Electrochemical synthesis of alkoxylated benzoxazine compounds, synthesis method and application

Abstract

The application relates to the technical field of synthesis of alkoxy benzoxazine compounds, in particular to an electrochemical synthesis of an alkoxy benzoxazine compound, a structural formula of which is shown as formula (I). In addition, the application also discloses a preparation method and application of the compound. The alkoxy benzoxazine compound has good antitumor activity.

Description

Technical Field

[0001] This invention relates to the field of alkyl oxidase benzoxazine compound synthesis technology, and particularly to an electrochemical synthesis method for alkyl oxidase benzoxazine compounds and its applications. Background Technology

[0002] The benzoxazine skeleton is widely distributed in nature and has a wide range of biological activities. It is an essential structural unit in drugs and pesticides and has been used clinically as an anti-anxiety and anticonvulsant, antifungal agent and progesterone receptor agonist. Since the development of synthetic chemistry, the functionalization and synthesis of benzoxazine derivatives have attracted great interest from organic chemists. Although researchers have reported a variety of strategies for constructing the benzoxazine skeleton, the synthesis of alkyl-oxidized benzoxazine compounds has not yet been reported.

[0003] Therefore, obtaining alkyl oxidase benzoxazine compounds with good pharmacological activity has become an urgent need. Summary of the Invention

[0004] The purpose of this invention is to provide an electrochemical synthesis method for alkyl oxidase benzoxazine compounds, and its application, in order to solve the problem of the lack of processes for synthesizing alkyl oxidase benzoxazine compounds in the prior art.

[0005] To achieve the above objectives, the present invention provides an alkyl oxidase benzoxazine compound with the structure shown in formula (I):

[0006]

[0007] Wherein, R is an alkyl group, and R1, R2, and R3 are each independently an aromatic group or a halogen.

[0008] This invention also discloses an electrochemical method for synthesizing alkyl oxidase benzoxazine compounds, applicable to the preparation of the alkyl oxidase benzoxazine compounds as described above. The synthesis method specifically includes the following steps:

[0009] S1: Add alcohols, vinyl aniline, and electrolytes to the reaction vessel respectively, and dissolve them with solvent;

[0010] S2: Use a carbon rod as the anode and a platinum sheet as the cathode, and stir the reaction under constant current and preset temperature conditions;

[0011] S3: After the reaction is complete, extract the mixture with ethyl acetate;

[0012] S4: The organic layer obtained by extraction was dried with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to obtain alkyl oxidase benzoxazine compounds.

[0013] The ratio of alcohols, vinyl aniline, and electrolytes is 0.9:0.3:0.09, where vinyl aniline and electrolytes are expressed in millimoles, and alcohols are expressed in milliliters.

[0014] The alcohol is one of methanol, ethylene glycol, cyclopropylmethanol, isopropanol, borneol, and menthol.

[0015] The solvent is at least one of acetonitrile, a mixture of acetonitrile and methanol, or a mixture of acetonitrile and water.

[0016] The preset temperature is 40℃-80℃.

[0017] The stirring reaction takes 1-3 hours.

[0018] The electrolyte is at least one of tetrabutylammonium hexafluorophosphonate, tetraethylammonium hexafluorophosphonate, tetrabutylammonium tetrafluoroborate, and tetrabutylammonium iodide.

[0019] The constant current is 10 to 20 mA.

[0020] The previously mentioned electrochemically synthesized alkyl oxidases of benzoxazine compounds are used in the preparation of antitumor drugs.

[0021] This invention discloses an electrochemical synthesis method for alkyl oxidase benzoxazine compounds, and its application. Under mild electrochemical conditions, a series of new compounds with good inhibitory activity against tumor cell lines were obtained by reacting vinylaniline with alcohol, filling the gap in the synthesis of alkyl oxidase benzoxazine compounds. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0023] Figure 1 This is a general formula for a method of synthesizing alkyl oxidase benzoxazine compounds provided by the present invention.

[0024] Figure 2 This invention provides a preparation process step for an electrochemical synthesis method of alkyl oxidase benzoxazine compounds. Detailed Implementation

[0025] Embodiments of the present invention are described in detail below, examples of which are illustrated in the accompanying drawings, wherein the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are exemplary and intended to explain the present invention, and should not be construed as limiting the present invention.

[0026] Please see Figure 1 The present invention provides an alkyl oxidase benzoxazine compound with the structure shown in formula (I):

[0027]

[0028] Wherein, R is an alkyl group, and R1, R2, and R3 are each independently an aromatic group or a halogen.

[0029] Please see Figure 2 The present invention also discloses an electrochemical method for synthesizing alkyl oxidase benzoxazine compounds, applicable to the preparation of the alkyl oxidase benzoxazine compounds as described above. The synthesis method specifically includes the following steps:

[0030] S1: Add alcohols, vinyl aniline, and electrolytes to the reaction vessel respectively, and dissolve them with solvent;

[0031] S2: Use a carbon rod as the anode and a platinum sheet as the cathode, and stir the reaction under constant current and preset temperature conditions;

[0032] S3: After the reaction is complete, extract the mixture with ethyl acetate;

[0033] S4: The organic layer obtained by extraction was dried with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to obtain alkyl oxidase benzoxazine compounds.

[0034] Furthermore, the ratio of alcohols, vinyl aniline, and electrolytes is 0.9:0.3:0.09, where vinyl aniline and electrolytes are expressed in millimoles, and alcohols are expressed in milliliters.

[0035] Furthermore, the alcohol is one of methanol, ethylene glycol, cyclopropylmethanol, isopropanol, borneol, and menthol.

[0036] Furthermore, the solvent is at least one of acetonitrile, a mixture of acetonitrile and methanol, or a mixture of acetonitrile and water.

[0037] Furthermore, the preset temperature is 40℃-80℃.

[0038] Furthermore, the stirring reaction time is 1-3 hours.

[0039] Furthermore, the constant current is 10 to 20 mA.

[0040] Furthermore, the electrolyte is at least one of tetrabutylammonium hexafluorophosphonate, tetraethylammonium hexafluorophosphonate, tetrabutylammonium tetrafluoroborate, and tetrabutylammonium iodide.

[0041] The previously mentioned electrochemically synthesized alkyl oxidases of benzoxazine compounds are used in the preparation of antitumor drugs.

[0042] This invention discloses an electrochemical synthesis method for alkyl oxidase benzoxazine compounds, and its application. Under mild electrochemical conditions, a series of new compounds with good inhibitory activity against tumor cell lines were obtained by reacting vinylaniline with alcohol, filling the gap in the synthesis of alkyl oxidase benzoxazine compounds. Specific Implementation Example 1:

[0044] The preparation of 4-(methoxymethyl)-4-methyl-2-phenyl-4H-benzo[d][1,3]oxazine (3a), with the following molecular formula:

[0045]

[0046] 0.9 mmol methanol, 0.3 mmol N-(2-(1-propen-2-yl))phenyl)benzamide, and 0.09 mmol tetrabutylhexafluorophosphonate ammonium were added to a 10 mL three-necked flask, dissolved in 6 mL acetonitrile. Using a carbon rod as the anode and a platinum sheet as the cathode, the reaction was carried out at a constant current of 10 mA and at 40 °C with stirring for 1.5 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:25 elution) to obtain the target product 3a. The characterization data are as follows:

[0047] Yellow oil (69%, 55.3 mg). 1 H NMR (400MHz, CDCl3) δ8.21-8.14(m, 2H), 7.56(m, 1H), 7.51(m, 1H), 7.48-7. 40(m, 3H), 7.34(m, 1H), 7.20(m, 1H), 4.47(s, 2H), 3.25(s, 3H), 1.51(s, 3H). 13 C NMR (100MHz, CDCl3) δ152.22, 140.92, 138.44, 134.52, 131.83, 130.92, 128.70, 12 8.40, 128.23, 126.11, 125.08, 76.60, 74.60, 51.20, 24.50.HRMS (m / z) (ESI): calcd for C 17 H18 NO2[M+H] + 268.1332, found 268.1333. Specific Implementation Example 2:

[0049] Preparation of 4-(methoxymethyl)-2,4-diphenyl-4H-benzo[d][1,3]oxazine (3b):

[0050]

[0051] 0.9 mmol methanol, 0.3 mmol N-(2-(1-phenylvinyl)phenyl)benzamide, and 0.09 mmol tetraethylhexafluorophosphonate ammonium were added to a 10 mL three-necked flask, dissolved in 6 mL acetonitrile. Using a carbon rod as the anode and a platinum sheet as the cathode, the reaction was carried out at a constant current of 15 mA and at 40 °C with stirring for 1.5 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:20 elution) to obtain the target product 3b, which was characterized as follows:

[0052] Yellowoil (57%, 56.3 mg). 1 HNMR (400MHz, CDCl3) δ8.11-8.06 (m, 2H), 7.64 (m, 1H), 7.44-7.36 (m, 4H), 7.33-7. 27(m, 5H), 7.24(m, 1H), 7.17-7.12(m, 1H), 4.74(m, 1H), 4.63(m, 1H), 3.30(s, 3H). 13 CNMR (100MHz, CDC) l3 )δ153.19, 142.99, 141.56, 136.29, 134.40, 131.96, 130.90, 129.78, 128.97, 128.71, 12 8.37, 128.15, 127.93, 127.50, 124.76, 82.39, 75.26, 52.61.HRMS (m / z) (ESI): calcdforC 22 H 20 NO2[M+H] + 330.1489, found 330.1483. Specific Implementation Example 3:

[0054] Preparation of 4-(4-fluorophenyl)-4-(methoxymethyl)-2-phenyl-4H-benzo[d][1,3]oxazine (3c):

[0055]

[0056] 0.9 mmol methanol, 0.3 mmol N-(2-(1-(4-fluorophenyl))enyl)phenyl)benzamide, and 0.09 mmol tetraethylhexafluorophosphonate ammonium were added to a 10 mL three-necked flask, dissolved in 6 mL acetonitrile. A carbon rod was used as the anode, and a platinum sheet as the cathode. The reaction was carried out at a constant current of 10 mA and at 60 °C with stirring for 1 hour. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:20 elution) to obtain the target product 3c, which was characterized as follows:

[0057] Yellow oil (59%, 61.5mg). 1 H NMR (400MHz, CDCl3) δ8.00-7.93(m, 2H), 7.54(m, 1H), 7.36-7.27(m, 4H), 7.20-7. 13(m, 3H), 7.10-7.05(m, 1H), 6.91-6.86(m, 2H), 4.63-4.51(m, 2H), 3.20(s, 3H). 13 C NMR (100MHz, CDCl3) δ162.37 (d, JC-F=245.0), 153.21, 142.67, 137.55 (d, JC-F=3.0), 136.10, 134.17, 131.98, 131.05, 129.38 (d, JC-F=8.0), 1 29.26, 129.08, 128.70, 128.19, 125.02, 115.22 (d, JC-F=21.0Hz), 81.80, 75.14, 52.52.19F (376MHz, CDCl3) δ-114.52.HRMS (m / z) (ESI): calcd for C 22 H 19 FNO2[M+H] + 348.1394, found 348.1400. Specific Implementation Example 4:

[0059] Preparation of 4-(4-chlorophenyl)-4-(methoxymethyl)-2-phenyl-4H-benzo[d][1,3]oxazine (3d):

[0060]

[0061] 0.9 mmol methanol, 0.3 mmol N-(2-(1-(4-chlorophenyl))enyl)phenyl)benzamide, and 0.09 mmol tetraethylhexafluorophosphonate ammonium were added to a 10 mL three-necked flask, dissolved in 6 mL acetonitrile. A carbon rod was used as the anode, and a platinum sheet as the cathode. The reaction was carried out at a constant current of 13 mA and at 50 °C with stirring for 1 hour. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:20 elution) to obtain the target product 3d, which was characterized as follows:

[0062] Yellow oil (63%, 68.8 mg). 1 H NMR (400MHz, CDCl3) δ 8.10-8.04 (m, 2H), 7.64 (m, 1H), 7.46-7.36 (m, 4H), 7.30-7.13 (m, 6H), 4.69-4.60 (m, 2H), 3.29 (s, 3H). 13 C NMR (100MHz, CDCl3) δ153.17, 142.82, 140.53, 135.85, 134.17, 133.85, 132.13, 131.05, 129.41 , 129.14, 128.96, 128.71, 128.50, 128.21, 125.04, 81.85, 74.95, 52.56.HRMS (m / z) (ESI): calcd forC 22 H 19 ClNO2[M+H] + 364.1099, found 364.1107. Specific Implementation Example 5:

[0064] Preparation of 4-(methoxymethyl)-4-methyl-2-(o-tolyl)-4H-benzo[d][1,3]oxazine (3e):

[0065]

[0066] 0.9 mmol of methanol, 0.3 mmol of 2-methyl-N-(2-(1-propen-2-yl))phenyl)benzamide, and 0.09 mmol of tetrabutylammonium tetrafluoroborate were added to a 10 mL three-necked flask. 6 mL of a mixture of acetonitrile and water (v:v = 5:1) was added to dissolve the product. A carbon rod was used as the anode, and a platinum sheet as the cathode. The reaction was carried out at a constant current of 20 mA and at 70 °C with stirring for 1.5 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:20 elution) to obtain the target product 3e, which was characterized as follows:

[0067] Yellow oil (54%, 45.6 mg). 1 H NMR (600MHz, CDCl3) δ7.73 (m, 1H), 7.50 (m, 1H), 7.47 (m, 1H), 7.34-7.28 (m, 2H), 7.26-7. 22(m, 2H), 7.21-7.17(m, 1H), 4.50-4.44(m, 2H), 3.26(s, 3H), 2.58(s, 3H), 1.54(s, 3H). 13 C NMR (150MHz, CDCl3) δ154.23, 141.08, 138.13, 137.82, 135.27, 131.44, 131.29, 129.87, 129.6 5, 128.46, 126.10, 125.76, 125.09, 76.54, 75.03, 51.19, 24.31, 21.35.HRMS (m / z) (ESI): calcd for C 18 H 20 NO2[M+H] + 282.1489, found 282.1493. Specific Implementation Example 6:

[0069] Preparation of 4-(methoxymethyl)-4-methyl-2-(p-tolyl)-4H-benzo[d][1,3]oxazine (3f):

[0070]

[0071] 0.9 mmol of methanol, 0.3 mmol of 4-methyl-N-(2-(1-propen-2-yl))phenyl)benzamide, and 0.09 mmol of tetrabutylammonium tetrafluoroborate were added to a 10 mL three-necked flask. 6 mL of a mixture of acetonitrile and water (v:v = 5:1) was added to dissolve the product. A carbon rod was used as the anode, and a platinum sheet as the cathode. The reaction was carried out at a constant current of 20 mA and at 70 °C with stirring for 1.5 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:20 elution) to obtain the target product 3f, which was characterized as follows:

[0072] Yellow oil (55%, 46.4 mg). 1 H NMR (600MHz, CDCl3) δ8.03-7.92(m, 2H), 7.57(m, 1H), 7.50(m, 1H), 7.35-7. 27(m, 3H), 7.19(m, 1H), 4.47(s, 2H), 3.25(s, 3H), 2.43(s, 3H), 1.51(s, 3H). 13 C NMR (150MHz, CDCl3) δ152.50, 140.98, 138.38, 137.88, 134.41, 131.77, 129.29, 128.40, 128.1 6, 126.12, 125.88, 125.03, 124.61, 76.60, 74.66, 51.20, 24.48, 21.57.HRMS (m / z) (ESI): calcd for C 18 H 20 NO2[M+H] + 282.1489, found 282.1492. Specific Implementation Example 7:

[0074] Preparation of 2-(4-chlorophenyl)-4-(methoxymethyl)-4-methyl-4H-benzo[d][1,3]oxazine (3g):

[0075]

[0076] 0.9 mmol of methanol, 0.3 mmol of 4-chloro-N-(2-(1-propen-2-yl))phenyl)benzamide, and 0.09 mmol of tetrabutyltetrafluoroborate were added to a 10 mL three-necked flask. 6 mL of a mixture of acetonitrile and ethyl acetate (v:v = 5:1) was added to dissolve the product. A carbon rod was used as the anode, and a platinum sheet as the cathode. The reaction was carried out at a constant current of 20 mA and at 80 °C with stirring for 1.5 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:20 elution) to obtain 3 g of the target product, characterized as follows:

[0077] Yellow oil (62%, 56.1 mg). 1 H NMR (400MHz, CDCl3) δ 8.17-8.08 (m, 2H), 7.54-7.48 (m, 2H), 7.41-7.30 (m, 3H), 7.22-7.17 (m, 1H), 4.45 (s, 2H), 3.24 (s, 3H), 1.50 (s, 3H). 13 CNMR (100MHz, CDCl3) δ150.95, 140.70, 138.34, 136.93, 133.02, 131.72, 129.95, 12 8.36, 128.30, 126.06, 125.13, 76.46, 74.58, 51.07, 24.21.HRMS (m / z) (ESI): calcd forC 17 H 17 ClNO2[M+H] + 302.0942, found 302.0945. Specific Implementation Example 8:

[0079] Preparation of 4-(methoxymethyl)-4-methyl-2-(naphth-2-yl)-4H-benzo[d][1,3]oxazine (3h):

[0080]

[0081] 0.9 mmol methanol, 0.3 mmol N-(2-(1-propen-2-yl))phenyl)-2-naphthylcarboxamide, and 0.09 mmol tetrabutyltetrafluoroborate were added to a 10 mL three-necked flask. 6 mL of a mixture of acetonitrile and ethyl acetate (v:v = 5:1) was added to dissolve the product. A carbon rod was used as the anode, and a platinum sheet as the cathode. The reaction was carried out at a constant current of 15 mA and at 80 °C with stirring for 2 hours. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:30 elution) to obtain the target product. The product was characterized as follows:

[0082] Yellow oil (50%, 47.6 mg). 1 H NMR (400MHz, CDCl3) δ8.64 (s, 1H), 8.30 (m, 1H), 7.98-7.92 (m, 1H), 7.87 (m, 2H), 7.63 (m, 1H), 7 .56-7.49(m, 3H), 7.39-7.33(m, 1H), 7.24-7.18(m, 1H), 4.54(s, 2H), 3.26(s, 3H), 1.55(s, 3H). 13 C NMR (100MHz, CDCl3) δ141.02, 138.40, 134.74, 132.98, 131.87, 131.79, 129.19, 129.00, 128.49, 127.84 , 127.80, 127.39, 126.40, 126.24, 125.76, 125.21, 76.70, 74.84, 51.25, 24.57.HRMS (m / z) (ESI): calcd forC 21 H 20 NO2[M+H] + 318.1489, found 318.1493. Specific Implementation Example 9:

[0084] Preparation of 4-(methoxymethyl)-4-methyl-2-(thiophen-2-yl)-4H-benzo[d][1,3]oxazine (3i):

[0085]

[0086] 0.9 mmol methanol, 0.3 mmol N-(2-(1-propen-2-yl))phenyl)thiophene-2-carboxamide, and 0.09 mmol tetrabutylammonium iodide were added to a 10 mL three-necked flask. 6 mL of a mixture of acetonitrile and water (v:v = 5:1) was added to dissolve the product. A carbon rod was used as the anode, and a platinum sheet as the cathode. The reaction was carried out at a constant current of 12 mA and at 70 °C with stirring for 2.5 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:35 elution) to obtain the target product 3i, which was characterized as follows:

[0087] Yellow oil (48%, 39.4 mg). 1 H NMR (600MHz, CDCl3) δ7.71 (s, 1H), 7.53-7.46 (m, 2H), 7.43 (m, 1H), 7.33-7.29 (m, 1H), 7.20-7.16(m, 1H), 7.09-7.05(m, 1H), 4.44(m, 2H), 3.23(s, 3H), 1.51(s, 3H). 13 C NMR (150MHz, CDCl3) δ149.28, 140.42, 139.36, 137.89, 131.36, 130.26, 130.00, 12 8.35, 127.74, 126.12, 125.04, 76.52, 74.76, 51.09, 24.46.HRMS (m / z) (ESI): calcd for C 15 H 16 NO2S[M+H] + 274.0896, found 274.0899. Specific Implementation Example 10:

[0089] Preparation of 6-bromo-4-(methoxymethyl)-4-methyl-2-phenyl-4H-benzo[d][1,3]oxazine (3j):

[0090]

[0091] 0.9 mmol methanol, 0.3 mmol N-(4-bromo-2-(prop-1-en-2-yl))phenyl)benzamide, and 0.09 mmol tetrabutylammonium iodide were added to a 10 mL three-necked flask, dissolved in 6 mL acetonitrile. A carbon rod was used as the anode, and a platinum sheet as the cathode. The reaction was carried out at a constant current of 10 mA and at 80 °C with stirring for 3 hours. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:40 elution) to obtain the target product 3j, which was characterized as follows:

[0092] Yellow oil (61%, 63.4 mg). 1 H NMR (400MHz, CDCl3) δ 8.16-8.11 (m, 2H), 7.63 (m, 1H), 7.48-7.38 (m, 5H), 4.47-4.39 (m, 2H), 3.28 (s, 3H), 1.48 (s, 3H). 13 C NMR (100MHz, CDCl3) δ152.47, 140.65, 139.73, 134.09, 133.23, 131.27, 131.00, 12 8.75, 128.57, 128.14, 118.72, 76.17, 73.87, 51.04, 23.85.HRMS (m / z) (ESI): calcd for C 17 H 17 BrNO2[M+H] + 346.0437, found 346.0437. Specific Implementation Example 11:

[0094] Preparation of 2-((4-methyl-2-phenyl-4H-benzo[d][1,3]oxazin-4-yl)methoxy)ethanol (3k):

[0095]

[0096] 0.9 mmol of ethylene glycol, 0.3 mmol of N-(2-(1-propen-2-yl))phenyl)benzamide, and 0.09 mmol of tetrabutylammonium iodide were added to a 10 mL three-necked flask, dissolved in 6 mL of acetonitrile. A carbon rod was used as the anode, and a platinum sheet as the cathode. The reaction was carried out at a constant current of 20 mA and at 70 °C with stirring for 3 hours. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:30 elution) to obtain the target product 3K, which was characterized as follows:

[0097] Yellow oil (60%, 53.5mg). 1 H NMR (400MHz, CDCl3) δ8.22-8.08(m, 2H), 7.52-7.40(m, 5H), 7.36-7.31(m, 1H), 7.17(m, 1H), 4.56-4.46(m, 2H), 3.72-3.61(m, 2H), 3.56-3.50(m, 1H), 3.39(m, 1H), 1.57(s, 3H). 13 C NMR (100MHz, CDCl3) δ152.94, 141.55, 137.77, 134.46, 131.37, 131.00, 128.74, 128.6 3, 128.29, 126.07, 124.95, 76.77, 76.45, 64.48, 62.32, 23.87.HRMS (m / z) (ESI): calcd for C 18 H 20 NO3[M+H] + 298.1438, found 298.1440. Specific Implementation Example 12:

[0099] Preparation of 4-((cyclopropylmethoxy)methyl)-4-methyl-2-phenyl-4H-benzo[d][1,3]oxazine (3l):

[0100]

[0101] 0.9 mmol of cyclopropylmethanol, 0.3 mmol of N-(2-(1-propen-2-yl))phenyl)benzamide, and 0.09 mmol of tetrabutylhexafluorophosphonate were added to a 10 mL three-necked flask. 6 mL of a mixture of acetonitrile and water (v:v = 5:1) was added to dissolve the product. A carbon rod was used as the anode, and a platinum sheet as the cathode. The reaction was carried out at a constant current of 15 mA and at 80 °C with stirring for 3 hours. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:30 elution) to obtain 3 μL of the target product, which was characterized as follows:

[0102] Yellow oil (63%, 58.1 mg). 1 H NMR (400MHz, CDCl3) δ8.16 (m, 2H), 7.55 (m, 2H), 7.48-7.39 (m, 3H), 7.34-7.29 (m, 1H), 7.21-7.16 (m, 1H), 4.46 (s, 2H), 3.25-3.20 (m, 1H), 3.16-3.10 (m, 1H), 1.53 (s, 3H), 1.05 (s, 1H), 0.55-0.49 (m, 2H), 0.19-0.13 (m, 2H). 13 C NMR (100MHz, CDCl3) δ152.35, 140.74, 138.80, 134.41, 131.55, 130.74, 128.54, 128.17, 128 .06, 125.99, 124.90, 76.24, 74.97, 67.95, 25.08, 11.21, 3.11, 3.00.HRMS (m / z) (ESI): calcd for C 20 H 22 NO2[M+H] + 308.1645, found 308.1643. Specific Implementation Example 13:

[0104] Preparation of methyl (4-methyl-2-phenyl-4H-benzo[d][1,3]oxazin-4-yl)acetate (3m):

[0105]

[0106] 0.9 mmol of acetic acid, 0.3 mmol of N-(2-(1-propen-2-yl))phenyl)benzamide, and 0.09 mmol of tetrabutylhexafluorophosphonate ammonium were added to a 10 mL three-necked flask. 6 mL of a mixture of acetonitrile and ethyl acetate (v:v = 5:1) was added to dissolve the product. A carbon rod was used as the anode, and a platinum sheet as the cathode. The reaction was carried out at a constant current of 10 mA and at 80 °C with stirring for 2.5 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:20 elution) to obtain the target product 3M, which was characterized as follows:

[0107] Yellow oil (67%, 59.4 mg). 1 H NMR (600MHz, CDCl3) δ 8.16 (m, 2H), 7.55 (m, 1H), 7.48-7.40 (m, 3H), 7.32 (m, 2H), 7.16 (m, 1H), 5.02 (m, 1H), 4.49 (m, 1H), 2.12 (s, 3H), 1.68 (s, 3H). 13 C NMR (150MHz, CDCl3) δ169.69, 151.47, 139.35, 138.06, 134.28, 131.87, 130.79, 128.50 , 128.34, 128.10, 124.96, 123.98, 80.88, 73.38, 24.09, 21.79.HRMS (m / z) (ESI): calcd for C 18 H 17 NO3[M+H] + 296.1281, found 296.1287. Specific Implementation Example 14:

[0109] Preparation of 4-(isopropoxymethyl)-4-methyl-2-phenyl-4H-benzo[d][1,3]oxazine (3n):

[0110]

[0111] 0.9 mmol isopropanol, 0.3 mmol N-(2-(1-propen-2-yl))phenyl)benzamide, and 0.09 mmol tetraethylhexafluorophosphonate ammonium were added to a 10 mL three-necked flask. 6 mL of a mixture of acetonitrile and ethyl acetate (v:v = 5:1) was added to dissolve the product. A carbon rod was used as the anode, and a platinum sheet as the cathode. The reaction was carried out at a constant current of 10 mA and at 60 °C with stirring for 2.5 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:30 elution) to obtain the target product 3n, which was characterized as follows:

[0112] Yellow oil (53%, 47.0 mg). 1 H NMR (400MHz, CDCl3) δ8.21-8.12(m, 2H), 7.57(m, 1H), 7.54-7.49(m, 1H), 7.48-7.39(m, 3H), 7.32 (m, 1H), 7.16 (m, 1H), 4.43 (m, 2H), 3.77 (m, 1H), 1.57 (s, 3H), 1.16 (m, 3H), 1.09 (m, 3H). 13 C NMR (100MHz, CDCl3) δ140.06, 138.33, 133.50, 130.14, 129.72, 127.55, 127.30, 127.0 5, 125.42, 123.62, 75.93, 74.75, 64.92, 23.88, 23.75, 23.29.HRMS (m / z) (ESI): calcd for C 19 H 22 NO2[M+H] + 296.1645, found 296.1644. Specific Implementation Example 15:

[0114] Preparation of 4-methyl-2-phenyl-4-(((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)methyl)-4H-benzo[d][1,3]oxazine (3o):

[0115]

[0116] 0.9 mmol of borneol, 0.3 mmol of N-(2-(1-propen-2-yl))phenyl)benzamide, and 0.09 mmol of tetrabutylhexafluorophosphonate were added to a 10 mL three-necked flask. 6 mL of a mixture of acetonitrile and ethyl acetate (v:v = 5:1) was added to dissolve the product. A carbon rod was used as the anode, and a platinum sheet as the cathode. The reaction was carried out at a constant current of 10 mA and at 60 °C with stirring for 2.5 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:20 elution) to obtain the target product 3O, which was characterized as follows:

[0117] Yellow oil (45%, 52.6 mg). 1 H NMR (400MHz, CDCl3) δ 8.15 (m, 2H), 7.64 (m, 1H), 7.49 (m, 1H), 7.43 (m, 3H), 7.31 (m, 1H), 7.15 (m, 1H), 4.36 (m, 1H), 4.25 (m, 1H), 3.89(m, 1H), 2.12(m, 1H), 1.99(s, 1H), 1.69(s, 1H), 1.62(s, 1H), 1.45(s, 3H), 1.20-1.02(m, 3H), 0.86-0.82(m, 9H). 13 C NMR (100MHz, CDCl3) δ151.58, 141.52, 140.28, 134.81, 130.95, 130.54, 128.40, 128.03, 127.90, 125.57, 124.69, 7 7.62, 75.72, 74.04, 49.46, 47.17, 45.20, 39.55, 28.33, 26.68, 22.54, 19.75, 18.95, 13.69.HRMS (m / z) (ESI): calcd for C 26 H 32 NO2[M+H] + 390.2428, found 390.2430. Specific Implementation Example 16:

[0119] Preparation of 4-((((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)methyl)-4-methyl-2-phenyl-4H-benzo[d][1,3]oxazine (3p):

[0120]

[0121] 0.9 mmol of menthol, 0.3 mmol of N-(2-(1-propen-2-yl))phenyl)benzamide, and 0.09 mmol of tetraethylhexafluorophosphonate ammonium were added to a 10 mL three-necked flask. 6 mL of a mixture of acetonitrile and ethyl acetate (v:v = 5:1) was added to dissolve the product. A carbon rod was used as the anode, and a platinum sheet as the cathode. The reaction was carried out at a constant current of 10 mA and at 60 °C with stirring for 2.5 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:20 elution) to obtain the target product 3p, which was characterized as follows:

[0122] Yellow oil (44%, 51.7 mg). 1 H NMR (400MHz, CDCl3) δ8.16 (m, 2H), 7.64 (m, 1H), 7.51-7.39 (m, 4H), 7.32-7.27 (m, 1H), 7.15 (m, 1H), 4.42-4.28 (m, 2H), 3.53-3.45 ( m, 1H), 2.18 (m, 1H), 1.88 (m, 1H), 1.68-1.61 (m, 2H), 1.55 (s, 3H), 1.20 (m, 1H), 0.97 (s, 2H), 0.95 (s, 1H), 0.86 (m, 6H), 0.80 (m, 3H). 13 C NMR (100MHz, CDCl3) δ151.67, 141.46, 140.31, 134.81, 131.14, 130.53, 128.47, 128.01, 127.95, 126.12, 124.66, 76.08, 74.87, 72.75, 48.99, 44.57, 34.32, 31.70, 24.51, 23.15, 22.37, 21.62, 16.30.HRMS (m / z) (ESI): calcdfor C 26 H 34 NO2[M+H] + 392.2584, found 392.2590. Specific Implementation Example 16:

[0124] Preparation of 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(methoxymethyl)-4-methyl-4H-benzo[d][1,3]oxazine (3q):

[0125]

[0126] 0.9 mmol of methanol, 0.3 mmol of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-N-(2-(1-propen-2-yl))phenyl)benzamide, and 0.09 mmol of tetrabutylammonium iodide were added to a 10 mL three-necked flask, dissolved in 6 mL of acetonitrile. Using a carbon rod as the anode and a platinum sheet as the cathode, the reaction was carried out at a constant current of 10 mA and at 50 °C with stirring for 3 hours. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:20 elution) to obtain the target product 3q, which was characterized as follows:

[0127] Yellow oil (52%, 63.0 mg). 1 H NMR (600MHz, CDCl3) δ7.77 (s, 1H), 7.72 (m, 1H), 7.51 (m, 2H), 7.34-7.31 (m, 1H), 7.19 (m, 2H), 6.70 ( t, JH-F=75.0Hz, 1H), 4.45 (m, 2H), 3.97 (m, 2H), 3.24 (s, 3H), 1.50 (s, 3H), 0.67 (m, 2H), 0.40 (m, 2H). 13 C NMR (150MHz, CDCl3) δ150.91, 149.85, 142.47, 140.64, 138.24, 132.86, 131.64, 128.29, 126.02, 125.05, 12 1.69, 121.64, 116.04 (t, JC-F=258.0Hz), 114.42, 76.40, 74.57, 73.92, 51.02, 24.11, 10.15, 3.23, 3.21.19F NMR (565MHz, CDCl3) δ-81.58, -81.71.HRMS (m / z) (ESI): calcd forC 22 H 24 F2NO4[M+H] + 404.1668, found 404.1672. Specific Implementation Example 17:

[0129] Preparation of 4-(4-(methoxymethyl)-4-methyl-4H-benzo[d][1,3]oxazin-2-yl)-N,N-dipropylbenzenesulfonamide (3r):

[0130]

[0131] 0.9 mmol of methanol, 0.3 mmol of 4-(N,N-dipropylsulfonamide)-N-(2-(1-propen-2-yl))phenyl)benzamide, and 0.09 mmol of tetraethylhexafluorophosphonate ammonium were added to a 10 mL three-necked flask, dissolved in 6 mL of acetonitrile. Using a carbon rod as the anode and a platinum sheet as the cathode, the reaction was carried out at a constant current of 20 mA and at 60 °C with stirring for 3 hours. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:25 elution) to obtain the target product 3r, which was characterized as follows:

[0132] Yellow oil (56%, 72.3 mg). 1 H NMR (600MHz, CDCl3) δ8.27(m, 2H), 7.84(m, 2H), 7.52(m, 2H), 7.35(m, 1H), 7.22(m, 1H), 4 .51-4.44(m, 2H), 3.24(s, 3H), 3.12-3.06(m, 4H), 1.55(m, 4H), 1.52(s, 3H), 0.88(m, 6H). 13 C NMR (150MHz, CDCl3) δ150.40, 141.86, 140.53, 138.54, 138.26, 131.95, 129.19, 128.61, 126. 90, 126.24, 125.66, 76.53, 74.97, 51.19, 50.13, 24.05, 22.11, 11.34.HRMS (m / z) (ESI): calcd for C 23 H 31 N₂O₄S[M+H] + 431.1999, found 431.2005.

[0133] Pharmacological studies of compounds:

[0134] The in vitro inhibitory activity of the synthesized compounds against four cancer cell lines (MGC-803, MIAPaCa-2, MDA-MB-231, and HeLa) was screened using the MTT assay. The results showed that most compounds exhibited good inhibitory activity against the tumor cell lines, with compound 3p showing the best inhibitory effect. As shown in Table 1, the IC50 values ​​of compound 3p against MGC-803, MIAPaCa-2, MDA-MB-231, and HeLa were 15.9±1.0, 9.2±0.9, 30.7±1.6, and 11.5±1.7 μM, respectively.

[0135] Table 1

[0136] 3f 18.5±1.4 10.4±0.8 33.5±2.1 12.7±1.1 3h 25.1±1.8 16.8±0.9 ＞40 19.3±1.5 3o 28.4±1.3 17.0±0.9 ＞40 20.5±2.5 3p 15.9±1.0 9.2±0.9 30.7±1.6 11.5±1.7 3r 21.9±1.4 15.3±0.6 36.5±1.9 22.3±1.0

[0137] This application discloses a metal-free and oxidant-free method for synthesizing novel alkyl oxidase benzoxazine compounds. Under mild electrochemical conditions, a series of new compounds were obtained by reacting vinylaniline with alcohol. The antitumor activity of all compounds was studied using the MTT assay. The experimental results showed that most compounds had good inhibitory activity against tumor cell lines, among which compound 3p had the best inhibitory effect on tumor cell lines.

[0138] The above description discloses only one preferred embodiment of the present invention, and should not be construed as limiting the scope of the present invention. Those skilled in the art will understand that all or part of the processes of the above embodiments can be implemented, and equivalent changes made in accordance with the claims of the present invention are still within the scope of the invention.

Claims

1. A method for the electrochemical synthesis of alkyl oxidized benzoxazine compounds, applied to the preparation of alkyl oxidized benzoxazine compounds, the structure of which is shown in formula (I): （I） in, R is an alkyl group, R 1 Methyl, R 2 It is an aromatic group, R 3 It is hydrogen; The synthesis method is characterized by comprising the following steps: Alcohols, vinyl aniline, and electrolytes were added to the reaction vessel separately, and then dissolved in solvent. A carbon rod is used as the anode and a platinum sheet is used as the cathode. The reaction is stirred under constant current and preset temperature conditions. After the reaction was complete, the mixture was extracted with ethyl acetate; The organic layer obtained by extraction was dried with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to obtain alkyl oxidase benzoxazine compounds.

2. The method for the electrochemical synthesis of alkyl oxidase benzoxazine compounds as described in claim 1, characterized in that, The ratio of alcohols, vinyl aniline, and electrolytes is 0.9:0.3:0.09, where vinyl aniline and electrolytes are expressed in millimoles, and alcohols are expressed in milliliters.

3. The method for the electrochemical synthesis of alkyl oxidase benzoxazine compounds as described in claim 1, characterized in that, The alcohol is at least one of methanol, ethylene glycol, cyclopropylmethanol, isopropanol, borneol, and menthol.

4. The method for the electrochemical synthesis of alkyl oxidase benzoxazine compounds as described in claim 1, characterized in that, The solvent is at least one of acetonitrile, a mixture of acetonitrile and methanol, or a mixture of acetonitrile and water.

5. The method for the electrochemical synthesis of alkyl oxidase benzoxazine compounds as described in claim 1, characterized in that, The preset temperature is 40℃-80℃.

6. The method for the electrochemical synthesis of alkyl oxidase benzoxazine compounds as described in claim 1, characterized in that, The stirring reaction takes 1-3 hours.

7. The method for the electrochemical synthesis of alkyl oxidase benzoxazine compounds as described in claim 1, characterized in that, The electrolyte is at least one of tetrabutylammonium hexafluorophosphonate, tetraethylammonium hexafluorophosphonate, tetrabutylammonium tetrafluoroborate, and tetrabutylammonium iodide.

8. The method for the electrochemical synthesis of alkyl oxidase benzoxazine compounds as described in claim 1, characterized in that, The constant current is 10~20 mA.

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