Hydroxylamine compound containing aryl allyl structure as well as synthesis method and application of hydroxylamine compound

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a hydroxylamine compound containing an aryl allyl structure as well as a synthesis method and application of the hydroxylamine compound. The structure of the hydroxylamine compound is shown as a formula (I), and in the formula (I), R1 is selected from unsubstituted alkyl, cycloalkyl, naphthyl, heteroaryl or substituted or unsubstituted phenyl; r2 is selected from substituted or unsubstituted phenyl; the synthesis method comprises the following steps: by taking nitrone and boric acid as raw materials, efficiently synthesizing through a boron migration reaction under the catalysis of R-1, 1 '-co-2-naphthol. The synthesis method has the characteristics that a metal catalyst is not needed, the operation is simple and convenient, the organic boric acid is easy to obtain and environment-friendly, the reaction condition is mild, the substrate application range is wide, the yield is medium to good and the like, and a new thought is provided for synthesis of the hydroxylamine compound. In-vitro experiments show that the compound has remarkable proliferation inhibition activity on A549, HeLa and MV-411 tumor cells, and has the development potential of antitumor drugs.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, specifically relating to a hydroxylamine compound containing an aryl allyl structure, its synthesis method, and its applications. Background Technology

[0002] Hydroxylamine is an essential backbone in modern organic synthesis. Its N-OH unit provides many unique chemical properties and serves as an attractive metal-binding site in organisms. It is an increasingly common structural element in pharmaceuticals and agrochemicals. Hydroxylamine moieties are found in bioactive natural products and their analogues, such as the anticancer drugs calicamicin and esperamicin, and the potent bacterial tRNA synthetase inhibitor SB-219383. As a versatile synthon, it can be further transformed into numerous bioactive compounds, playing a significant role in drug development.

[0003] Nitrones, N-oxides of imines, are important 1,3-dipolar compounds in organic chemistry due to their N→O polar bond. They are widely used in cycloaddition reactions, reacting with various dipolarophiles such as alkenes, alkynes, and propadiene to construct a series of heterocyclic molecular skeletons. Furthermore, nitrones can undergo nucleophilic addition reactions with organometallic compounds and cyano compounds, making them crucial electrophiles. Compounds containing nitron functional groups are used as spin trapping agents, therapeutic agents, and pharmaceutical intermediates, and are increasingly applied in the synthesis of various natural products.

[0004] Organoboronic acids are readily available and environmentally friendly, and have achieved great success in research areas such as transition metal-catalyzed Suzuki-Miyaura cross-coupling reactions. However, efforts are still being made to advance organoboronic acid reaction types that involve lower-cost metals or even no metals at all. Boron migration reactions have become an important research direction in organic synthesis in recent years, achieving functional group rearrangement and transformation through intramolecular or intermolecular boron atom migration, providing an efficient method for constructing complex chiral molecules. Compared to traditional transition metal-catalyzed boron acid coupling reactions, this boron migration reaction does not require transition metals and has the advantage of being simple to operate. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a hydroxylamine compound containing an aryl allyl structure, the structural formula of which is shown in formula (I): ; In formula (I), R1 is one of substituted or unsubstituted phenyl or unsubstituted alkyl, cycloalkyl, naphthyl, heteroaryl; R2 is substituted or unsubstituted phenyl.

[0006] Further, R1 is one of phenyl, o-methylphenyl, o-methoxyphenyl, o-fluorophenyl, o-chlorophenyl, o-bromophenyl, m-methylphenyl, m-methoxyphenyl, m-fluorophenyl, m-chlorophenyl, p-methylphenyl, p-methoxyphenyl, p-tert-butylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-iodophenyl, p-ethynylphenyl, methyl p-formate phenyl, p-trifluoromethylphenyl, 3,5-dimethylphenyl, 3,4-dimethylphenyl, 3,4-dimethoxyphenyl, 2,6-dichlorophenyl, 2-naphthyl, 2-furanyl, isopropyl, n-propyl, and cyclohexyl; and R2 is one of phenyl, o-methylphenyl, o-fluorophenyl, o-chlorophenyl, m-methylphenyl, m-methoxyphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, methyl p-formate phenyl, and 3,5-dimethoxyphenyl.

[0007] Furthermore, the compound shown in formula (I) is selected from one of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0008] The present invention also provides a method for synthesizing the hydroxylamine compound, the specific steps of which are as follows: Under inert nitrogen gas protection and / or anhydrous and oxygen-free conditions, the raw material nitrone intermediate (II) and boric acid intermediate (III), 4Å molecular sieve, and catalyst R-1,1'-bi-2-naphthol were mixed in organic solvent A and subjected to boron migration reaction at room temperature. After the reaction was completed, the hydroxylamine compound was obtained by separation and purification. The structural formula of nitroketone intermediate (II) is as follows: ; The structural formula of boric acid intermediate (III) is as follows: ; The structural formula of catalyst R-1,1'-bi-2-naphthol is: ; The definitions of R1 and R2 are the same as in equation (I).

[0009] Furthermore, the organic solvent A is selected from one of 1,2-dichloroethane, diethyl ether, 1,4-dioxane, dichloromethane, tetrahydrofuran, methyl tert-butyl ether, toluene, acetonitrile, ethyl acetate, chloroform, chlorobenzene, and carbon tetrachloride (preferably 1,2-dichloroethane).

[0010] Furthermore, the molar ratio of the nitrone intermediate (II) to the boric acid intermediate (III) is 1.0:(3.0-4.5) (preferably 1.0:4.0).

[0011] Furthermore, the amount of catalyst used is 5-50% (preferably 20%) of the molar amount of the nitrone intermediate.

[0012] The present invention also provides the use of the hydroxylamine compound containing the aryl allyl structure in the preparation of antitumor drugs.

[0013] The present invention also provides the application of hydroxylamine compounds containing aryl allyl structures synthesized by the above-described synthesis method in the preparation of antitumor drugs.

[0014] Furthermore, the antitumor drug is a drug that inhibits the growth of human lung cancer cells A549, human cervical cancer cells HeLa, and / or human myeloid monocytic leukemia cells MV-411.

[0015] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows: This invention, based on the synthesis of nitroketones and boric acid, utilizes R-1,1'-bi-2-naphthol as a catalyst to induce a boric acid migration reaction in nitroketones, ultimately generating a class of hydroxylamine compounds containing an aryl allyl structure. This synthetic method is characterized by the absence of metal catalysts, simple operation, readily available and environmentally friendly organoboronic acids, mild reaction conditions, a wide range of applicable substrates, and moderate to good yields, providing a new approach for the synthesis of hydroxylamine compounds. The hydroxylamine compounds containing an aryl allyl structure provided by this invention possess significant anti-tumor cell proliferation biological activity. In vitro cytotoxicity tests on human lung cancer cells A549, human cervical cancer cells HeLa, and human myeloid monocytic leukemia cells MV-411 show that the hydroxylamine compounds containing an aryl allyl structure, as shown in formula (I), have a significant inhibitory effect on tumor cell growth and may be developed into new anti-tumor drugs. Attached Figure Description

[0016] Figure 1 Compound 3ea provided in Example 1 of this application 1 H NMR spectrum; Figure 2 Compound 3ea provided in Example 1 of this application 13 C NMR spectrum; Figure 3 The compound 3fa provided in Example 1 of this application 1 H NMR spectrum; Figure 4 The compound 3fa provided in Example 1 of this application 13 C NMR spectrum; Figure 5 The compound 3ua provided in Example 1 of this application 1 H NMR spectrum; Figure 6 The compound 3ua provided in Example 1 of this application 13 C NMR spectrum; Figure 7 The compound 3ya provided in Example 1 of this application 1 H NMR spectrum; Figure 8 The compound 3ya provided in Example 1 of this application 13 C NMR spectrum; Figure 9 The compound 3zba provided in Example 1 of this application 1 H NMR spectrum; Figure 10 The compound 3zba provided in Example 1 of this application 13 C NMR spectrum; Figure 11 The compound 3zca provided in Example 1 of this application 1 H NMR spectrum; Figure 12 The compound 3zca provided in Example 1 of this application 13 C NMR spectrum; Figure 13 The compound 3ag provided in Example 1 of this application 1 H NMR spectrum; Figure 14 The compound 3ag provided in Example 1 of this application 13 C NMR spectrum; Figure 15 The compound 3ag provided in Example 1 of this application 19 F-NMR spectrum; Figure 16 Compound 3ai provided in Example 1 of this application 1 H NMR spectrum; Figure 17 Compound 3ai provided in Example 1 of this application 13 C NMR spectrum; Figure 18 Compound 3aj provided in Example 1 of this application 1 H NMR spectrum; Figure 19 Compound 3aj provided in Example 1 of this application 13 C NMR spectrum; Figure 20 The compound 3am provided in Example 1 of this application 1 H NMR spectrum; Figure 21 The compound 3am provided in Example 1 of this application 13 C NMR spectrum; Figure 22 The compound 3ao provided in Example 1 of this application 1 H NMR spectrum; Figure 23 Compound 3ao provided in Example 1 of this application 13 C NMR spectrum; Figure 24 This is an HPLC chromatogram of compound 3aa provided in Example 1 of this application. Detailed Implementation

[0017] Example 1: Synthesis of a hydroxylamine compound containing an aryl allyl structure 1. Synthetic methods of compound 3fa 50 mg of molecular sieve (4 Å molecular sieve, the same below) and a magnetic stir bar were added to a 10 mL reaction tube. After heating and drying with a torch for half an hour, the mixture was allowed to cool naturally to room temperature. Under inert nitrogen protection, the starting materials nitroketone intermediate 1f (0.2 mmol), boric acid intermediate 2a (0.8 mmol), catalyst R-1,1'-bi-2-naphthol (20% of the molar amount of nitroketone intermediate 1f), and 2 mL of anhydrous 1,2-dichloroethane (DCE) were added to the reaction tube. The boron migration reaction was carried out at room temperature for 72 hours, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the reaction mixture was purified by silica gel column chromatography with 1% (v / v) triethylamine as the base (eluent: petroleum ether / ethyl acetate = 10:1, v / v) to obtain the hydroxylamine compound 3fa.

[0018] Compound 3fa: 40% yield (25.4 mg), colorless oily liquid; 1 H NMR (500 MHz, Chloroform-d) δ 7.62 (d, J = 7.8 Hz, 1H), 7.57 (dd, J = 8.0, 1.3 Hz, 1H), 7.39 – 7.36(m, 2H), 7.35 – 7.32 (m, 1H), 7.31 – 7.27 (m, 2H), 7.25 – 7.20 (m, 1H), 7.12 (td, J = 7.7, 1.7 Hz, 1H), 6.72 (d, J = 15.9 Hz, 1H), 6.27 (s, 1H), 4.81 (d,J = 8.7 Hz, 1H), 2.69 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 140.25,136.68, 133.30, 129.36, 128.87, 128.83, 128.69, 128.07, 127.98, 127.96,126.68, 124.45, 75.28, 46.12. HRMS (ESI) m / z: [M+H] + Calculated for C 16 H 17 BrNO + ,318.0488; found, 318.0489. The synthetic methods for compounds 3aa, 3ba, 3ca, 3da, 3ea, 3ga, 3ha, 3ia, 3ja, 3ka, 3la, 3ma, 3na, 3oa, 3pa, 3qa, 3ra, 3sa, 3ta, 3ua, 3va, 3wa, 3xa, 3ya, 3za, 3zaa, 3zba, and 3zca are the same as those for compound 3fa. The substrate and catalyst feed ratios and post-processing procedures are identical to those for compound 3fa. The synthetic reaction formulas are shown in Table 1 below.

[0019] Table 1. Synthetic reaction formulas for compound 3aa-3zca Note: The reaction time was 72 h; the column chromatography eluent ratio (petroleum ether / ethyl acetate) was optimized within the range of 20:1 to 5:1 based on the product polarity. The same applies below, and will not be repeated.

[0020] Characterization data for some representative compounds are as follows: Compound 3aa: 70% yield (33.6 mg), colorless oily liquid; 1 H NMR (500 MHz, Chloroform-d) δ 7.42 (d, J = 7.6 Hz, 2H), 7.38 – 7.26 (m, 7H), 7.22 (t, J = 7.3 Hz, 1H), 6.60 (d, J = 15.7 Hz, 1H), 6.57 – 6.36 (m, 1H), 4.22 (d, J = 8.2 Hz, 1H), 2.63 (s, 3H), 1.27 (d, J = 5.2 Hz, 1H). 13 C NMR (126 MHz, Chloroform-d) δ140.91, 136.72, 132.92, 129.09, 128.88, 128.67, 128.20, 127.89, 127.81,126.63, 77.84, 46.04. HRMS (ESI) m / z: [M+H] + Calculated for C 16 H 18 NO + , 240.1383;found, 240.1380. The enantiomeric excess (ee) of compound 3aa was determined by high performance liquid chromatography (HPLC) using a chiral stationary phase (CHIRALPAK AD-H, flow rate = 1.0 mL / min, eluent: n-hexane / isopropanol = 95 / 5, 254 nm). The ratio of the two enantiomers in the obtained product was approximately 1:1. The HPLC chromatogram of compound 3aa is shown in [Figure number missing]. Figure 24 .

[0021] Compound 3ea: 31% yield (17.0 mg), colorless oily liquid; 1 H NMR (500 MHz, Chloroform-d) δ 7.40 – 7.34 (m, 2H), 7.28 (dd, J = 8.4, 6.8 Hz, 2H), 7.25 – 7.17 (m,2H), 7.16 – 7.09 (m, 2H), 6.59 (d, J = 15.8 Hz, 1H), 6.43 (s, 1H), 4.13 (d, J= 8.4 Hz, 1H), 2.64 (s, 3H), 2.25 (d, J = 12.1 Hz, 6H). 13 C NMR (126 MHz, Chloroform-d) δ 138.73, 136.68, 133.86, 133.20, 130.00, 129.07, 128.68,128.46, 128.05, 127.98, 127.31, 126.67, 72.82, 46.16. HRMS (ESI) m / z [M+H] + Calculated for C 16 H 17 ClNO + , 274.0993; found, 274.0992. Compound 3ua: 45% yield (24.0 mg), colorless oily liquid; 1 H NMR (500 MHz, Chloroform-d) δ 7.38 (d, J = 7.4 Hz, 2H), 7.29 (dd, J = 8.4, 6.8 Hz, 2H), 7.24 – 7.19(m, 1H), 7.04 (s, 2H), 6.91 (s, 1H), 6.59 (d, J = 15.8 Hz, 1H), 6.43 (s, 1H), 4.13 (d, J = 8.4 Hz, 1H), 2.65 (s, 3H), 2.32 (s, 6H).13 C NMR (126 MHz, Chloroform-d) δ 140.89, 138.46, 136.81, 132.61, 129.46 (d, J = 4.1 Hz), 128.64, 127.81, 126.64, 125.80, 78.12, 46.00, 21.48, 21.46. HRMS (ESI) m / z:[M+H] + Calculated for C 18 H 22 NO + , 268.1696; found, 268.1691. Compound 3ya: 44% yield (25.2 mg), colorless oily liquid; 1 H NMR (500 MHz, Chloroform-d) δ 8.42 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.2 Hz,1H), 7.70 (d, J = 7.1 Hz, 1H), 7.55 (ddd, J = 8.5, 6.8, 1.5 Hz, 1H), 7.51 –7.45 (m, 2H), 7.37 – 7.32 (m, 2H), 7.28 – 7.24 (m, 2H), 7.22 – 7.16 (m, 1H), 6.68 (d, J = 15.4 Hz, 2H), 4.98 (d, J = 7.5 Hz, 1H), 2.70 (s, 3H). 13 C NMR (126MHz, Chloroform-d) δ 136.74, 134.28, 133.00, 131.36, 129.05, 129.02, 128.81,128.63, 128.26, 127.84, 126.63, 126.27, 125.88, 125.77, 125.74, 123.90,77.36, 46.25. HRMS (ESI) m / z [M+H] + Calculated for C 20 H 20 NO + , 290.1539; found,290.1533. Compound 3za: 19% yield (8.7 mg), colorless oily liquid;1 1H NMR (600 MHz, Chloroform-d) δ 7.43 – 7.40 (m, 3H), 7.36 – 7.29 (m, 3H), 7.25 (d, J = 7.4 Hz, 1H), 6.64(d, J = 15.9 Hz, 1H), 6.51 (s, 1H), 6.37 (dd, J = 3. , 1.8 Hz, 1H), 6.32 (d,J = 3.3 Hz, 1H), 4.40 (d, J = 8.4 Hz, 1H), 2.66 (s, 3H). 13 13C NMR (151 MHz,Chloroform-d) δ 153.20, 142.37, 136.58, 128.92, 128.74, 128.10, 126.74,110.51, 108.30, 69.88, 45.40. HRMS (ESI) m / z: [M+H] + calculated for C 14 H 16 NO2 + ,230.1176; found, 230.1176. Compound 3zaa: Yield 65% (26.7 mg), white solid; 1 1H NMR (500 MHz, Chloroform-d)δ 7.41 (d, J = 7.4 Hz, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.26 – 7.22 (m, 1H),6.47 (d, J = 16.0 Hz, 1H), 6.17 (s, 1H), 2.83 (s, 1H), 2.65 (s, 3H), 2.16 (s,1H), 0.95 (dd, J = 26.4, 6.8 Hz, 6H). 13 13C NMR (1 MHz, Chloroform-d) δ 136.94,134.77, 128.70, 127.72, 126. , 125.72, 78.05, 46.19, 29.53, 20.60. HRMS(ESI) m / z: [M+H] + calculated for C 13 H 20 NO +, 206.1539; found, 206.1540. Compound 3zba: 68% yield (27.9 mg), white solid; 1 H NMR (500 MHz, Chloroform-d)δ 7.45 – 7.36 (m, 2H), 7.35 – 7.29 (m, 2H), 7.26 – 7.22 (m, 1H), 6.49 (d, J =16.0 Hz, 1H), 6.16 (s, 1H), 3.13 (td, J = 9.2, 4.2 Hz, 1H), 2.66 (s, 3H), 1.89 (s, 1H), 1.58 (d, J = 11.7 Hz, 1H), 1.46 – 1.21 (m, 3H), 0.93 (t, J =7.3 Hz, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 136.91, 133.76, 128.70, 128.25,127.72, 126.53, 77.36, 45.80, 34.84, 19.57, 14.26. HRMS (ESI) m / z [M+H] + Calculated for C 13 H 20 NO + , 206.1539; found, 206.1540. Compound 3zca: 73% yield (35.9 mg), white solid; 1 H NMR (500 MHz, Chloroform-d)δ 7.44 – 7.38 (m, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.27 – 7.20 (m, 1H), 6.45(d, J = 16.0 Hz, 1H), 6.21 (s, 1H), 2.87 (s, 1H), 2.64 (s, 3H), 1.86 – 1.61 (m, 6H), 1.31 – 0.93 (m, 5H). 13C NMR (126 MHz, Chloroform-d) δ 136.85, 134.79,128.72, 127.76, 126.57, 125.93, 77.36, 45.88, 39.49, 31.02, 26.72, 26.45 (d,J = 5.0 Hz). HRMS (ESI) m / z: [M+H] + Calculated for C 16 H 24 NO + , 246.1852; found,246.1852. 2. Synthesis method of compound 3aj 50 mg of molecular sieve and a magnetic stir bar were added to a 10 mL reaction tube. After heating and drying with a torch for half an hour, the mixture was allowed to cool naturally to room temperature. Under inert nitrogen protection, 0.2 mmol of nitrone intermediate 1a, 0.8 mmol of boric acid intermediate 2j, 2 mL of anhydrous 1,2-dichloroethane (DCE) catalyst R-1,1'-bi-2-naphthol were added to the reaction tube. The boron migration reaction was carried out at room temperature for 72 hours, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the reaction mixture was purified by silica gel column chromatography alkalized with 1% triethylamine (eluent: petroleum ether / ethyl acetate = 10:1, v / v) to obtain the hydroxylamine compound 3aj.

[0022] Compound 3aj: 66% yield (33.6 mg), colorless oily liquid; 1 H NMR (600 MHz, Chloroform-d) δ 7.41 (d, J = 7.1 Hz, 2H), 7.35 (t, J = 7.7 Hz, 2H), 7.29 – 7.26 (m, 2H), 7.10 (d, J = 7.8 Hz, 2H), 6.56 (d, J = 15.8 Hz, 1H), 6.39 (s, 1H), 4.18 (d, J= 8.4 Hz, 1H), 2.62 (s, 3H), 2.32 (s, 3H). 13C NMR (151 MHz, Chloroform-d) δ141.37, 137.70, 134.00, 132.67, 129.36, 128.84, 128.30, 128.11, 127.66,126.52, 77.97, 46.05, 21.33. HRMS (ESI) m / z [M+H] + Calculated for C 17 H 20 NO + ,254.1539; found, 254.1539. The synthesis methods for compounds 3ab, 3ac, 3ad, 3ae, 3af, 3ag, 3ah, 3ai, 3ak, 3al, 3am, 3an, 3ao, and 3ap are the same as those for compound 3aj, with identical substrate and catalyst feed ratios and post-processing procedures. The synthetic reaction formulas are shown in Table 2 below.

[0023] Table 2 Synthetic reaction formulas for compound 3ab-3ap Compound 3ag: 58% yield (29.7 mg), colorless oily liquid; 1 H NMR (500 MHz, Chloroform-d) δ 7.44 – 7.32 (m, 4H), 7.31 – 7.25 (m, 2H), 7.27 – 7.20 (m,2H), 7.12 (dt, J = 7.7, 1.2 Hz, 1H), 7.07 (dt, J = 10.2, 2.1 Hz, 1H), 6.95 –6.87 (m, 1H), 6.55 (d, J = 15.6 Hz, 1H), 6.48 (s, 1H), 4.19 (d, J = 7.9 Hz,1H), 2.61 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 164.15, 162.19, 140.84,139.14 (d, J = 7.6 Hz), 131.58, 130.86, 130.10 (d, J = 8.6 Hz), 128.93,128.15, 127.88, 122.51 (d, J = 2.7 Hz), 114.64 (d, J = 21.3 Hz), 113.04 (d, J= 22.0 Hz), 77.62, 46.15. 19 F NMR (471 MHz, Chloroform-d) δ -113.52. HRMS (ESI)m / z [M+H] + Calculated for C 16 H 17 FNO + , 258.1289; found, 258.1288. Compound 3ah: 47% yield (25.5 mg), colorless oily liquid; 1 H NMR (500 MHz, Chloroform-d) δ 7.32 – 7.23 (m, 5H), 7.22 – 7.00 (m, 5H), 6.43 (d, J = 15.5 Hz, 2H), 4.09 (d, J = 7.7 Hz, 1H), 2.52 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ140.84, 138.67, 134.63, 131.32, 131.02, 129.92, 129.88, 128.94, 128.13,127.88, 127.76, 126.47, 124.86, 46.14. HRMS (ESI) m / z [M+H] + Calculated for C 16 H 17 ClNO + , 274.0993; found, 274.0992. Compound 3ai: 36% yield (22.7 mg), yellow oily liquid; 1H NMR (500 MHz, Chloroform-d) δ 7.48 (t, J = 2.0 Hz, 1H), 7.37 – 7.29 (m, 5H), 7.25 – 7.21 (m, 2H), 7.11(t, J = 7.8 Hz, 1H), 6.52 – 6.26 (m, 2H), 4.15 (d, J = 7.4 Hz, 1H), 2.58 (s,3H). 13 C NMR (126 MHz, Chloroform-d) δ 140.77, 138.94, 131.26, 131.00, 130.68,130.17, 129.40, 128.95, 128.14, 127.91, 125.32, 122.86, 77.58, 46.12. HRMS(ESI) m / z [M+H] + Calculated for C 16 H 17 BrNO + , 318.0488; found, 318.0486. Compound 3ak: 80% yield (41.1 mg), colorless oily liquid; 1 H NMR (500 MHz, Chloroform-d) δ 7.31 (d, J = 7.6 Hz, 2H), 7.28 – 7.21 (m, 4H), 7.20 – 7.17 (m, 1H), 6.93– 6.84 (m, 2H), 6.46 (d, J = 15.8 Hz, 1H), 6.30 (s, 1H), 4.09 (d, J = 8.3 Hz,1H), 2.51 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 163.45, 161.48, 141.05,132.96, 132.94, 131.55, 129.16, 129.14, 128.89, 128.15, 128.08, 127.79,115.65, 115.48, 77.73, 46.12. 19 F NMR (471 MHz, Chloroform-d) δ -114.20. HRMS(ESI) m / z [M+H] + Calculated for C 16 H17 FNO + , 258.1289; found, 258.1290. Compound 3al: 42% yield (22.7 mg), colorless oily liquid; 1 H NMR (500 MHz, Chloroform-d) δ 7.42 (d, J = 7.2 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.32 – 7.27 (m, 5H), 6.56 (d, J = 15.7 Hz, 1H), 6.44 (d, J = 21.2 Hz, 1H), 4.20 (d, J = 8.1 Hz, 1H), 2.63 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 140.92, 135.28, 133.45,131.48, 130.11, 128.93, 128.82, 128.12, 127.86, 127.81, 77.74, 46.13. HRMS(ESI) m / z [M+H] + Calculated for C 16 H 17 ClNO + , 274.0993; found, 274.0992. Compound 3am: 58% yield (36.7 mg), white solid; 1 H NMR (500 MHz, Chloroform-d) δ7.42 – 7.37 (m, 4H), 7.35 (t, J = 7.5 Hz, 2H), 7.30 – 7.26 (m, 1H), 7.22 (d,J = 8.5 Hz, 2H), 6.52 (d, J = 15.4 Hz, 1H), 6.47 (s, 1H), 4.18 (d, J = 7.6Hz, 1H), 2.60 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 140.80, 135.71,131.75, 131.55, 130.21, 128.92, 128.15, 128.12, 127.87, 121.59, 77.66, 46.12.HRMS (ESI) m / z [M+H] +Calculated for C 16 H 17 BrNO + , 318.0488; found, 318.0489. Compound 3an: 21% yield (12.7 mg), white solid; 1 H NMR (500 MHz, Chloroform-d) δ7.53 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 7.4 Hz, 2H),7.38 – 7.32 (m, 2H), 7.31 – 7.27 (m, 1H), 6.70 – 6.42 (m, 2H), 4.22 (d, J =7.6 Hz, 1H), 2.63 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 140.60, 140.24,132.17, 131.33, 129.76, 129.00, 128.15, 128.00, 126.76, 125.63 (q, J = 3.9Hz), 123.18, 77.63, 46.17. 19 F NMR (471 MHz, Chloroform-d) δ -62.52. HRMS (ESI)m / z [M+H] + Calculated for C 17 H 17 F3NO + , 308.1257; found, 308.1257. Compound 3ao: 41% yield (24.0 mg), yellow solid; 1 H NMR (500 MHz, Chloroform-d) δ7.97 – 7.93 (m, 2H), 7.43 – 7.38 (m, 4H), 7.37 – 7.33 (m, 2H), 7.30 – 7.26(m, 1H), 6.62 (d, J = 14.9 Hz, 2H), 4.21 (d, J = 7.4 Hz, 1H), 3.89 (s, 3H), 2.62 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 166.97, 141.26, 140.72, 132.26,131.69, 130.01, 129.21, 128.96, 128.15, 127.93, 126.48, 77.72, 52.22, 46.19.HRMS (ESI) m / z [M+H] + Calculated for C 18 H 20 NO3 + , 298.1438; found, 298.1438. Example 2 Cytotoxicity Experiment 1. Experimental Materials The human lung cancer cells A549, human cervical cancer cells HeLa, and human myeloid monocytic leukemia cells MV-411 used in this experiment were purchased from European Certified Cell Culture Collections; RPMI-1640 medium was purchased from HyClone, USA; fetal bovine serum (FBS) was purchased from BioNTech, Germany; penicillin-streptomycin solution (100×) was purchased from Beyotime Biotechnology Co., Ltd.; and tetramethylthiazolyl blue (MTT) and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich, USA.

[0024] 2. Experimental Methods 2.1 Cell Culture A549, HeLa, and MV-411 cells were cultured in RPMI-1640 complete medium (hereinafter referred to as RPMI 1640 medium) containing 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin at 37°C, 55% humidity, and 5% CO2. When the cells reached the logarithmic growth phase, they were passaged, experimented on, and cryopreserved.

[0025] 2.2 MTT assay for cell viability Cell plating and drug administration: Collect cells in the logarithmic growth phase and plate them at a density of 3 × 10⁻⁶ cells / mL. 3The cells were seeded at a density of cells / well in 96-well plates and incubated at 37°C with 5% CO2 for 24 h. The old culture medium was then aspirated from the wells. The test compound, dissolved in DMSO, was diluted with RPMI 1640 medium to the corresponding concentrations (0.1, 1, 10, 100 μM) and added to each well of the 96-well plate at 100 μL. Three replicates were performed for each concentration. Each plate also included a positive control group (cisplatin, administered via the same route as the test compound group), a normal cell group (containing only cells and RPMI 1640 medium), and a blank control group (containing only RPMI 1640 medium and no cells). After administration, the 96-well plates were incubated at 37°C with 5% CO2 for 72 h.

[0026] Cell viability assay: After 72 h of incubation, 20 μL of MTT solution (5 mg / mL) was added to each well, and incubation continued for 1.5 h. Subsequently, the culture medium in the plate was removed, 150 μL of DMSO was added to each well, and the plate was shaken at medium speed for 5 min on a horizontal shaker. The absorbance at 562 nm was measured using a microplate reader.

[0027] Data processing: Calculate the relative inhibition rate of cell growth by the drug, i.e., the cell inhibition rate, using the following formula: Cell inhibition rate = .

[0028] Where C, C0, and X represent the average absorbance values ​​of the three wells in the normal cell group, blank control group, and drug-treated group, respectively. Finally, the cell inhibition rate curve was fitted using Graphpad Prism 5.0 software, and the IC50 of the cell growth inhibition rate of the test compound was calculated. 50 value.

[0029] 2.3 Experimental Results The positive control group showed that cisplatin's IC50 on A549 tumor cells... 50 The IC50 concentration of compound 3ag against A549 tumor cells was 22.3 μmol / L. 50 The IC50 concentration of compound 3ai against A549 tumor cells was 6.142 μmol / L. 50 The IC50 concentration of compound 3ao against A549 tumor cells was 5.746 μmol / L. 50 It is 3.485 μmol / L.

[0030] The positive control group showed that cisplatin's IC50 on HeLa tumor cells... 50 The IC50 concentration of compound 3zba against HeLa tumor cells was 7.6 μmol / L. 50 The IC50 concentration of compound 3zca against HeLa tumor cells was 12.576 μmol / L. 50The IC50 concentration of compound 3ag against HeLa tumor cells was 9.235 μmol / L. 50 The IC50 concentration of compound 3ao against HeLa tumor cells was 1.863 μmol / L. 50 It is 4.856 μmol / L.

[0031] The IC50 of cisplatin in the positive control group against MV-411 tumor cells 50 The IC50 concentration of compound 3ea was 5.2 μmol / L, and its effect on MV-411 tumor cells was [not specified]. 50 The IC50 concentration of compound 3ao against MV-411 tumor cells was 4.302 μmol / L. 50 The concentration was 7.648 μmol / L. The IC50 of some target compounds and the positive control drug cisplatin against three types of tumor cells was [not specified]. 50 The values ​​are shown in Table 3.

[0032] Table 3: IC50 of each compound against tumor cells A549, HeLa, and MV-411 50 value 3. Experimental Conclusions A549, HeLa, and MV-411 cells are effective tools and evaluation indicators for testing the cytotoxicity of compounds against tumor cells. Experimental results show that the hydroxylamine compounds containing an aryl allyl structure described in this invention exhibit certain cytotoxicity against A549, HeLa, and MV-411 cells, and possess inhibitory activity against their proliferation, suggesting that these compounds have the potential for further development into anti-tumor drugs.

Claims

1. A hydroxylamine compound containing an aryl allyl structure, characterized in that, Its structural formula is shown in equation (I): ； In formula (I), R1 is one of substituted or unsubstituted phenyl or unsubstituted alkyl, cycloalkyl, naphthyl, heteroaryl; R2 is substituted or unsubstituted phenyl.

2. The hydroxylamine compound according to claim 1, characterized in that, R1 is one of phenyl, o-methylphenyl, o-methoxyphenyl, o-fluorophenyl, o-chlorophenyl, o-bromophenyl, m-methylphenyl, m-methoxyphenyl, m-fluorophenyl, m-chlorophenyl, p-methylphenyl, p-methoxyphenyl, p-tert-butylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-iodophenyl, p-ethynylphenyl, methyl p-formate phenyl, p-trifluoromethylphenyl, 3,5-dimethylphenyl, 3,4-dimethylphenyl, 3,4-dimethoxyphenyl, 2,6-dichlorophenyl, 2-naphthyl, 2-furanyl, isopropyl, n-propyl, and cyclohexyl; R2 is one of phenyl, o-methylphenyl, o-fluorophenyl, o-chlorophenyl, m-methylphenyl, m-methoxyphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, methyl p-formate phenyl, and 3,5-dimethoxyphenyl.

3. The hydroxylamine compound according to any one of claims 1-2, characterized in that, The compound shown in formula (I) is selected from one of the structures shown below: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 4. A method for synthesizing the hydroxylamine compound according to any one of claims 1-3, characterized in that, The specific steps are as follows: Under inert nitrogen gas protection and / or anhydrous and oxygen-free conditions, the raw material nitrone intermediate (II) and boric acid intermediate (III), 4Å molecular sieve, and catalyst R-1,1'-bi-2-naphthol were mixed in organic solvent A and subjected to boron migration reaction at room temperature. After the reaction was completed, the hydroxylamine compound was obtained by separation and purification. The structural formula of nitroketone intermediate (II) is as follows: ; The structural formula of boric acid intermediate (III) is as follows: ; The structural formula of catalyst R-1,1'-bi-2-naphthol is: ; The definitions of R1 and R2 are the same as those in any of claims 1-3.

5. The synthesis method according to claim 4, characterized in that, The organic solvent A is selected from one of 1,2-dichloroethane, diethyl ether, 1,4-dioxane, dichloromethane, tetrahydrofuran, methyl tert-butyl ether, toluene, acetonitrile, ethyl acetate, chloroform, chlorobenzene, and carbon tetrachloride.

6. The synthesis method according to claim 4, characterized in that, The molar ratio of the nitrone intermediate (II) to the boric acid intermediate (III) is 1.0:(3.0-4.5).

7. The synthesis method according to claim 4, characterized in that, The amount of catalyst used is 5-50% of the molar amount of the nitrone intermediate.

8. The use of the hydroxylamine compound containing an aryl allyl structure as described in claims 1-3 in the preparation of antitumor drugs.

9. The use of the hydroxylamine compound containing an aryl allyl structure synthesized by the synthetic method according to any one of claims 4-7 in the preparation of antitumor drugs.

10. The application according to claim 8 or 9, characterized in that, The antitumor drug is a drug that inhibits the growth of human lung cancer cells A549, human cervical cancer cells HeLa, and / or human myeloid monocytic leukemia cells MV-411.

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