A preparation method of 3-substituted-1,2-benzoxazine-4-one compounds

Abstract

A 3-substituted-1,2-benzoxazine-4-ketone compound and a preparation method thereof. The structural formula of the compound is: wherein: R is a benzylamino group, a cyclopropylamino group, a glycine methyl ester group, a dimethylamino group, a morpholine group, an amino group, a p-toluenesulfonamide group, a methoxy group, an isopropoxy group, an estrone group, a n-butyl mercaptan group, a benzyl mercaptan group, and an ethyl thioglycolate group. The present invention uses simple and easily available amines, alcohols, and thiol compounds as nucleophiles, and through a simple nucleophilic substitution reaction, on the basis of retaining a biologically active 1,2-benzoxazine-4-ketone heterocyclic skeleton, successfully realizes the conversion of the nitro functional group in the 3-nitro-1,2-benzoxazine-4-ketone compound, and efficiently constructs new C-N bonds, C-O bonds, and C-S bonds at the 3-position of the heterocycle. The 3-substituted-1,2-benzoxazine-4-ketone compound synthesized by the method has good development potential and application prospects in the field of biomedicine.

Description

Technical Field

[0001] The present invention relates to a 3-substituted-1,2-benzoxazine-4-one compound and a preparation method thereof. Background Art

[0002] Benzoxazine-4-one compounds have become one of the hot areas of organic synthesis and drug development due to their unique structure and wide range of biological activities, and are widely used in organic synthesis and biomedicine. For example, benzoxazine-4-one compounds have specific molecular interactions with HSV-1 protease and are a class of HSV-1 protease inhibitors with micromolar effects (see reference: Jarvest, RL et al. Bioorg. Med. Chem. Lett. 1996, 6 ,2463); A new class of 2-aryl-3,1-benzoxazine-4-one compounds can act as coagulation factors and are considered to be potential oral antithrombotic drugs (see reference: Jakobsen, P. et al. Bioorg. Med. Chem. 2000, 8 ,2095); Cetilistat is a new type of lipase inhibitor that can be used to treat obesity in type 2 diabetes (see reference: Kopelman, P. et al. Int. J. Obesity. 2007, 31 , 494). However, Engelhart et al. β -ketosulfonamide derivatives, the synthesized 1,2-benzoxazine-4-one compounds can effectively improve the oral bioavailability of the MbtA inhibitor Sal-AMS and have potential activity in the field of biomedicine (see reference: Courtney, CA et al. J. Org. Chem. 2013, 78 , 7470). However, in the existing literature, there are very few reports on the research of 1,2-benzoxazine-4-one compounds, especially the synthesis methods of 3-substituted-1,2-benzoxazine-4-one derivatives.

[0003] Therefore, it is of great research significance to develop a method for efficiently synthesizing 3-substituted-1,2-benzoxazine-4-one compounds. The following are the main synthetic methods reported in the literature:

[0004] (I) In 1962, Ziegler et al. generated o-hydroxybenzoyl nitrile intermediate by reacting acetic anhydride with o-hydroxyphenylglyoxal-phenylhydrazone compounds under heating conditions, and further converted it into 1,2-benzoxazine-4-one products (see reference: Ziegler, E. et al. Beautiful. Chem. 1962,93 , 1062).

[0005] (ii) In 1969, Viehe et al. used cinnamaldehyde and nitrogen trioxide as raw materials in acetic acid solvent and discovered a new heterocyclic skeleton. According to mass spectrometry and infrared data, it was speculated that it might be 3-nitro-4 H -1,2-benzoxazin-4-one structure (see reference: Viehe, HG et al. Sun. Chem., Int. Ed . 1969, 8 , 979).

[0006] (III) In 2013, the Aldrich research group in the United States β -ketosulfonamide as the starting material, through a typical Meyer nitrosation reaction, the oxime intermediate was synthesized, and then the intermediate was reacted with cesium carbonate N,N -dimethylformamide solution system, the final product was synthesized through intramolecular cyclization reaction with a yield of 58% (see reference: Courtney, CA et al. J. Org. Chem. 2013, 78 , 7470).

[0007] (IV) In 2015, Ryosuke et al. obtained a small amount of 1,2-benzoxazine-4-one compounds in the process of constructing furazan derivatives. The relevant structure was verified by single crystal structure (see reference: Ryosuke, M. et al. J. Heterocycl. Chem. 2016, 53 , 1094).

[0008] (V) In 2015, Li et al. synthesized 1,2-benzoxazine-4-one compounds from aromatic alkynes and tert-butyl nitrite by [4+2] cycloaddition reaction, with yields ranging from 32% to 77% (see reference: Li, JH et al. Adv. Synth. Catalog. 2015, 357 , 3489).

[0009] (VI) In 2021, Pedro et al. used the method reported by Yang et al. to synthesize the 1,2-benzoxazin-4-one skeleton and successfully achieved the alkynyl functional group transformation of alkynylcyclobutene in dimethyl sulfoxide solvent using tert-butyl nitrite as the nitrogen and oxygen source (see reference: Pedro, A. et al. Chem. Common. 2021,57 , 8456).

[0010] In summary, there are only a few methods for synthesizing 3-substituted-1,2-benzoxazine-4-one compounds. However, these reactions have the disadvantages of harsh reaction conditions, difficult sources of reaction raw materials, complicated preparation processes, the need to use toxic and environmentally unfriendly nitrogen oxide gas as a raw material, and low yields. Summary of the invention

[0011] In order to solve the problems of the prior art, the purpose of the present invention is to overcome the shortcomings of the existing technology and provide a 3-substituted-1,2-benzoxazine-4-one compound and a preparation method thereof. The present invention uses simple and easily available amines, alcohols, and thiol compounds as nucleophiles, and through a simple nucleophilic substitution reaction, on the basis of retaining the biologically active 1,2-benzoxazine-4-one heterocyclic skeleton, successfully realizes the transformation of the nitro functional group in the 3-nitro-1,2-benzoxazine-4-one compound, and efficiently constructs new CN bonds, CO bonds, and CS bonds at the 3-position of the heterocyclic ring. The 3-substituted-1,2-benzoxazine-4-one compound synthesized by the method of the present invention has good development potential and application prospects in the field of biomedicine.

[0012] In order to achieve the above invention purpose, the present invention adopts the following inventive concept:

[0013] The reaction mechanism adopted by the method of the present invention is:

[0014]

[0015] Where: RH = benzylamine, cyclopropylamine, glycine methyl ester hydrochloride, aqueous dimethylamine, morpholine, aqueous ammonia, p-toluenesulfonamide, methanol, isopropanol, estrone, n-butyl mercaptan, benzyl mercaptan, ethyl thioglycolate.

[0016] Using easily available amines, alcohols, and thiol compounds as nucleophiles, through simple nucleophilic substitution reactions, the nitro functional group in 3-nitro-1,2-benzoxazine-4-one compounds was successfully transformed while retaining the biologically active 1,2-benzoxazine-4-one heterocyclic skeleton. New CN bonds, CO bonds, and CS bonds were efficiently constructed at the 3-position of the heterocycle.

[0017] According to the above inventive concept, the present invention adopts the following technical solution:

[0018] A 3-substituted-1,2-benzoxazine-4-one compound, the structural formula of the compound is:

[0019] ;

[0020] Wherein: R is any one of benzylamino, cyclopropylamino, glycine methyl ester, dimethylamino, morpholine, amino, p-toluenesulfonamide, methoxy, isopropoxy, estrone, n-butyl mercaptan, benzyl mercaptan, and ethyl thioglycolate.

[0021] A method for preparing a 3-substituted-1,2-benzoxazine-4-one compound according to the present invention comprises the following steps:

[0022] (1) 3-nitro-4 H -Benzo[ e [1,2]oxazine-4-one, nucleophile, and base are added into 1.5-3.0 mL of 1,4-dioxane solvent at a molar ratio of (1.0-1.5): (1.0-8.0): (0-4.0), and stirred at 25-50°C to react;

[0023] (2) After monitoring by TLC until the starting material completely disappears, cool to room temperature to obtain a crude product;

[0024] (3) The crude product is purified by silica gel column chromatography to obtain 3-substituted-1,2-benzoxazine-4-one compounds.

[0025] Preferably, in step (1), the 3-nitro-4 H -Benzo[ e The structural formula of ][1,2]oxazine-4-one is:

[0026] .

[0027] Preferably, in step (1), the nucleophilic reagent is at least one of benzylamine, cyclopropylamine, glycine methyl ester hydrochloride, dimethylamine, morpholine, ammonia water, p-toluenesulfonamide, methanol, isopropanol, estrone, n-butyl mercaptan, benzyl mercaptan, and ethyl thioglycolate.

[0028] Preferably, in step (1), the base is at least one of potassium carbonate and cesium carbonate.

[0029] Preferably, in step (1), the reaction is carried out under stirring at 25-50° C. for 11-18 hours.

[0030] Preferably, in step (1), 3-nitro-4 H -Benzo[ e The dosage ratio of ][1,2]oxazine-4-one and 1,4-dioxane solvent is 0.3mmol:1.5~3.0mL.

[0031] Preferably, in the step (3), when the crude product is purified by silica gel column chromatography, a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 to 20:1 is used as the developing solvent.

[0032] Preferably, in the step (3), when the crude product is purified by silica gel column chromatography, excess nucleophilic reagent is removed and a mixed solvent of dichloromethane and methanol in a volume ratio of 60:1 is used.

[0033] Compared with the prior art, the present invention has the following obvious outstanding substantive features and significant advantages:

[0034] 1. The present invention uses easily available amines, alcohols, and thiol compounds as nucleophiles, and through simple nucleophilic substitution reactions, successfully achieves the transformation of the nitro functional group in 3-nitro-1,2-benzoxazine-4-one compounds on the basis of retaining the biologically active benzoxazine-4-one heterocyclic skeleton, and efficiently constructs new CN bonds, CO bonds, and CS bonds at the 3-position of the heterocyclic ring;

[0035] 2. The 3-substituted-1,2-benzoxazine-4-one compounds synthesized by the method of the present invention have good development potential and application prospects in the field of biomedicine. DETAILED DESCRIPTION

[0036] The above scheme is further described below in conjunction with specific implementation examples. The preferred embodiments of the present invention are described in detail as follows: Embodiment 1

[0037] A 3-(benzylamino)-4 H -Benzo[ e The preparation method of ][1,2]oxazine-4-one compound comprises the following steps:

[0038] (1) Add 3-nitro-4-nitropropene to a 15 ml reaction tube. H -Benzo[ e [1,2]oxazin-4-one (57.6 mg, 0.3 mmol), 1,4-dioxane (1.5 mL) solvent and benzylamine (66.3 μL, 0.6 mmol) were reacted at room temperature of 25°C for 12 hours;

[0039] (2) Monitor by TLC until the reaction starting material disappears, cool to room temperature, and obtain a product mixed solution;

[0040] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1 as the developing solvent to obtain a light yellow solid (74.7 mg, yield 99%), namely 3-(benzylamino)-4 H -Benzo[ e[1,2]Oxazine-4-one compound, the structural formula is: ; Melting point: 130-132 ℃.

[0041] The basic parameters of this compound are as follows:

[0042] IR (KBr, cm-1): 3356, 3031, 2940, 1653, 1609, 1550, 1519, 1460, 1360,1295, 1211, 1118, 1079, 1020, 912, 755, 697, 591, 489;

[0043] 1H NMR (500 MHz, CDCl3): δ 8.09 (dd, J = 8.1, 1.6 Hz, 1H), 7.67 (ddd,J = 8.7, 7.0, 1.6 Hz, 1H), 7.43-7.33 (m, 5H), 7.33-7.24 (m, 2H), 5.83 (brs,1H), 4.49 (d, J = 5.8 Hz, 2H);

[0044] 13C NMR (126 MHz, CDCl3): δ 165.4, 163.5, 153.8, 137.7, 135.5, 128.8,128.1, 127.8, 125.3, 123.7, 116.7, 116.7, 45.5;

[0045] HRMS (ESI) m / z: calcd for C15H13N2O2 [M+H]+ 253.0972, found 253.0973.

[0046] Embodiment 2

[0047] A method for preparing a 3-(cyclopropylamino)-4H-benzo[e][1,2]oxazine-4-one compound comprises the following steps:

[0048] (1) 3-Nitro-4H-benzo[e][1,2]oxazin-4-one (57.6 mg, 0.3 mmol), 1,4-dioxane (1.5 ml) solvent and cyclopropylamine (42.9 μl, 0.6 mmol) were added to a 15 ml reaction tube in sequence and reacted at room temperature of 25°C for 12 hours;

[0049] (2) Monitor by TLC until the reaction starting material disappears, cool to room temperature, and obtain a product mixed solution;

[0050] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 5:1 as the developing solvent to obtain a yellow solid (64.2 mg, yield>99%), namely 3-(cyclopropylamino)-4-nitropropane H -Benzo[ e [1,2]Oxazine-4-one compound, the structural formula is: ;

[0051] Melting point: 116-118 ℃.

[0052] The basic parameters of this compound are as follows:

[0053] IR (KBr, cm-1): 3353, 3008, 1653, 1609, 1536, 1462, 1375, 1291, 1216,1153, 1119, 1053, 986, 910, 760, 635, 491;

[0054] 1H NMR (500 MHz, CDCl3): δ 8.06 (dd, J = 8.2, 2.2 Hz, 1H), 7.69-7.63(m, 1H), 7.39 (dd, J = 8.7, 2.7 Hz, 1H), 7.26 (td, J = 7.6, 2.7 Hz, 1H), 5.70(brs, 1H), 2.68-2.61 (m, 1H), 0.84 (d, J = 6.6 Hz, 2H), 0.62 (s, 2H);

[0055] 13C NMR (126 MHz, CDCl3): δ 165.4, 163.5, 155.0, 135.4, 125.2, 123.7,116.7, 116.6, 23.4, 7.2;

[0056] HRMS (ESI) m / z: calcd for C11H11N2O2 [M+H]+ 203.0815, found 203.0815.

[0057] Embodiment 3

[0058] A method for preparing a (4-oxo-4H-benzo[e][1,2]oxazin-3-yl)glycine methyl ester compound comprises the following steps:

[0059] (1) 3-Nitro-4H-benzo[e][1,2]oxazin-4-one (57.6 mg, 0.3 mmol), glycine methyl ester hydrochloride (76.9 mg, 0.6 mmol) and 1,4-dioxane (1.5 ml) were added to a 15 ml reaction tube and reacted at room temperature of 25°C for 18 hours;

[0060] (2) Monitor by TLC until the reaction starting material disappears, cool to room temperature, and obtain a product mixed solution;

[0061] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 5:1 as the developing solvent to obtain a white solid (68.2 mg, yield 97%), namely (4-oxo-4H-benzo[e][1,2]oxazin-3-yl)glycine methyl ester compound, with the structural formula: ;

[0062] Melting point: 140-141 ℃.

[0063] The basic parameters of this compound are as follows:

[0064] IR (KBr, cm-1): 3366, 2952, 1742, 1663, 1615, 1558, 1524, 1463, 1362,1299, 1267, 1209, 1128, 969, 921, 861, 762, 705, 650, 597;

[0065] 1H NMR (500 MHz, CDCl3): δ 8.09 (d, J = 7.9 Hz, 1H), 7.67 (t, J = 7.5Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 6.01 (s, 1H), 4.09 (d, J = 5.6 Hz, 2H), 3.79 (s, 3H);

[0066] 13C NMR (126 MHz, CDCl3): δ 170.0, 165.0, 163.3, 153.5, 135.6, 125.3,124.0, 116.9, 116.7, 52.6, 42.8;

[0067] HRMS (ESI) m / z: calcd for C11H10N2O4Na [M+Na]+ 257.0533, found257.0532.

[0068] Embodiment 4

[0069] A 3-(dimethylamino)-4 H -Benzo[ e The preparation method of ][1,2]oxazine-4-one compound comprises the following steps:

[0070] (1) Add 3-nitro-4-nitropropene to a 15 ml reaction tube. H -Benzo[ e [1,2]oxazin-4-one (57.6 mg, 0.3 mmol), 1,4-dioxane (1.5 mL) solvent and dimethylamine aqueous solution (76.0 μL, 0.6 mmol) were reacted at room temperature of 25°C for 13 hours;

[0071] (2) Monitor by TLC until the reaction starting material disappears, cool to room temperature, and obtain a product mixed solution;

[0072] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the developing solvent to obtain a yellow solid (49.4 mg, yield 87%), namely 3-(dimethylamino)-4 H -Benzo[ e [1,2]Oxazine-4-one compound, the structural formula is: ;

[0073] Melting point: 72-73 ℃.

[0074] The basic parameters of this compound are as follows:

[0075] IR (KBr, cm -1 ): 3745, 2874, 1655, 1605, 1520, 1459, 1406, 1315, 1217,1173, 1016, 927, 861, 768, 617, 496;

[0076] 1 H NMR (500 MHz, CDCl3): δ 8.07 (d, J = 8.1 Hz, 1H), 7.64 (t, J = 7.8Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.30-7.23 (m, 1H), 3.11 (s, 6H);

[0077] 13C NMR (126 MHz, CDCl3): δ 167.7, 162.6, 158.0, 135.0, 125.7, 123.9,119.5, 116.2, 40.4;

[0078] HRMS (ESI) m / z: calcd for C 10 H 11 N2O2 [M+H] + 191.0815, found 191.0814.

[0079] A 3-morpholine-4 H -Benzo[ e The preparation method of ][1,2]oxazine-4-one compound comprises the following steps:

[0080] (1) Add 3-nitro-4-nitropropene to a 15 ml reaction tube. H -Benzo[ e [1,2]oxazin-4-one (57.6 mg, 0.3 mmol), 1,4-dioxane (1.5 mL) solvent and morpholine (53.0 μL, 0.6 mmol) were reacted at room temperature of 25°C for 12 hours;

[0081] (2) Monitor by TLC until the reaction starting material disappears, cool to room temperature, and obtain a product mixed solution;

[0082] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the developing solvent to obtain a light yellow solid (64.5 mg, yield 93%), namely 3-morpholine-4 H -Benzo[ e [1,2]Oxazine-4-one compound, the structural formula is: ;

[0083] Melting point: 132-133 ℃.

[0084] The basic parameters of this compound are as follows:

[0085] IR (KBr, cm-1): 2963, 2917, 2868, 1656, 1618, 1506, 1461, 1308, 1263,1217, 1155, 1119, 1001, 929, 869;

[0086] 1H NMR (500 MHz, CDCl3): δ 8.09 (dt, J = 8.2, 1.2 Hz, 1H), 7.68 (ddd,J = 8.7, 6.9, 1.6 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.31 (ddd, J = 8.0, 7.1,1.0 Hz, 1H), 3.89-3.84 (m, 4H), 3.57-3.52 (m, 4H);

[0087] 13C NMR (126 MHz, CDCl3): δ 167.0, 162.4, 157.6, 135.3, 125.7, 124.3,119.7, 116.3, 66.6, 48.1;

[0088] HRMS (ESI) m / z: calcd for C12H13N2O3 [M+H]+ 233.0921, found 233.0922.

[0089] Embodiment 6

[0090] A method for preparing a 3-amino-4H-benzo[e][1,2]oxazine-4-one compound comprises the following steps:

[0091] (1) 3-Nitro-4H-benzo[e][1,2]oxazin-4-one (57.6 mg, 0.3 mmol), 1,4-dioxane (1.5 ml) solvent and ammonia (93.0 μl, 0.6 mmol) were added to a 15 ml reaction tube in sequence and reacted at room temperature of 25°C for 12 hours;

[0092] (2) Monitor by TLC until the reaction starting material disappears, cool to room temperature, and obtain a product mixed solution;

[0093] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1 as the developing solvent to obtain a light yellow solid (52 mg, yield>99%), i.e., 3-amino-4H-benzo[e][1,2]oxazine-4-one compound with the structural formula: , melting point: 155-156 ℃.

[0094] The basic parameters of this compound are as follows:

[0095] IR (KBr, cm-1): 3446, 3322, 3175, 1660, 1593, 1459, 1311, 1212, 1151,1117, 1004, 914, 855, 758, 587, 542, 477;

[0096] 1H NMR (500 MHz, CDCl3): δ 8.09 (dd, J = 8.1, 1.6 Hz, 1H), 7.67 (ddd,J = 8.7, 7.0, 1.6 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.32-7.26 (m, 1H), 5.07(s, 2H);

[0097] 13C NMR (126 MHz, CDCl3): δ 165.3, 163.5, 155.5, 135.5, 125.3, 124.1,117.2, 116.8;

[0098] HRMS (ESI) m / z: calcd for C8H7N2O2 [M+H]+ 163.0502, found 163.0504.

[0099] Embodiment 7

[0100] A method for preparing a 4-methyl-N-(4-oxo-4H-benzo[e][1,2]oxazin-3-yl)benzenesulfonamide compound comprises the following steps:

[0101] (1) 3-Nitro-4H-benzo[e][1,2]oxazin-4-one (57.6 mg, 0.3 mmol), p-toluenesulfonamide (105 mg, 0.6 mmol), potassium carbonate (83 mg, 0.6 mmol) and 1,4-dioxane (1.5 ml) solvent were added to a 15 ml reaction tube in sequence and reacted at room temperature of 25°C for 12 hours;

[0102] (2) Monitor by TLC until the reaction starting material disappears, cool to room temperature, and obtain a product mixed solution;

[0103] (3) The crude product was purified by silica gel column chromatography. The developing solvent was first a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 to remove excess nucleophilic reagent, and then a mixed solvent of dichloromethane and methanol in a volume ratio of 60:1 was used. After purification, a white solid (52.8 mg, yield 56%) was obtained, namely 4-methyl-N-(4-oxo-4H-benzo[e][1,2]oxazin-3-yl)benzenesulfonamide compound with the structural formula: , melting point: 208-210 ℃.

[0104] The basic parameters of this compound are as follows:

[0105] IR (KBr, cm-1): 3243, 1657, 1606, 1444, 1364, 1328, 1270, 1199, 1162,1091, 1049, 955, 871, 824, 765, 667, 546;

[0106] 1H NMR (400 MHz, CDCl3): δ 8.17 (brs, 1H), 8.07 (dd, J = 8.1, 1.5 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.75 (ddd, J = 8.7, 7.1, 1.6 Hz, 1H), 7.44 (d,J = 8.7 Hz, 1H), 7.39-7.33 (m, 3H), 2.42 (s, 3H);

[0107] 13C NMR (126 MHz, CDCl3): δ 163.1, 162.9, 149.3, 145.3, 136.6, 135.4,129.8, 128.8, 125.4, 125.3, 117.5, 116.7, 21.8;

[0108] HRMS (ESI) m / z: calcd for C15H13N2O4S [M+H]+ 317.0591, found317.0591.

[0109] Embodiment 8

[0110] A method for preparing a 3-(methoxy)-4H-benzo[e][1,2]oxazine-4-one compound comprises the following steps:

[0111] (1) 3-Nitro-4H-benzo[e][1,2]oxazin-4-one (57.6 mg, 0.3 mmol), potassium carbonate (83 mg, 0.6 mmol), 1,4-dioxane (1.5 ml) solvent and methanol (24.0 μl, 0.6 mmol) were added to a 15 ml reaction tube in sequence and reacted at 35 °C for 16 hours;

[0112] (2) Monitor by TLC until the reaction starting material disappears, cool to room temperature, and obtain a product mixed solution;

[0113] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the developing solvent to obtain a white solid (48.2 mg, yield 91%), namely 3-(methoxy)-4H-benzo[e][1,2]oxazine-4-one compound with the structural formula: , melting point: 136-137 ℃.

[0114] The basic parameters of this compound are as follows:

[0115] IR (KBr, cm-1): 3013, 2945, 1669, 1605, 1554, 1453, 1298, 1210, 1118,1046, 1118, 1046, 992, 760, 637, 489;

[0116] 1H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 7.8Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 4.01 (s, 3H);

[0117] 13C NMR (126 MHz, CDCl3): δ 164.8, 162.7, 159.9, 135.9, 125.6, 124.7,119.8, 116.5, 55.7;

[0118] HRMS (ESI) m / z: calcd for C9H8NO3 [M+H]+ 178.0499, found 178.0498.

[0119] Embodiment 9

[0120] A method for preparing a 3-(isopropoxy)-4H-benzo[e][1,2]oxazine-4-one compound comprises the following steps:

[0121] (1) 3-Nitro-4H-benzo[e][1,2]oxazin-4-one (57.6 mg, 0.3 mmol), cesium carbonate (399.0 mg, 1.2 mmol), 1,4-dioxane (1.5 ml) solvent and isopropanol (184.0 μl, 2.4 mmol) were added to a 15 ml reaction tube in sequence and reacted at 50 °C for 16 hours;

[0122] (2) Monitor by TLC until the reaction starting material disappears, cool to room temperature, and obtain a product mixed solution;

[0123] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1 as the developing solvent to obtain a white solid (30.8 mg, yield 50%), namely 3-(isopropoxy)-4H-benzo[e][1,2]oxazine-4-one compound with the structural formula: , melting point: 72-74 ℃.

[0124] The basic parameters of this compound are as follows:

[0125] IR (KBr, cm-1): 3077, 2983, 2933, 1672, 1608, 1539, 1459, 1378, 1293,1211, 1147, 1109, 1037, 954, 864, 807, 757, 496;

[0126] 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 8.1 Hz, 1H), 7.68 (t, J = 7.8Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 5.12 (hept, J =5.8 Hz, 1H), 1.44 (d, J = 6.2 Hz, 6H);

[0127] 13C NMR (126 MHz, CDCl3): δ 165.0, 162.4, 158.8, 135.6, 125.5, 124.4,119.8, 116.4, 72.0, 21.5;

[0128] HRMS (ESI) m / z: calcd for C11H11NO3Na [M+Na]+ 228.0631, found228.0631.

[0129] Embodiment 10

[0130] A method for preparing a 3-((8R, 9S, 13S, 14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)oxy)-4H-benzo[e][1,2]oxazin-4-one compound, comprising the following steps:

[0131] (1) 3-Nitro-4H-benzo[e][1,2]oxazin-4-one (86.5 mg, 0.45 mmol), potassium carbonate (83.0 mg, 0.6 mmol), estrone (81.2 mg, 0.3 mmol) and 1,4-dioxane (1.5 ml) solvent were added to a 15 ml reaction tube in sequence and reacted at 50 °C for 16 hours;

[0132] (2) Monitor by TLC until the reaction starting material disappears, cool to room temperature, and obtain a product mixed solution;

[0133] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the developing solvent to obtain a white solid (118.4 mg, yield 95%), namely 3-((8R, 9S, 13S, 14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)oxy)-4H-benzo[e][1,2]oxazin-4-one compound, with the structural formula: , melting point: 181-182 ℃.

[0134] The basic parameters of this compound are as follows:

[0135] IR (KBr, cm-1): 2929, 2864, 1735, 1675, 1611, 1549, 1492, 1459, 1380,1292, 1207, 1147, 1043, 954, 894, 760, 489;

[0136] 1H NMR (500 MHz, CDCl3): δ 8.20 (dd, J = 8.2, 1.7 Hz, 1H), 7.75 (ddd,J = 8.7, 7.0, 1.7 Hz, 1H), 7.48-7.30 (m, 3H), 7.03-6.95 (m, 2H), 2.92 (dd, J = 8.0, 3.3 Hz, 2H), 2.50 (dd, J = 19.1, 8.7 Hz, 1H), 2.45-2.37 (m, 1H), 2.31 (td, J = 10.9, 4.2 Hz, 1H), 2.14 (dt, J = 18.9, 8.9 Hz, 1H), 2.09-1.93 (m,3H), 1.68-1.42 (m, 6H), 0.92 (s, 3H);

[0137] 13C NMR (101 MHz, CDCl3): δ 220.9, 164.6, 162.6, 160.6, 150.5, 138.5,137.6, 136.0, 126.8, 125.6, 125.1, 120.9, 120.3, 118.1, 116.6, 50.5, 48.0,44.2, 38.0, 35.9, 31.6, 29.5, 26.4, 25.8, 21.7, 13.9;

[0138] HRMS (ESI) m / z: calcd for C26H26NO4 [M+H]+ 416.1856, found 416.1860.

[0139] Embodiment 11

[0140] A method for preparing a 3-(butyl mercaptan)-4H-benzo[e][1,2]oxazine-4-one compound comprises the following steps:

[0141] (1) 3-Nitro-4H-benzo[e][1,2]oxazin-4-one (57.6 mg, 0.3 mmol), potassium carbonate (83.0 mg, 0.6 mmol), 1,4-dioxane (1.5 ml) solvent and n-butyl mercaptan (65.0 μl, 0.6 mmol) were added to a 15 ml reaction tube in sequence and reacted at 30 °C for 17 hours;

[0142] (2) Monitor by TLC until the reaction starting material disappears, cool to room temperature, and obtain a product mixed solution;

[0143] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the developing solvent to obtain a white solid (74.7 mg, yield>99%), namely 3-(butylthiol)-4H-benzo[e][1,2]oxazine-4-one compound, with the structural formula: , melting point: 44-45 ℃.

[0144] The basic parameters of this compound are as follows:

[0145] IR (KBr, cm-1): 2958, 2860, 1668, 1610, 1497, 1458, 1337, 1206, 1137,1105, 926, 850, 755, 634;

[0146] 1H NMR (500 MHz, CDCl3): δ 8.09 (dd, J = 8.1, 1.7 Hz, 1H), 7.73 (ddd,J = 8.7, 7.0, 1.7 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.40-7.33 (m, 1H), 3.06(t, J = 7.4 Hz, 2H), 1.75 (tt, J = 8.8, 6.8 Hz, 2H), 1.49 (h, J = 7.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H);

[0147] 13C NMR (126 MHz, CDCl3): δ 166.6, 162.4, 161.7, 136.0, 125.3, 125.3,116.9, 116.0, 30.3, 29.1, 22.3, 13.7;

[0148] HRMS (ESI) m / z: calcd for C12H14NO2S [M+H]+ 236.0740, found 236.0739.

[0149] Embodiment 12

[0150] A method for preparing a 3-(benzylthio)-4H-benzo[e][1,2]oxazine-4-one compound comprises the following steps:

[0151] (1) 3-Nitro-4H-benzo[e][1,2]oxazin-4-one (57.6 mg, 0.3 mmol), potassium carbonate (83.0 mg, 0.6 mmol), 1,4-dioxane (1.5 ml) solvent and benzyl mercaptan (72.0 μl, 0.6 mmol) were added to a 15 ml reaction tube in sequence and reacted at room temperature of 25°C for 12 hours;

[0152] (2) Monitor by TLC until the reaction starting material disappears, cool to room temperature, and obtain a product mixed solution;

[0153] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 6:1 as the developing solvent to obtain a white solid (81.9 mg, yield>99%), namely 3-(benzylthio)-4H-benzo[e][1,2]oxazin-4-one compound with the structural formula: , melting point: 129-130 ℃.

[0154] The basic parameters of this compound are as follows:

[0155] IR (KBr, cm-1): 3040, 1666, 1600, 1497, 1403, 1333, 1251, 1201, 1144,1104, 1024, 928, 870, 758, 694, 631,567, 526, 467;

[0156] 1H NMR (500 MHz, CDCl3): δ 8.09 (dd, J = 8.1, 1.7 Hz, 1H), 7.74 (ddd,J = 8.8, 7.0, 1.7 Hz, 1H), 7.48-7.41 (m, 3H), 7.41-7.27 (m, 4H), 4.28 (s,2H);

[0157] 13C NMR (126 MHz, CDCl3): δ 166.4, 162.4, 161.2, 136.0, 136.0, 129.4,128.7, 127.8, 125.4, 125.3, 117.0, 116.1, 34.0;

[0158] HRMS (ESI) m / z: calcd for C15H12NO2S [M+H]+ 270.0583, found 270.0582.

[0159] Embodiment 13

[0160] A method for preparing ethyl 2-((4-oxo-4H-benzo[e][1,2]oxazin-3-yl)thio)acetate compound comprises the following steps:

[0161] (1) 3-Nitro-4H-benzo[e][1,2]oxazin-4-one (57.6 mg, 0.3 mmol), potassium carbonate (83.0 mg, 0.6 mmol), 1,4-dioxane (1.5 ml) solvent and ethyl mercaptoacetate (66.0 μl, 0.6 mmol) were added to a 15 ml reaction tube in sequence and reacted at room temperature of 25°C for 11 hours;

[0162] (2) Monitor by TLC until the reaction starting material disappears, cool to room temperature, and obtain a product mixed solution;

[0163] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the developing solvent to obtain a white solid (78.7 mg, yield 99%), namely, ethyl 2-((4-oxo-4H-benzo[e][1,2]oxazin-3-yl)thio)acetate compound, with the structural formula: , melting point: 89-90 ℃.

[0164] The basic parameters of this compound are as follows:

[0165] IR (KBr, cm-1): 2988, 2930, 1736, 1668, 1605, 1510, 1460, 1377, 1313,1176, 1108, 1029, 940, 895, 856, 756, 698, 634, 527, 457;

[0166] 1H NMR (500 MHz, CDCl3): δ 8.11 (dd, J = 8.1, 1.7 Hz, 1H), 7.76 (ddd,J = 8.7, 7.0, 1.6 Hz, 1H), 7.50-7.37 (m, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.85(s, 2H), 1.30 (t, J = 7.1 Hz, 3H);

[0167] 13C NMR (126 MHz, CDCl3): δ 168.1, 166.2, 162.4, 160.2, 136.2, 125.6,125.2, 117.0, 116.1, 62.1, 31.9, 14.2;

[0168] HRMS (ESI) m / z: calcd for C12H11NO4NaS [M+Na]+ 288.0301, found288.0301.

[0169] Embodiment 14

[0170] A method for preparing 3-substituted-1,2-benzoxazine-4-one compounds, wherein in step (1), 3-nitro-4H-benzo[e][1,2]oxazine-4-one and a nucleophilic reagent are added to 3.0 mL of 1,4-dioxane solvent at a molar ratio of 1.5:2.0 to prepare a reactant mixture.

[0171] The nucleophilic reagent is at least one of benzylamine, cyclopropylamine, glycine methyl ester hydrochloride, dimethylamine, morpholine, ammonia water, p-toluenesulfonamide, methanol, isopropanol, estrone, n-butyl mercaptan, benzyl mercaptan, and ethyl thioglycolate.

[0172] The yield of various 3-substituted-1,2-benzoxazine-4-one compound products prepared in this example is not less than 50%.

[0173] Embodiment 15

[0174] A method for preparing 3-substituted-1,2-benzoxazine-4-one compounds, wherein in step (1), 3-nitro-4H-benzo[e][1,2]oxazine-4-one, a nucleophilic agent and a base are added into 3.0 mL of 1,4-dioxane solvent at a molar ratio of 1.5:2.0:4.0 to prepare a reactant mixture.

[0175] The nucleophilic reagent is at least one of benzylamine, cyclopropylamine, glycine methyl ester hydrochloride, dimethylamine, morpholine, ammonia water, p-toluenesulfonamide, methanol, isopropanol, estrone, n-butyl mercaptan, benzyl mercaptan, and ethyl thioglycolate.

[0176] The base is at least one of potassium carbonate and cesium carbonate.

[0177] The yield of various 3-substituted-1,2-benzoxazine-4-one compound products prepared in this example is not less than 50%.

[0178] Embodiment 16

[0179] A method for preparing 3-substituted-1,2-benzoxazine-4-one compounds, wherein in step (1), 3-nitro-4H-benzo[e][1,2]oxazine-4-one, a nucleophilic agent and a base are added into 3.0 mL of 1,4-dioxane solvent at a molar ratio of 1.0:2.0:4.0 to prepare a reactant mixture.

[0180] The nucleophilic reagent is at least one of benzylamine, cyclopropylamine, glycine methyl ester hydrochloride, dimethylamine, morpholine, ammonia water, p-toluenesulfonamide, methanol, isopropanol, estrone, n-butyl mercaptan, benzyl mercaptan, and ethyl thioglycolate.

[0181] The base is at least one of potassium carbonate and cesium carbonate.

[0182] The yield of various 3-substituted-1,2-benzoxazine-4-one compound products prepared in this example is not less than 50%.

[0183] Compounds containing 3-substituted-1,2-benzoxazine-4-ones have biological activity and are valuable in medicine, but the synthesis of such compounds is difficult. Therefore, on this basis, the present invention develops a method for preparing 3-substituted-1,2-benzoxazine-4-one compounds, and the synthesized compounds are all unknown compounds, which have potential application value in the field of biomedicine.

[0184] In summary, the above-mentioned Example 3-substituted-1,2-benzoxazine-4-one compounds and their synthesis methods. The structural formula of this type of compound is: ; Wherein: R is benzylamino, cyclopropylamino, glycine methyl ester, dimethylamino, morpholine, amino, p-toluenesulfonamide, methoxy, isopropoxy, estrone, n-butyl mercaptan, benzyl mercaptan, ethyl thioglycolate. The above embodiment of the present invention uses simple and easily available amines, alcohols, and thiol compounds as nucleophiles, and through simple nucleophilic substitution reactions, on the basis of retaining the biologically active 1,2-benzoxazine-4-one heterocyclic skeleton, successfully realizes the transformation of the nitro functional group in 3-nitro-1,2-benzoxazine-4-one compounds, and efficiently constructs new CN bonds, CO bonds, and CS bonds at the 3-position of the heterocyclic ring. The 3-substituted-1,2-benzoxazine-4-one compounds synthesized by this method have good development potential and application prospects in the field of biomedicine.

[0185] The embodiments of the present invention are described above, but the present invention is not limited to the above embodiments. Various changes can be made according to the purpose of the invention. Any changes, modifications, substitutions, combinations or simplifications made according to the spirit and principle of the technical solution of the present invention should be equivalent replacement methods. As long as they meet the purpose of the invention and do not deviate from the technical principles and inventive concepts of the present invention, they belong to the protection scope of the present invention.

Claims

1. A method for synthesizing 3-substituted-1,2-benzoxazine-4-one compounds, characterized in that: The steps are as follows: (1) 3-nitro-4 H -Benzo[ e [1,2]Oxazine-4-one, a nucleophile, and a base are added into 1.5-3.0 mL of a 1,4-dioxane solvent at a molar ratio of (1.0-1.5): (1.0-8.0): (0-4.0), and the reaction is carried out by stirring at 25-50°C; the nucleophile is one of benzylamine, cyclopropylamine, glycine methyl ester hydrochloride, dimethylamine, morpholine, ammonia water, p-toluenesulfonamide, methanol, isopropanol, estrone, n-butyl mercaptan, benzyl mercaptan, and ethyl thioglycolate; (2) After monitoring by TLC until the starting material completely disappears, cool to room temperature to obtain a crude product; (3) Purifying the crude product by silica gel column chromatography to obtain 3-substituted-1,2-benzoxazine-4-one compounds; The structural formula of 3-substituted-1,2-benzoxazine-4-one compounds is: ; Wherein: R is any one of benzylamino, cyclopropylamino, glycine methyl ester, dimethylamino, morpholine, amino, p-toluenesulfonamide, methoxy, isopropoxy, estrone, n-butyl mercaptan, benzyl mercaptan, and ethyl thioglycolate; the method achieves the transformation of the nitro functional group in 3-nitro-1,2-benzoxazine-4-one compounds on the basis of retaining the biologically active 1,2-benzoxazine-4-one heterocyclic skeleton, and constructs a CN bond, a CO bond, and a CS bond at the 3-position of the heterocyclic ring.

2. The method for synthesizing 3-substituted-1,2-benzoxazine-4-one compounds according to claim 1, characterized in that: In the step (1), the 3-nitro-4 H -Benzo[ e The structural formula of ][1,2]oxazine-4-one is: 。 3. The method for synthesizing 3-substituted-1,2-benzoxazine-4-one compounds according to claim 1, characterized in that: In the step (1), the base is at least one of potassium carbonate and cesium carbonate.

4. The method for synthesizing 3-substituted-1,2-benzoxazine-4-one compounds according to claim 1, characterized in that: In the step (1), the reaction is carried out under stirring at 25-50° C. for 11-18 hours.

5. The method for synthesizing 3-substituted-1,2-benzoxazine-4-one compounds according to claim 1, characterized in that: In the step (1), 3-nitro-4 H -Benzo[ e The usage ratio of ][1,2]oxazine-4-one and 1,4-dioxane solvent is 0.3mmol:1.5~3.0mL.

6. The method for synthesizing 3-substituted-1,2-benzoxazine-4-one compounds according to claim 1, characterized in that: In the step (3), when the crude product is purified by silica gel column chromatography, a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 to 20:1 is used as a developing solvent.

7. The method for synthesizing 3-substituted-1,2-benzoxazine-4-one compounds according to claim 1, characterized in that: In the step (3), when the crude product is purified by silica gel column chromatography, the excess nucleophilic reagent is removed, and the developing solvent is a mixed solvent of dichloromethane and methanol in a volume ratio of 60:1.

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