,J=8.9Hz,1H),7.16–7.13(m,1H),7.13–7.09(m,2H),7.08–7.02(m,1H),4.57(d,J=3.7Hz,1H),3 .31–3.14(m,2H),2.91–2.81(m,2H),2.79(d,J=12.6Hz,1H),2.73–2.69(m,2H),2.65(dd,J=4.3,3.2Hz,2H),2. 62–2.59(m,4H),2.57(d,J=3.7Hz,1H),2.47(d,J=12.8Hz,1H),2.43(d,J=12.4Hz,2H),2.29(d,J=12.4Hz,2H); 13 C NMR (100MHz, CDCl3) δ156.6,146.8,146.2,142.3,141.4,139.9,138.4,137.0,136.8, 135.6,134.3,134.0,129.1,128.9(2C),128.6(2C),128.0(1),128.0(3)(2C),127.9(6 ),127.0(2C),126.7,126.2,126.1(2C),123.3,122.9,119.2(2C),66.5,62.3(4),62. 3(1),55.1,52.4,43.8,41.2,37.7,32.3,31.7,29.9,27.1; HRMS(ESI-TOF,m / z):calcd for C 43 H 41 ClN4Na[M+Na] + :671.2912,found:671.2914.

Claims

1. A 2,3-diazabicyclo[3.1.1]heptane derivative, whose molecular structure 1 is as follows: R 1 is hydrogen; a C1-C10 straight or branched alkyl group; a substituted or unsubstituted aryl group; a heterocycle having 1 to 4 nitrogen, oxygen or sulfur atoms; and the group can be further substituted, and the substituent is selected from a hydroxyl group, an amino group, a halogen group, a nitro group (-NO2), a cyano group (-CN) or a C1-C4 alkyl group; R 2 is a C1-C10 straight or branched alkyl group; a substituted or unsubstituted aryl group; a heterocyclic ring having 1 to 4 nitrogen, oxygen or sulfur atoms; R 3 is a C1-C10 straight chain or branched alkyl group; a substituted or unsubstituted aryl group; an acyl group or a sulfonyl group; R 4 is a C1-C10 straight or branched alkyl group; a substituted or unsubstituted aryl group; a heterocycle having 1 to 4 nitrogen, oxygen or sulfur atoms; and a functional group selected from trifluoromethyl and nitro.

2. A method for synthesizing the 2,3-diazabicyclo[3.1.1]heptane derivative according to claim 1, characterized in that: Using bicyclo[1.1.0]butane 2 as a raw material, Lewis acid as a catalyst, hydrazone 3 as a ternary synthon, adding a solvent, and undergoing a cycloaddition reaction at room temperature to generate the 2,3-diazabicyclo[3.1.1]heptane 1; The molecular structure of bicyclo[1.1.0]butane 2 is as follows, The molecular structure of hydrazone 3 is as follows, The synthetic route is shown in the following reaction formula:

3. The synthesis method according to claim 2, characterized in that: The catalyst is one of Lu(OTf)3, Eu(OTf)3, Ga(OTf)3 or In(OTf)3, the molar ratio of bicyclo[1.1.0]butane 2 and hydrazone 3 is 5:1-1:5; the molar ratio of bicyclo[1.1.0]butane 2 and the catalyst is 1:0.01-1:0.

5.

4. The synthesis method according to claim 3, characterized in that: The solvent is one or more of 1,4-dioxane, dimethyl sulfoxide, acetonitrile, toluene, methanol, N,N-dimethylformamide or tetrahydrofuran; the reaction temperature is 25-130° C.; and the reaction time is 0.5-24 hours.

5. The synthesis method according to claim 3, characterized in that: The catalyst is In(OTf)3, and the molar ratio of bicyclo[1.1.0]butane 2 to In(OTf)3 is 13:

1.

6. The synthesis method according to claim 4, characterized in that: The solvent is tetrahydrofuran.

7. The synthesis method according to claim 4, characterized in that: The reaction time is 12 hours.

8. The synthesis method according to claim 4, characterized in that: The reaction temperature was 25°C.

9. The synthesis method according to claim 3, characterized in that: The molar ratio of the bicyclo[1.1.0]butane 2 to the hydrazone 3 is 1.3:1.

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