A pyrrolidinone dihydroisoxazole compound, a preparation method and application thereof

Abstract

The application provides a pyrrolidinone dihydroisoxazole compound and a preparation method and application thereof, and belongs to the technical field of organic synthesis. Specifically, under the catalysis of a Lewis base, a pyrrolidinone dihydroisoxazole compound is synthesized from a beta-oxoacrylamide and 4-nitroisoxazole as raw materials by a one-step method. The pyrrolidinone dihydroisoxazole compound is synthesized by adopting the simple and easily obtained beta-oxoacrylamide and 4-nitroisoxazole as starting raw materials, and undergoing a de-arrangement [3+2]-cycloaddition reaction under the catalysis of a Lewis base. The method has the advantages of simple operation, mild reaction condition, economic and easily obtained reagents and raw materials, high yield of the target product, wide substrate application range, and good in-vitro anti-tumor activity.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a pyrrolidinone dihydroisoxazole compound and a preparation method and application thereof. BACKGROUND

[0002] Dihydroisoxazole is an important five-membered heterocyclic compound, which widely exists in natural products and drug molecular structures. It is often used as a pharmacophore to enhance molecular stability, improve solubility or participate in target hydrogen bond interactions, and has various biological activities and pharmacological activities such as antibacterial, antitumor, antimalarial, analgesic and antiamebic activities. In addition, pyrrolidinone is also an important functional module, which widely exists in drug molecules, bioactive molecules and functional materials. For example, phenylpiracetam and piracetam are antidepressants for improving brain function, and are used for treating sequelae of cerebrovascular diseases and Alzheimer's disease; Fenofibrate is a dual inhibitor of cyclooxygenase and lipoxygenase, and is an organic compound mainly used as a developing agent; Doxapram is a central nervous stimulant used for treating acute respiratory depression; Levetiracetam is a new type of antiepileptic drug, mainly used for treating partial seizures and generalized seizures. Therefore, developing an efficient synthesis strategy of pyrrolidinone dihydroisoxazole hybrid skeleton will provide key technical support for drug research and development.

[0003] Caramella's group reported an alkaline-mediated [3+2] cycloaddition reaction of five-membered cyclic α,β-unsaturated amides and nitriles, and synthesized a series of pyrrolidinone dihydroisoxazole compounds with moderate regioselectivity (Tetrahedron 1999, 55, 7027-7044). Zhang's group reported an asymmetric [3+2] cycloaddition reaction of 4-ester-5-aminoisoxazole and quinone imine catalyzed by chiral phosphoric acid, and synthesized a multi-bridged compound containing a pyrrolidinone dihydroisoxazole skeleton through a tandem cyclization / lactamization reaction process with moderate yield and excellent enantioselectivity (Chem. Commun., 2020, 56, 13591-13594). Although some progress has been made in the synthesis of pyrrolidinone dihydroisoxazole compounds, the existing systems still have the problems of poor regioselectivity, use of excessive base, and narrow substrate expansion range.

[0004] Therefore, it is of important application value to further develop an efficient method for synthesizing pyrrolidinone dihydroisoxazole compounds, and it is of great significance to develop an efficient, economical and green synthesis method with a wide substrate expansion range. SUMMARY

[0005] In view of the problems in the prior art, the pyrrolidinone dihydroisoxazole compound and a preparation method and application thereof are provided, wherein a simple and easily available beta-oxoacrylamide and 4-nitroisoxazole are used as starting materials, a de- aromatization [3+2]-cycloaddition reaction occurs under the catalysis of a Lewis base, and the pyrrolidinone dihydroisoxazole compound is synthesized.

[0006] The present application is realized by the following technical solutions:

[0007] The present application provides a pyrrolidinone dihydroisoxazole compound, and the structural formula of the pyrrolidinone dihydroisoxazole compound is as follows:

[0008]

[0009] 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; R 3 is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxy, 3-methylphenyl, 3-methoxyphenyl, 3-chlorophenyl, 2-methylphenyl, 2-bromophenyl, 2-naphthyl, 2-thienyl, cyclohexyl.

[0010] In the present application, the preparation method of the pyrrolidinone dihydroisoxazole compound is also provided, wherein beta-oxoacrylamide and 4-nitroisoxazole are used as raw materials, and the pyrrolidinone dihydroisoxazole compound is synthesized by a one-step method under the catalysis of a Lewis base;

[0011] The structural formula of the beta-oxoacrylamide is as follows: ;

[0012] The structural formula of the 4-nitroisoxazole is as follows: .

[0013] Further, the molar ratio of the beta-oxoacrylamide, 4-nitroisoxazole and Lewis base is 1-1.2:1:0.05-0.2; the Lewis base is one or more of triethylamine, diisopropylethylamine, tributylamine, 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 and sodium carbonate.

[0014] Further, the molar ratio of the beta-oxoacrylamide, 4-nitroisoxazole and Lewis base is 1-1.2:1:0.05-0.2; the Lewis base is one or more of triethylamine, diisopropylethylamine, tributylamine, 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 and sodium carbonate.

[0015] Further, the solvent for synthesizing the pyrrolidinone dihydroisoxazole compound by the one-step method is one of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, acetone, toluene, p-xylene, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate and tert-butyl methyl ether.

[0016] Further, the solvent for synthesizing the pyrrolidinone dihydroisoxazole compound by the one-step method is acetonitrile.

[0017] Further, the reaction temperature for synthesizing the pyrrolidinone dihydroisoxazole compound by the one-step method is 0-40 DEG C, and the stirring reaction time is 8-12 h.

[0018] Further, after the reaction of synthesizing the pyrrolidinone dihydroisoxazole compound by the one-step method is completed, the reaction solution is concentrated under vacuum, and the residue is subjected to silica gel column chromatography to obtain the pyrrolidinone dihydroisoxazole compound.

[0019] Further, the silica gel column chromatography uses a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent.

[0020] In the present application, the pyrrolidinone dihydroisoxazole compound is also provided for use in the preparation of an antitumor drug.

[0021] The present application has the following beneficial effects:

[0022] In the present application, the pyrrolidinone dihydroisoxazole compound is also provided for use in the preparation of an antitumor drug. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 The pyrrolidinone dihydroisoxazole compound 3aa of Example 1 is 1HNMR spectrum;

[0024] Figure 2 HNMR spectrum of pyrrolidinone dihydroisoxazole compound 3aa of Example 1 13 CNMR spectrum;

[0025] Figure 3 CNMR spectrum of pyrrolidinone dihydroisoxazole compound 3ab of Example 2 1 HNMR spectrum;

[0026] Figure 4 HNMR spectrum of pyrrolidinone dihydroisoxazole compound 3ab of Example 2 13 CNMR spectrum;

[0027] Figure 5 CNMR spectrum of pyrrolidinone dihydroisoxazole compound 3ac of Example 3 1 HNMR spectrum;

[0028] Figure 6 HNMR spectrum of pyrrolidinone dihydroisoxazole compound 3ac of Example 3 13 CNMR spectrum;

[0029] Figure 7 CNMR spectrum of pyrrolidinone dihydroisoxazole compound 3ad of Example 4 1 HNMR spectrum;

[0030] Figure 8 HNMR spectrum of pyrrolidinone dihydroisoxazole compound 3ad of Example 4 13 CNMR spectrum;

[0031] Figure 9 CNMR spectrum of pyrrolidinone dihydroisoxazole compound 3ae of Example 5 1 HNMR spectrum;

[0032] Figure 10 HNMR spectrum of pyrrolidinone dihydroisoxazole compound 3ae of Example 5 13 CNMR spectrum;

[0033] Figure 11 CNMR spectrum of pyrrolidinone dihydroisoxazole compound 3ba of Example 6 1 HNMR spectrum;

[0034] Figure 12 HNMR spectrum of pyrrolidinone dihydroisoxazole compound 3ba of Example 6 13 CNMR spectrum;

[0035] Figure 13 CNMR spectrum of pyrrolidinone dihydroisoxazole compound 3ca of Example 7 1 HNMR spectrum;

[0036] Figure 14 For example 7, pyrrolidone and dihydroisoxazole compound 3ca 13 CNMR spectrum;

[0037] Figure 15 For example 8, pyrrolidone and dihydroisoxazole compound 3da 1 HNMR spectrum;

[0038] Figure 16 For example 8, pyrrolidone and dihydroisoxazole compound 3da 13 CNMR spectrum;

[0039] Figure 17 For example 9, pyrrolidone and dihydroisoxazole compounds 3ea 1 HNMR spectrum;

[0040] Figure 18 For example 9, pyrrolidone and dihydroisoxazole compounds 3ea 13 CNMR spectrum;

[0041] Figure 19 For example 10, pyrrolidone and dihydroisoxazole compound 3fa 1 HNMR spectrum;

[0042] Figure 20 For example 10, pyrrolidone and dihydroisoxazole compound 3fa 13 CNMR spectrum;

[0043] Figure 21 For example 11, pyrrolidone and dihydroisoxazole compound 3ga 1 HNMR spectrum;

[0044] Figure 22 For example 11, pyrrolidone and dihydroisoxazole compound 3ga 13 CNMR spectrum;

[0045] Figure 23 For example 12, pyrrolidone and dihydroisoxazole compound 3ha 1 HNMR spectrum;

[0046] Figure 24 For example 12, pyrrolidone and dihydroisoxazole compound 3ha 13 CNMR spectrum;

[0047] Figure 25 For example 13, pyrrolidone and dihydroisoxazole compound 3ia 1 HNMR spectrum;

[0048] Figure 26 HNMR and 13 CNMR spectra of the pyrrolidinone dihydroisoxazole compound 3ia for Example 13 are shown in

[0049] Figure 27 HNMR and 1 CNMR spectra of the pyrrolidinone dihydroisoxazole compound 3ia for Example 13 are shown in

[0050] Figure 28 HNMR and 13 CNMR spectra of the pyrrolidinone dihydroisoxazole compound 3ia for Example 13 are shown in DETAILED DESCRIPTION

[0051] The technical solutions of the present application will be described clearly and completely below in conjunction with the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative effort belong to the scope of protection of the present application.

[0052] Example 1

[0053] β-(4-methylbenzoyl)-N-methoxyacrylamide 1a (26.3 mg, 0.12 mmol, 1.2 equiv.) and 3-phenyl-4-nitroisoxazole 2a (19.0 mg, 0.1 mmol, 1.0 equiv.) were added into a 10 mL reaction tube, 1 mL dry acetonitrile (0.1 M) was added, and the mixture was stirred at room temperature until the solid was completely dissolved; then triethylamine (1.01 mg, 0.01 mmol, 0.1 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 10 h. After the reaction was completed, the acetonitrile was removed under reduced pressure, and then column chromatography (200 mesh silica gel column chromatography) separation was performed (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as eluent) to obtain the product pyrrolidinone dihydroisoxazole compound 3aa, white solid, separation yield 32.7 mg, yield 80%, 3aa 1 HNMR and 13 CNMR spectra of the pyrrolidinone dihydroisoxazole compound 3ia for Example 13 are shown in Figure 1 and Figure 2 ; 1 H NMR (500 MHz, CDCl3) δ 7.93 –7.85 (m, 2H), 7.82 (d, J = 7.9 Hz, 2H), 7.71 (d, J = 7.8 Hz, 0.2H), 7.62 – 7.58(m, 0.2H), 7.48 (dt,J = 14.4, 7.0 Hz, 3H), 7.39 (q, J = 5.2, 4.1 Hz, 0.3H), 7.24(s, 2H), 7.18 (d, J = 7.8 Hz, 0.2H), 6.99 (s, 1H), 4.29 (dd, J = 18.7, 4.4 Hz,1H), 4.17 (s, 0.3H), 4.12 (d, J = 4.6 Hz, 0.1H), 4.00 (s, 3H), 3.93 (dd, J =18.6, 4.1 Hz, 1H), 3.80 – 3.75 (m, 0.1H), 3.67 – 3.61 (m, 0.1H), 3.53 (t, J =4.2 Hz, 1H), 2.40 (s, 3H), 2.35 (s, 0.3H); 13 C NMR (126 MHz, CDCl3) δ 197.26,166.14, 154.98, 145.44, 132.65, 131.75, 129.49, 129.38, 128.47, 127.66,124.81, 97.79, 96.78, 64.73, 41.15, 37.61, 21.76; HRMS (ESI) m / z [M+Na] + calcdfor C 21 H 19 N3O6Na: 432.1172, Found: 432.1175; 3aa structural formula is shown below:

[0054] .

[0055] Example 2

[0056] β-(4-Methylbenzoyl)-N-methoxyacrylamide 1a (26.3 mg, 0.12 mmol, 1.2 equiv.) and 3-(4-methylphenyl)-4-nitroisoxazole 2b (20.4 mg, 0.1 mmol, 1.0 equiv.) were added into a 10 mL reaction tube, 1 mL dry acetonitrile (0.1 M) was added, and the mixture was stirred at room temperature until the solid was completely dissolved; then triethylamine (1.01 mg, 0.01 mmol, 0.1 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 11 h; after the reaction was completed, the acetonitrile was removed under reduced pressure, and then column chromatography (200 mesh silica gel column chromatography) was performed (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 as eluent) to separate the product pyrrolidone and dihydroisoxazole compound 3ab, white solid, separation yield 33.0 mg, yield 78%, 3ab 1 HNMR and 13 CNMR spectra are shown in Figure 3 and Figure 4 , respectively; 1 H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 7.9 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.26 (dd, J = 14.2, 8.1 Hz, 4H), 6.97 (s, 1H), 4.28 (dd, J = 18.7, 4.4 Hz, 1H), 4.00 (s, 3H), 3.92(dd, J = 18.7, 4.1 Hz, 1H), 3.52 (t, J = 4.2 Hz, 1H), 2.39 (d, J = 2.3 Hz, 6H) ; 13 CNMR (126 MHz, CDCl3) δ 197.22, 166.16, 154.98, 145.40, 142.41, 132.69,130.08, 129.48, 128.46, 127.58, 121.90, 97.87, 96.66, 64.74, 41.20, 37.58,21.76, 21.52;HRMS (ESI) m / z [M+Na] + calcd for C 22 H 21 N3O6Na: 446.1328, Found:446.1330;3ab structure is shown below:

[0057] .

[0058] Example 3

[0059] β-(4-Methylbenzoyl)-N-methoxyacrylamide 1a (26.3 mg, 0.12 mmol, 1.2 equiv.) and 3-(4-chlorophenyl)-4-nitroisoxazole 2c (22.5 mg, 0.1 mmol, 1.0 equiv.) were added into a 10 mL reaction tube, 1 mL dry acetonitrile (0.1 M) was added, and the mixture was stirred at room temperature until the solid was completely dissolved; then triethylamine (1.01 mg, 0.01 mmol, 0.1 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 9 h; after the reaction was completed, the acetonitrile was removed under reduced pressure, and then column chromatography (200 mesh silica gel column chromatography) was performed (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 as eluent) to separate the product pyrrolidinone and dihydroisoxazole compound 3ac, white solid, separation yield 36.8 mg, yield 83%, 3ac 1 HNMR and 13 CNMR spectra are shown in Figure 5 and Figure 6 , respectively; 1 H NMR (500 MHz, CDCl3) δ 7.82 –7.75 (m, 2H), 7.76 – 7.71 (m, 2H), 7.66 – 7.61 (m, 0.33H), 7.48 – 7.44 (m,0.31H), 7.42 – 7.35 (m, 2H), 7.30 – 7.25 (m, 0.31H), 7.18 (d, J = 8.3 Hz, 2H),7.14 – 7.10 (m, 0.32H), 6.89 (s, 1H), 4.14 (dd, J = 18.6, 4.3 Hz, 1H), 4.08 (s,0.45H), 4.06 – 4.04 (m, 0.18H), 3.92 (s, 3H), 3.86 (dd, J = 18.7, 4.5 Hz, 1H),3.65 (dd, J = 18.1, 3.9 Hz, 0.16H), 3.54 (dd, J = 18.1, 5.5 Hz, 0.17H), 3.41 (t, J= 4.4 Hz, 1H), 2.33 (s, 3H), 2.29 (s, 0.45H); 13 C NMR (126 MHz, CDCl3) δ195.95, 193.97, 166.76, 164.88, 156.72, 153.18, 144.50, 143.81, 137.07,135.56, 132.15, 131.55, 128.66, 128.48, 128.40, 128.29, 127.99, 127.65,127.43, 127.15, 125.33, 122.29, 96.61, 95.76, 91.70, 64.59, 63.78, 40.09,38.31, 37.05, 36.61, 20.74, 20.63; HRMS (ESI) m / z [M+Na] + calcd forC 21 H 18 N3O6NaCl: 466.0782, Found: 466.0786; 3ac structural formula is shown below:

[0060] .

[0061] Example 4

[0062] β-(4-methylbenzoyl)-N-methoxyacrylamide 1a (26.3 mg, 0.12 mmol, 1.2 equiv.) and 3-(4-trifluoromethylphenyl)-4-nitroisoxazole 2d (25.8 mg, 0.1 mmol, 1.0 equiv.) were added to a 10 mL reaction tube, followed by 1 mL of dry acetonitrile (0.1 M). The mixture was stirred at room temperature until the solid was completely dissolved. Triethylamine (1.01 mg, 0.01 mmol, 0.1 equiv.) was then added to the reaction mixture, and the mixture was stirred at room temperature for 10 h. After the reaction was complete, the acetonitrile was removed under reduced pressure, and the product was separated by column chromatography (200 mesh silica gel column chromatography) using a 5:1 mixture of petroleum ether and ethyl acetate as the eluent to obtain the product pyrrolidone dihydroisoxazole compound 3ad, a white solid with a yield of 28.6 mg (60%). 1 HNMR and 13 CNMR spectra are as follows: Figure 7 and Figure 8 As shown; 1 H NMR (500 MHz, CDCl3) δ 8.08 (d, J= 8.3 Hz, 2H), 7.85 – 7.79 (m, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 6.99 (s, 1H), 4.22 (dd, J = 18.6, 4.3 Hz, 1H), 4.00 (s,3H), 3.95 (dd, J = 18.7, 4.8 Hz, 1H), 3.51 (t, J = 4.5 Hz, 1H), 2.41 (s, 3H); 13 CNMR (126 MHz, CDCl3) δ 196.93, 165.84, 154.09, 145.61, 133.24 (q, J = 33.0 Hz),132.54, 129.54, 128.47, 128.40, 128.20, 123.48 (q, J = 272.7 Hz), 126.27 (q, J =3.8 Hz), 97.52, 96.98, 64.84, 41.10, 37.68, 21.75; HRMS (ESI) m / z [M+Na] + calcdfor C 22 H 18 F3N3O6Na: 500.1045, Found: 500.1047; The structural formula of 3ad is shown below:

[0063] .

[0064] Example 5

[0065] β-(4-methylbenzoyl)-N-methoxyacrylamide 1a (26.3 mg, 0.12 mmol, 1.2 equiv.) and 3-(3-chlorophenyl)-4-nitroisoxazole 2e (22.5 mg, 0.1 mmol, 1.0 equiv.) were added into a 10 mL reaction tube, 1 mL dry acetonitrile (0.1 M) was added, and the mixture was stirred at room temperature until the solid was completely dissolved; then triethylamine (1.01 mg, 0.01 mmol, 0.1 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 12 h; after the reaction was completed, the acetonitrile was removed under reduced pressure, and then column chromatography (200 mesh silica gel column chromatography) was performed (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 as eluent) to obtain the product pyrrolidone and dihydroisoxazole compound 3ae, white solid, separation yield 33.2 mg, yield 75%, 3ae 1 HNMR and 13 CNMR spectra are shown in Figure 9 and Figure 10 , respectively; 1 H NMR (500 MHz, CDCl3) δ 7.94(t, J = 1.9 Hz, 1H), 7.85 – 7.80 (m, 2H), 7.79 (dt, J = 7.8, 1.4 Hz, 1H), 7.50(ddd, J = 8.1, 2.1, 1.1 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.28 (s, 2H), 6.98 (s,1H), 4.23 (dd, J = 18.7, 4.3 Hz, 1H), 4.00 (s, 3H), 3.95 (dd, J = 18.6, 4.5 Hz,1H), 3.49 (t, J = 4.3 Hz, 1H), 2.42 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 196.98,165.93, 154.04, 145.55, 135.53, 132.58, 131.78, 130.58, 129.52, 128.49,127.81, 126.62, 125.71, 97.47, 96.95, 64.87, 41.08, 37.65, 21.79;HRMS (ESI)m / z [M+Na] + calcd for C21 H 18 N3O6NaCl: 466.0782, Found: 466.0786;3ae structural formula is shown below:

[0066] .

[0067] Example 6

[0068] β-(4-Methylbenzoyl)-N-benzyloxyacrylamide 1b (35.4 mg, 0.12 mmol, 1.2 equiv.) and 3-phenyl-4-nitroisoxazole 2a (19.0 mg, 0.1 mmol, 1.0 equiv.) were added into a 10 mL reaction tube, 1 mL dry acetonitrile (0.1 M) was added, and the mixture was stirred at room temperature until the solid was completely dissolved; then triethylamine (1.01 mg, 0.01 mmol, 0.1 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 9 h; after the reaction was completed, the acetonitrile was removed under reduced pressure, and then column chromatography (200 mesh silica gel column chromatography) was performed (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 as eluent) to separate the product pyrrolidinone and dihydroisoxazole compound 3ba, white solid, separation yield 38.8 mg, yield 80%, 3ba 1 HNMR and 13 CNMR spectra are shown in Figure 11 and Figure 12 ; 1 H NMR (500 MHz, CDCl3) δ 7.81– 7.76 (m, 2H), 7.72 – 7.67 (m, 2H), 7.43 – 7.34 (m, 5H), 7.30 – 7.24 (m,3H), 7.14 (d, J = 1.2 Hz, 2H), 6.88 (s, 1H), 5.11 – 5.04 (m, 2H), 4.13 (dd, J =18.7, 4.4 Hz, 1H), 3.80 (dd, J = 18.7, 4.4 Hz, 1H), 3.40 (t, J = 4.3 Hz, 1H),2.28 (s, 3H) ; 13C NMR (126 MHz, CDCl3) δ 197.12, 166.28, 155.15, 145.41,134.16, 132.70, 131.76, 129.85, 129.50, 129.39, 129.18, 128.55, 128.48,127.76, 124.91, 97.79, 97.19, 79.42, 41.15, 37.67, 21.79; HRMS (ESI) m / z [M+Na] + calcd for C 27 H 23 N3O6Na: 508.1485, Found: 508.1488; the structure of 3ba is shown below:

[0069] .

[0070] Example 7

[0071] β-(4-Methoxybenzoyl)-N-benzyloxyacrylamide 1c (37.3 mg, 0.12 mmol, 1.2 equiv.) and 3-phenyl-4-nitroisoxazole 2a (19.0 mg, 0.1 mmol, 1.0 equiv.) were added into a 10 mL reaction tube, 1 mL dry acetonitrile (0.1 M) was added, and the mixture was stirred at room temperature until the solid was completely dissolved; then triethylamine (1.01 mg, 0.01 mmol, 0.1 equiv.) was added into the reaction system, and the mixture was stirred at room temperature for 10 h; after the reaction was completed, the acetonitrile was removed under reduced pressure, and then column chromatography (200 mesh silica gel column chromatography) was performed (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 as the eluent) to separate the product pyrrolidinone and dihydroisoxazole compound 3ca, which was a white solid, and the isolated yield was 32.6 mg, and the yield was 65%, and the 1 HNMR and 13 CNMR spectra of 3ca are shown in Figure 13 and Figure 14 , respectively; 1H NMR (500 MHz, CDCl3) δ 7.95– 7.84 (m, 4H), 7.86 – 7.70 (m, 0.4H), 7.60 – 7.54 (m, 0.5H), 7.54 – 7.44 (m,5H), 7.40 – 7.34 (m, 3.3H), 6.99 (s, 1H), 6.92 – 6.87 (m, 2H), 6.86 – 6.82(m, 0.2H), 5.33 – 5.30 (m, 0.2H), 5.22 – 5.13 (m, 2H), 4.22 (dd, J = 18.6, 4.4Hz, 1H), 4.11 (dd, J = 5.1, 4.1 Hz, 0.1H), 3.88 (dd, J = 18.5, 4.3 Hz, 1.12H), 3.83 (s, 3H), 3.80 (s, 0.3H), 3.56 (dd, J = 18.0, 5.2 Hz, 0.1H), 3.48 (t, J = 4.3Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ 195.72, 193.91, 167.98, 166.37, 164.44,163.94, 158.55, 155.12, 134.15, 134.09, 131.74, 130.76, 130.46, 129.84,129.39, 129.16, 129.04, 128.69, 128.53, 128.17, 127.73, 127.38, 124.91,113.99, 113.87, 113.84, 97.76, 97.26, 92.82, 79.91, 79.43, 55.60, 55.53,41.17, 39.47, 37.83, 37.39; HRMS (ESI) m / z [M+Na] + calcd for C 27 H 23 N3O7Na: 524.1434, Found: 524.1436; The structural formula of 3ca is shown below:

[0072] .

[0073] Example 8

[0074] To a 10 mL reaction vial was added β-(4-fluorobenzoyl)-N-benzyloxyacrylamide 1d (35.9 mg, 0.12 mmol, 1.2 equiv.) and 3-phenyl-4-nitroisoxazole 2a (19.0 mg, 0.1 mmol, 1.0 equiv.) and 1 mL of dry acetonitrile (0.1 M) was added and stirred at room temperature until the solids were completely dissolved; then triethylamine (1.01 mg, 0.01 mmol, 0.1 equiv.) was added to the reaction and stirred at room temperature for 10 h; upon completion of the reaction, the acetonitrile was removed under reduced pressure and then column chromatography (200 mesh silica gel column chromatography) was performed using a mixture of petroleum ether and ethyl acetate (5:1 by volume) as the eluent to isolate the product pyrrolidinone and dihydroisoxazole compound 3da as a white solid with an isolated yield of 35.7 mg, 73% yield, 3da 1 HNMR and 13 CNMR spectra are shown in Figures Figure 15 and Figure 16 respectively; 1 H NMR (500 MHz, CDCl3) δ 7.90 – 7.82 (m,2H), 7.79 (dt, J = 6.9, 1.6 Hz, 2H), 7.49 – 7.36 (m, 5H), 7.34 – 7.26 (m, 3H),7.03 (t, J = 8.6 Hz, 2H), 6.88 (s, 1H), 5.09 (d, J = 2.0 Hz, 2H), 4.15 (dd, J =18.6, 4.4 Hz, 1H), 3.81 (dd, J = 18.6, 4.3 Hz, 1H), 3.42 (t, J = 4.3 Hz, 1H) ; 13 CNMR (126 MHz, CDCl3) δ 194.88, 165.38 (d, J = 256.9 Hz), 165.06, 153.97,132.97, 130.74, 130.47 (d, J = 3.0 Hz), 130.08 (d, J = 9.7 Hz), 128.79, 128.35,128.15, 127.48, 126.63, 123.76, 115.00 (d, J= 22.0 Hz), 96.58, 96.14, 78.49,39.97, 36.61; HRMS (ESI) m / z [M+Na] + calcd for C 26 H 20 FN3O6Na: 512.1234, Found: 512.1236; The structural formula of 3da is shown below:

[0075] .

[0076] Example 9

[0077] β-(4-chlorobenzoyl)-N-benzyloxyacrylamide 1e (35.9 mg, 0.12 mmol, 1.2 equiv.) and 3-phenyl-4-nitroisoxazole 2a (19.0 mg, 0.1 mmol, 1.0 equiv.) were added to a 10 mL reaction tube, followed by 1 mL of dry acetonitrile (0.1 M). The mixture was stirred at room temperature until the solid was completely dissolved. Triethylamine (1.01 mg, 0.01 mmol, 0.1 equiv.) was then added to the reaction mixture, and the mixture was stirred at room temperature for 11 h. After the reaction was complete, the acetonitrile was removed under reduced pressure, and the product was separated by column chromatography (200 mesh silica gel column chromatography) using a 5:1 mixture of petroleum ether and ethyl acetate as the eluent to obtain the product pyrrolidone dihydroisoxazole compound 3ea, a white solid with a yield of 38.4 mg and a yield of 76%. 1 HNMR and 13 CNMR spectra are as follows: Figure 17 and Figure 18 As shown; 1 H NMR (500 MHz, CDCl3) δ 7.80 – 7.75 (m,2H), 7.76 – 7.71 (m, 2H), 7.44 – 7.35 (m, 5H), 7.33 – 7.25 (m, 5H), 6.86 (s,1H), 5.08 (d, J = 2.2 Hz, 2H), 4.12 (dd, J = 18.7, 4.4 Hz, 1H), 3.79 (dd, J = 18.7, 4.4 Hz, 1H), 3.41 (t, J = 4.3 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 196.48,166.08, 155.04, 140.94, 134.03, 133.36, 131.83, 129.87, 129.76, 129.43,129.24, 129.20, 128.57, 127.71, 124.80, 97.66, 97.18, 79.57, 41.01, 37.77; HRMS (ESI) m / z [M+Na] + calcd for C 26 H 20 N3O6NaCl: 528.0938, Found: 528.0940; The structure of 3ea is shown below:

[0078] .

[0079] Example 10

[0080] β-(4-Bromobenzoyl)-N-benzyloxyacrylamide If (35.9 mg, 0.12 mmol, 1.2 equiv.) and 3-phenyl-4-nitroisoxazole 2a (19.0 mg, 0.1 mmol, 1.0 equiv.) were added into a 10 mL reaction tube, 1 mL dry acetonitrile (0.1 M) was added, and the mixture was stirred at room temperature until the solid was completely dissolved. Then triethylamine (1.01 mg, 0.01 mmol, 0.1 equiv.) was added into the reaction system, and the mixture was stirred at room temperature for 10 h. After the reaction was completed, the acetonitrile was removed under reduced pressure, and then column chromatography (200 mesh silica gel column chromatography) was performed (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent) to separate the product pyrrolidinone and dihydroisoxazole compound 3fa, which was a white solid, with an isolated yield of 37.3 mg and a yield of 68%. The 1 HNMR and 13 CNMR spectra of 3fa are shown in Figure 19 and Figure 20 ; 1 H NMR (500 MHz, CDCl3) δ 7.83 – 7.77 (m,2H), 7.73 – 7.67 (m, 2H), 7.56 – 7.51 (m, 2H), 7.48 – 7.41 (m, 5H), 7.31 (dd, J = 6.7, 4.6 Hz, 3H), 6.87 (s, 1H), 5.10 (d, J = 1.7 Hz, 2H), 4.15 (dd, J= 18.7, 4.4 Hz, 1H), 3.80 (dd, J = 18.7, 4.4 Hz, 1H), 3.43 (t, J = 4.3 Hz, 1H) ; 13 C NMR (126 MHz, CDCl3) δ 195.54, 164.98, 153.96, 132.95, 132.71, 131.16, 130.76, 128.81, 128.73, 128.37, 128.17, 127.49, 126.65, 123.76, 96.53, 96.13, 78.54, 39.93, 36.68; HRMS (ESI) m / z [M+Na] + calcd for C 26 H 20 BrO6N3Na: 572.0433, Found:572.0437; 3fa structural formula is shown below:

[0081] .

[0082] Example 11

[0083] β-(3-Chlorobenzoyl)-N-benzyloxyacrylamide 1g (35.9 mg, 0.12 mmol, 1.2 equiv.) and 3-phenyl-4-nitroisoxazole 2a (19.0 mg, 0.1 mmol, 1.0 equiv.) were added into a 10 mL reaction tube, 1 mL dry acetonitrile (0.1 M) was added, and the mixture was stirred at room temperature until the solid was completely dissolved; then triethylamine (1.01 mg, 0.01 mmol, 0.1 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 10 h; after the reaction was completed, the acetonitrile was removed under reduced pressure, and then column chromatography (200 mesh silica gel column chromatography) was performed (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 as eluent) to separate the product pyrrolidinone and dihydroisoxazole compound 3ga, white solid, separation yield 35.4 mg, yield 70%, 3ga 1 HNMR and 13 CNMR spectra are shown in Figure 21 and Figure 22 ; 1 H NMR (500 MHz, CDCl3) δ 7.78 (dt, J =6.8, 1.7 Hz, 3H), 7.69 (dt, J = 7.8, 1.3 Hz, 1H), 7.46 (ddd,J = 8.0, 2.2, 1.1Hz, 1H), 7.45 – 7.37 (m, 5H), 7.33 – 7.27 (m, 4H), 6.86 (s, 1H), 5.12 – 5.04(m, 2H), 4.14 (dd, J = 18.8, 4.4 Hz, 1H), 3.80 (dd, J = 18.8, 4.4 Hz, 1H), 3.42(t, J = 4.3 Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ 196.51, 165.95, 155.01, 136.48,135.20, 134.28, 134.01, 131.84, 130.22, 129.86, 129.44, 129.24, 128.56,128.46, 127.71, 126.44, 124.79, 97.61, 97.13, 79.54, 40.98, 37.91; HRMS (ESI)m / z [M+Na] + calcd for C 26 H 20 N3O6NaCl: 528.0938, Found: 528.0940; The structural formula of 3ga is shown below:

[0084] .

[0085] Example 12

[0086] β-(2-methylbenzoyl)-N-benzyloxyacrylamide 1h (35.9 mg, 0.12 mmol, 1.2 equiv.) and 3-phenyl-4-nitroisoxazole 2a (19.0 mg, 0.1 mmol, 1.0 equiv.) were added to a 10 mL reaction tube, followed by 1 mL of dry acetonitrile (0.1 M). The mixture was stirred at room temperature until the solid was completely dissolved. Triethylamine (1.01 mg, 0.01 mmol, 0.1 equiv.) was then added to the reaction mixture, and the mixture was stirred at room temperature for 13 h. After the reaction was complete, the acetonitrile was removed under reduced pressure, and the product was separated by column chromatography (200 mesh silica gel column chromatography) using a 5:1 mixture of petroleum ether and ethyl acetate as the eluent. The product, pyrrolidone dihydroisoxazole compound 3ha, was obtained as a white solid with a yield of 29.1 mg and a yield of 60%. 1 HNMR and 13 CNMR spectra are as follows:Figure 23 and Figure 24 as shown; 1 H NMR (500 MHz, CDCl3) δ 7.82– 7.77 (m, 2H), 7.64 (dd, J = 7.9, 1.4 Hz, 1H), 7.45 – 7.36 (m, 5H), 7.33 –7.26 (m, 4H), 7.18 (td, J = 7.7, 1.3 Hz, 1H), 7.16 – 7.12 (m, 1H), 6.91 (s,1H), 5.15 – 5.05 (m, 2H), 4.09 (dd, J = 18.7, 4.4 Hz, 1H), 3.82 (dd, J = 18.7,4.3 Hz, 1H), 3.39 (t, J = 4.3 Hz, 1H), 2.32 (s, 3H) ; 13 C NMR (126 MHz, CDCl3) δ200.89, 166.27, 155.04, 139.53, 135.10, 134.12, 132.69, 132.38, 131.76,129.87, 129.40, 129.25, 129.21, 128.56, 127.73, 125.89, 124.88, 97.79, 97.19,79.43, 41.33, 40.09, 21.54;HRMS (ESI) m / z [M+Na] + calcd for C 27 H 23 N3O6Na:508.1485, Found: 508.1487;3ha structural formula is shown below:

[0087] .

[0088] Example 13

[0089] β-(2-bromobenzoyl)-N-benzyloxyacrylamide 1i (35.9 mg, 0.12 mmol, 1.2 equiv.) and 3-phenyl-4-nitroisoxazole 2a (19.0 mg, 0.1 mmol, 1.0 equiv.) were added into a 10 mL reaction tube, 1 mL dry acetonitrile (0.1 M) was added, and the mixture was stirred at room temperature until the solid was completely dissolved; then triethylamine (1.01 mg, 0.01 mmol, 0.1 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 12 h; after the reaction was completed, the acetonitrile was removed under reduced pressure, and then column chromatography (200 mesh silica gel column chromatography) was performed (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 as eluent) to separate the product pyrrolidone and dihydroisoxazole compound 3ia, white solid, separation yield 41.2 mg, yield 75%, 3ia 1 HNMR and 13 CNMR spectra are shown in Figure 25 and Figure 26 , respectively; 1 H NMR (500 MHz, CDCl3) δ 7.83 – 7.75 (m,2H), 7.54 (dd, J = 7.8, 1.3 Hz, 1H), 7.47 – 7.36 (m, 6H), 7.33 – 7.23 (m, 5H),6.84 (s, 1H), 5.14 – 5.06 (m, 2H), 4.08 (dd, J = 19.2, 4.4 Hz, 1H), 3.88 (dd, J =19.2, 4.5 Hz, 1H), 3.43 (t, J = 4.5 Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ 199.75,164.54, 153.95, 137.50, 133.22, 132.94, 131.84, 130.74, 128.80, 128.44,128.35, 128.16, 127.49, 126.69, 126.54, 123.71, 118.35, 96.52, 95.75, 78.33,40.17, 40.11;HRMS (ESI) m / z [M+Na] + calcd for C 26 H 20 BrO6N3Na: 572.0433, Found:572.0437;3ia structure is shown below:

[0090] .

[0091] Example 14

[0092] β-(4-Methylbenzoyl)-N-allyloxypropenamide 1j (29.4 mg, 0.12 mmol, 1.2 equiv.) and 3-phenyl-4-nitroisoxazole 2a (19.0 mg, 0.1 mmol, 1.0 equiv.) were added into a 10 mL reaction tube, 1 mL dry acetonitrile (0.1 M) was added, and the mixture was stirred at room temperature until the solid was completely dissolved; then triethylamine (1.01 mg, 0.01 mmol, 0.1 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 10 h; after the reaction was completed, the acetonitrile was removed under reduced pressure, and then column chromatography (200 mesh silica gel column chromatography) was performed (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 as eluent) to separate the product pyrrolidinone and dihydroisoxazole compound 3ja, white solid, separation yield 33.1 mg, yield 76%, 3ja 1 HNMR and 13 CNMR spectra are shown in Figure 27 and Figure 28 , respectively; 1 H NMR (500 MHz, CDCl3) δ 7.94– 7.85 (m, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.50 (ddd, J = 14.5, 7.9, 6.2 Hz, 3H),7.26 (d, J = 8.1 Hz, 2H), 6.98 (s, 1H), 6.07 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H),5.41 (dd, J = 17.3, 1.7 Hz, 1H), 5.34 (dd, J = 10.2, 1.5 Hz, 1H), 4.67 (d, J = 6.6Hz, 2H), 4.25 (dd, J = 18.6, 4.4 Hz, 1H), 3.92 (dd, J = 18.6, 4.4 Hz, 1H), 3.52(t, J = 4.3 Hz, 1H), 2.41 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 197.02, 166.46,155.18, 145.40, 132.70, 131.71, 131.52, 129.49, 129.37, 128.47, 127.73,124.92, 121.54, 97.64, 97.19, 78.37, 41.12, 37.64, 21.78; HRMS (ESI) m / z [M+Na] + calcd for C 23 H 21 N3O6Na: 458.1328, Found: 458.1329; The structure of 3ja is shown below:

[0093] .

[0094] Application Example: Anti-tumor activity test

[0095] Human non-small cell lung cancer cell line (A549) was selected as the research object (Table 1), and the in vitro anti-tumor activity of pyrrolidone dihydroisoxazole compounds was evaluated.

[0096] The counted A549 cell suspension was added dropwise to a 96-well plate, and the plate was seeded at 3000-5000 cells per well, with a liquid volume of 100 μL per well, and placed in a cell culture incubator for culture; different compounds were added to the wells at a final concentration of 2.5 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 incubation was continued for 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 placed on a shaking bed for low-speed shaking for 30 min to fully dissolve the crystals; the absorbance of each well was measured at OD 490 nm on an enzyme-linked immunosorbent assay instrument, and the inhibition rate was calculated, as shown in Table 1 below:

[0097] Table 1 In vitro anti-tumor activity of pyrrolidone dihydroisoxazole compounds (inhibition rate %)

[0098]

[0099] As shown in Table 1, pyrrolidone dihydroisoxazole compounds showed good cytotoxicity to human non-small cell lung cancer cell lines, with a maximum inhibition rate of 83.54% (3ae).

[0100] The above merely provides the preferred embodiments of the present application, and is not used to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the principles and technical scope of the present application shall fall into the scope of the present application.

Claims

1. A pyrrolizine dihydroisoxazole compound, characterized by, The structural formula of the pyrrolidinone dihydroisoxazole 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; R 3 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-bromophenyl, 2-naphthyl, 2-thienyl, cyclohexyl.

2. A process for the preparation of the pyrrolizine compound of claim 1, characterized by, Under the catalysis of a Lewis base, a pyrrolidinone dihydroisoxazole compound is synthesized by a one-step method from a β-oxoacrylamide and 4-nitroisoxazole. The structural formula of the β-oxoacrylamide is: ; The structural formula of the 4-nitroisoxazole is: ; For R 1 , R 2 , R 3 the restrictions are identical to claim 1.

3. The process for the preparation of pyrrolidinonedihydroisoxazoles according to claim 2, characterized in that, The molar ratio of the β-oxoacrylamide, 4-nitroisoxazole and Lewis base is 1-1.2:1:0.05-0.2; the Lewis base is one or more of triethylamine, diisopropylethylamine, tributylamine, 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 and sodium carbonate.

4. The process for the preparation of pyrrolidinonedihydroisoxazoles according to claim 3, characterized in that, The molar ratio of the β-oxoacrylamide, 4-nitroisoxazole and Lewis base is 1.2:1:0.1; the Lewis base is triethylamine.

5. The method for preparing pyrrolidone dihydroisoxazole compounds according to claim 2, characterized in that, The solvent for synthesizing the pyrrolidinone dihydroisoxazole compound by the one-step method is one of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, acetone, toluene, p-xylene, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate and tert-butyl methyl ether.

6. The method for preparing pyrrolidone-dihydroisoxazole compounds according to claim 5, characterized in that, The solvent for synthesizing the pyrrolidinone dihydroisoxazole compound by the one-step method is acetonitrile.

7. The method for preparing pyrrolidone-dihydroisoxazole compounds according to claim 2, characterized in that, The reaction temperature for synthesizing the pyrrolidinone dihydroisoxazole compound by the one-step method is 0-40°C, and the stirring reaction time is 8-12h.

8. The method for preparing pyrrolidone-dihydroisoxazole compounds according to claim 2, characterized in that, After the reaction of synthesizing the pyrrolidinone dihydroisoxazole compound by the one-step method is completed, the reaction solution is vacuum concentrated, and the residue is subjected to silica gel column chromatography to obtain the pyrrolidinone dihydroisoxazole compound.

9. The method for preparing pyrrolidone-dihydroisoxazole compounds according to claim 2, characterized in that, The silica gel column chromatography uses a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 as an eluent.

10. Use of the pyrrolidinone dihydroisoxazole compound of claim 1 in the preparation of an antitumor drug.

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