A series of 2,4-disubstituted 4H-benzo[d][1,3]oxazines, their preparation methods and applications

Abstract

The present invention belongs to the field of chemical drugs, and specifically relates to a series of 2,4-disubstituted 4H-benzo[d][1,3]oxazine compounds, a preparation method thereof, and an application thereof. The present invention adopts a preparation method for directly synthesizing a series of 2,4-disubstituted 4H-benzo[d][1,3]oxazine compounds by directly reacting an o-acylaryl isocyanide compound with a radical initiator azobisisobutyronitrile (AIBN) under the conditions of metal-free, catalyst-free, and base-free. The preparation method has simple and mild reaction conditions, high safety, high product yield, low raw material cost, and does not require the use of any catalyst and alkali solution, and is more suitable for industrial production. The series of 2,4-disubstituted 4H-benzo[d][1,3]oxazine compounds prepared by the present invention have potential biological activities and medicinal values, and can carry out gram-scale reactions.

Description

Technical Field

[0001] The present invention belongs to the field of chemical drugs, and particularly relates to a series of 2,4-disubstituted 4H-benzo[d][1,3]oxazine compounds, a preparation method thereof and an application thereof. Background Art

[0002] Benzoxazine compounds have biological activities and medicinal values such as antifungal and antimalarial activities, and are widely used in the synthesis of various drug molecules. In 2012, the Zhang research group reported a copper-catalyzed fluorine-mediated selective C-O cyclization reaction of N-o-tolylbenzamide, and successfully synthesized 4H-benzo[d][1,3]oxazine; in 2017, the Shen research group developed a method for obtaining 2-substituted 4H-benzo[d][1,3]oxazine through a cascade reaction of aldehyde with 2-aminobenzyl alcohol and 2-aminobenzylamine under the catalysis of 9-azabicyclo[3.3.1]nonane-N-oxy radical (ABNO). In recent years, many benzoxazine drug intermediates have been reported. The Kushwaha research group developed an alkylation cyclization reaction based on benzoylmethyl bromide under the action of a base to synthesize 3,4-dihydro-2H-benzo[b][1,4]oxazine. In addition, benzoxazine compounds have also been found to be used as electrical insulating materials (Laobuthee, A.; Chirachanchai, S.; Ishida, H.; Tashiro, K. J.Am. Chem. Soc. 2001, 123 , 9947-9955.). Therefore, it has certain research significance to develop a simple and efficient method for synthesizing benzoxazine compounds. Summary of the Invention

[0003] The purpose of the present invention is to solve the deficiencies of the prior art, and provide a series of 2,4-disubstituted 4H-benzo[d][1,3]oxazine compounds, a preparation method thereof and an application thereof. The following specific technical solutions are adopted:

[0004] According to the first aspect of the present invention, there is provided a series of 2,4-disubstituted 4H-benzo[d][1,3]oxazine compounds, and their structures are shown in Formula I:

[0005] Formula I; R 1 is selected from hydrogen, fluorine, chlorine, bromine or methyl, and R 2 is selected from alkyl, aryl or methoxy.

[0006] The series of 2,4-disubstituted 4H-benzo[d][1,3]oxazine compounds prepared by the present invention have good yields, wide substrate applicability, and potential biological activities and medicinal values, and can be subjected to gram-scale reactions.

[0007] According to the second aspect of the present invention, there is also provided a method for preparing the above-mentioned 2,4-disubstituted 4H-benzo[d][1,3]oxazine series, comprising the following steps:

[0008] Dissolve o-acylaryl isocyanide and azobisisobutyronitrile (AIBN) in an organic solvent and react for 14 h - 24 h to obtain the 2,4-disubstituted 4H-benzo[d][1,3]oxazine series.

[0009] The reaction equation is as follows:

[0010] ;

[0011] For the substrate o-acylaryl isocyanide, R1 is selected from hydrogen, methyl, fluorine, chlorine or bromine groups, and R2 is selected from alkyl, aryl or methoxy groups.

[0012] The present invention adopts a method for preparing the 2,4-disubstituted 4H-benzo[d][1,3]oxazine series by directly reacting an o-acylaryl isocyanide compound with a radical initiator AIBN under metal-free, catalyst-free and base-free conditions. This preparation method has simple and mild reaction conditions, high safety, high product yield, low raw material cost, and does not require the use of any catalyst and alkali solution, making it more suitable for industrial production.

[0013] Preferably, the o-acylaryl isocyanide is (2-isocyanophenyl)(phenyl)methanone, (5-bromo-2-isocyanophenyl)(phenyl)methanone, (2-isocyano-5-methylphenyl)(phenyl)methanone, (4-fluoro-2-isocyanophenyl)(phenyl)methanone, (2-isocyano-4-methylphenyl)(phenyl)methanone, (3-bromo-2-isocyanophenyl)(phenyl)methanone, (3-chloro-2-isocyanophenyl)(phenyl)methanone, (5-chloro-2-isocyanophenyl)(phenyl)methanone, (4-bromophenyl)(2-isocyanophenyl)methanone, (2-isocyanophenyl)(p-tolyl)methanone, (2-isocyanophenyl)(m-tolyl)methanone, (2-isocyanophenyl)(2-methoxyphenyl)methanone, 1-(2-isocyanophenyl)ethan-1-one.

[0014] Preferably, the molar ratio of o-acylaryl isocyanide to azobisisobutyronitrile is 1:3. When the molar ratio is lower than this range, the substrate reaction is incomplete and the yield of the target product obtained is low.

[0015] Preferably, the organic solvent is toluene, fluorobenzene, trifluorotoluene, chlorobenzene, 1,2-dichloroethane. More preferably, the organic solvent is toluene. When the organic solvent is toluene, the reactants have good solubility, the reaction efficiency is high, and the yield of the 2,4-disubstituted 4H-benzo[d][1,3]oxazine series obtained is the highest.

[0016] Preferably, the reaction temperature is 100 °C. When the system temperature is lower than 100 °C, the reaction is incomplete and the yield is low; when the system temperature is higher than 100 °C, the yield shows no obvious change.

[0017] Preferably, the reaction system needs to be carried out under an inert gas atmosphere. After the reaction is completed, the crude product also needs to be separated and purified by reduced pressure and concentration.

[0018] According to the third aspect of the present invention, there is also provided the use of the above-mentioned 2,4-disubstituted 4H-benzo[d][1,3]oxazine series in the preparation of drugs.

[0019] The synthetic product prepared by the present invention has the same parent ring skeleton as multiple drug molecules, so the product has potential biological activity and medicinal value.

[0020] The beneficial effects of the present invention are as follows: The present invention adopts a preparation method for synthesizing 2,4-disubstituted 4H-benzo[d][1,3]oxazine series by directly reacting o-acylaryl isocyanide compounds with a radical initiator AIBN under metal-free, catalyst-free, and base-free conditions. This preparation method has simple and mild reaction conditions, high safety, high product yield, low raw material cost, and does not require the use of any catalysts and alkali solutions, making it more suitable for industrial production. The 2,4-disubstituted 4H-benzo[d][1,3]oxazine series prepared by the present invention has potential biological activity and medicinal value and can be subjected to gram-scale reactions. Detailed implementation manners

[0021] The following will clearly and completely describe the concept and technical effects generated by the present invention in combination with the embodiments to fully understand the purpose, solution, and effects of the present invention. It should be noted that, without conflict, the embodiments in the present application and the features in the embodiments can be combined with each other.

[0022] Example 1

[0023] A 2,4-disubstituted 4H-benzo[d][1,3]oxazine series, the structure of which is shown in Formula 3a:

[0024] 3a;

[0025] The specific preparation method is as follows: Take a clean reaction tube, add (2-isocyanatophenyl)(phenyl)methanone (0.2 mmol, 1.0 equiv) and AIBN (0.6 mmol, 3.0 equiv), seal it, evacuate and refill with gas three times, and end with argon. After adding toluene (2 mL) with a syringe, react at 100 °C for 14 h until the reaction is complete as detected by TLC. The crude product is separated and purified by flash column chromatography (PE:EA = 30:1) through reduced pressure and concentration operations to obtain 2,2'-(4-phenyl-4H-benzo[d][1,3]oxazine-2,4-diyl)bis(2-methylpropanenitrile), 3a, 57.5 mg, with a yield of 84%.

[0026] The NMR and mass spectrometry test results of 3a are as follows: 1 H NMR(400 MHz, CDCl3) δ 7.94 – 7.92 (m, 1H),7.66 – 7.60 (m, 2H), 7.41 –7.30 (m, 5H), 7.23 – 7.18 (m, 1H), 1.76 (s, 3H),1.74(s, 3H), 1.62 (s, 3H), 1.59 (s, 3H). 13 C NMR (100 MHz, CDCl3)δ 157.2,138.9, 137.9, 129.7, 128.8, 128.3, 127.6, 127.1, 126.3, 125.9, 124.5,123.8,121.6, 85.7, 41.6, 38.3, 26.1, 25.2, 24.0, 22.7.HRMS (ESI, m / z): Calcd forC 22 H 21 N3ONa + : ([M+Na] + ), 366.1577,found, 366.1575。

[0027] Example 2

[0028] A 2,4-disubstituted 4H-benzo[d][1,3]oxazine series compound, whose structure is shown in Formula 3b:

[0029] 3b;

[0030] The specific preparation method is as follows: Take a clean reaction test tube, add (5-bromo-2-isocyanophenyl)(phenyl)methanone (0.2 mmol, 1.0 equiv) and AIBN (0.6 mmol, 3.0 equiv), seal it, evacuate and refill with gas three times, and end with argon. After adding toluene (2 mL) with a syringe, react at 100 °C for 14 h until the reaction is complete as detected by TLC. The crude product is separated and purified by flash column chromatography (PE:EA = 30:1) through reduced pressure and concentration operations to obtain 2,2'-(6-bromo-4-phenyl-4H-benzo[d][1,3]oxazine-2,4-diyl)bis(2-methylacrylonitrile), 3b, 46.3 mg, with a yield of 55%.

[0031] The NMR and mass spectrometry test results of 3b are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J J = 1.7 Hz, 1H), 7.65 – 7.58 (m, 2H), 7.48 (dd, J J = 8.4, 2.0 Hz, 1H), 7.45 – 7.32 (m, 3H), 7.09 (d, J J = 8.4 Hz, 1H), 1.75 (s, 3H), 1.73 (s, 3H), 1.61 (s, 3H), 1.58 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 157.7, 138.3, 137.0, 133.0, 129.0, 128.8, 128.5, 127.9, 127.0, 126.2, 123.3, 121.3, 120.7, 85.4, 41.7, 38.3, 25.9, 25.2, 24.0, 22.7. HRMS (ESI, m / z): Calcd for C 22 H 20 BrN3ONa + : ([M + Na] + +), 444.0682, found, 444.0672.

[0032] Example 3

[0033] A series of 2,4-disubstituted 4H-benzo[d][1,3]oxazine compounds, whose structures are shown in Formula 3c:

[0034] 3c;

[0035] The specific preparation method is as follows: Take a clean reaction test tube, add (2-isocyano-5-methylphenyl)(phenyl)methanone (0.2 mmol, 1.0 equiv) and AIBN (0.6 mmol, 3.0 equiv), seal it, evacuate and refill with gas three times, and end with argon. After adding toluene (2 mL) with a syringe, react at 100 °C for 14 h until the reaction is complete as detected by TLC. The crude product is separated and purified by flash column chromatography (PE:EA = 30:1) through reduced pressure and concentration operations to obtain 2,2'-(6-methyl-4-phenyl-4H-benzo[d][1,3]oxazine-2,4-diyl)bis(2-methylacrylonitrile), 3c, 33.8 mg, with a yield of 47%.

[0036] The NMR and mass spectrometry test results of 3c are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.63 – 7.54 (m, 3H), 7.34 – 7.22 (m, 3H), 7.07 (dd, J = 8.0, 1.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 2.33 (s, 3H), 1.67 (s, 3H), 1.65 (s, 3H), 1.54 (s, 3H), 1.50 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 156.4, 139.2, 137.6, 135.5, 130.3, 128.7, 128.2, 127.1, 126.3, 126.1, 124.2, 123.9, 121.7, 85.7, 41.7, 38.2, 26.0, 25.3, 24.0, 22.7, 21.6. HRMS (ESI, m / z): Calcd for C 23 H 23 N3ONa + : ([M + Na] + ), 380.1733, found, 380.1741。

[0037] Example 4

[0038] A 2,4-disubstituted 4H-benzo[d][1,3]oxazine series compound, whose structure is shown in Formula 3d:

[0039] 3d;

[0040] The specific preparation method is as follows: Take a clean reaction tube, add (4-fluoro-2-isocyanophenyl)(phenyl)methanone (0.2 mmol, 1.0 equiv) and AIBN (0.6 mmol, 3.0 equiv), seal it, evacuate and refill with gas three times, and end with argon. After adding toluene (2 mL) with a syringe, react at 100 °C for 20 h until the reaction is complete as detected by TLC. The crude product is separated and purified by flash column chromatography (PE:EA = 30:1) through reduced pressure and concentration operations to obtain 2,2'-(7-fluoro-4-phenyl-4H-benzo[d][1,3]oxazine-2,4-diyl)bis(2-methylacrylonitrile), 3d, 40.7 mg, with a yield of 56%.

[0041] The NMR and MS test results of 3d are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J J = 6.0 Hz, 1H), 7.62 (d, J J = 7.5 Hz, 2H), 7.46 – 7.33 (m, 3H), 7.06 (t, J J = 8.4 Hz, 1H), 6.95 (d, J J = 9.0 Hz, 1H), 1.78 (s, 3H), 1.76 (s, 3H), 1.64 (s, 3H), 1.60 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 163.0 (d, J J = 247.9 Hz), 158.4, 139.9 (d, J J = 11.1 Hz), 138.7, 128.9, 128.4, 127.5 (d, J J = 9.1 Hz), 127.0, 123.6, 121.4, 120.4 (d, J J = 3.4 Hz), 114.4 (d, J J = 21.7 Hz), 113.2 (d, J J = 22.7 Hz), 85.9, 41.7, 38.3, 26.0, 25.2, 24.0, 22.6. HRMS (ESI, m / z): Calcd for C 22 H 20 FN3ONa + : ([M + Na] + +), 384.1483, found, 384.1484。

[0042] Example 5

[0043] A series of 2,4-disubstituted 4H-benzo[d][1,3]oxazines, the structure of which is shown in Formula 3e:

[0044] 3e;

[0045] The specific preparation method is as follows: Take a clean reaction test tube, add (2-isocyano-4-methylphenyl)(phenyl)methanone (0.2 mmol, 1.0 equiv) and AIBN (0.6 mmol, 3.0 equiv), seal it, evacuate and replace the gas three times, and end with argon. After adding toluene (2 mL) with a syringe, react at 100 °C for 13 h until the reaction is complete as detected by TLC. The crude product was purified by flash column chromatography (PE:EA = 20:1) through reduced pressure and concentration operations to obtain 2,2'-(7-methyl-4-phenyl-4H-benzo[d][1,3]oxazine-2,4-diyl)bis(2-methylacrylonitrile), 3e, 47.2 mg, yield 66%.

[0046] The NMR and mass spectrometry test results of 3e are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J J = 8.0 Hz, 1H), 7.65 – 7.59 (m, 2H), 7.40 – 7.28 (m, 3H), 7.14 (dd, J J = 8.0, 1.0 Hz, 1H), 7.04 (s, 1H), 2.34 (s, 3H), 1.75 (s, 3H), 1.73 (s, 3H), 1.61 (s, 3H), 1.58 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 157.2, 139.8, 139.1, 137.7, 128.6, 128.2, 128.2, 127.1, 126.8, 125.7, 123.8, 121.6, 121.6, 85.8, 41.7, 38.2, 26.0, 25.3, 24.0, 22.7, 20.9. HRMS (ESI, m / z): Calcd for C 23 H 23 N3ONa + : ([M + Na] + +), 380.1733, found, 380.1733。

[0047] Example 6

[0048] A 2,4-disubstituted 4H-benzo[d][1,3]oxazine series compound, whose structure is shown in Formula 3f:

[0049] 3f;

[0050] The specific preparation method is as follows: Take a clean reaction test tube, add (3-bromo-2-isocyanatophenyl)(phenyl)methanone (0.2 mmol, 1.0 equiv) and AIBN (0.6 mmol, 3.0 equiv), seal it, evacuate and refill with gas three times, and end with argon. After adding toluene (2 mL) with a syringe, react at 100 °C for 14 h, and wait until the reaction is complete as detected by TLC. The crude product is separated and purified by flash column chromatography (PE:EA = 30:1) through reduced pressure and concentration operations to obtain 2,2'-(8-bromo-4-phenyl-4H-benzo[d][1,3]oxazine-2,4-diyl)bis(2-methylacrylonitrile), 3f, 64.8 mg, with a yield of 77%.

[0051] The NMR and mass spectrometry test results of 3f are as follows: 1 H NMR(400 MHz, CDCl3) δ 7.84 (d, J = 7.8 Hz,1H), 7.57 – 7.50 (m,3H), 7.35 – 7.23 (m, 3H), 7.11 (t, J = 8.0 Hz, 1H), 1.72(s, 3H), 1.70(s, 3H), 1.56 (s, 3H), 1.51 (s, 3H). 13 C NMR (100 MHz, CDCl3)δ158.4, 138.2, 136.1,133.8, 129.0, 128.4, 128.1, 127.1, 126.5, 125.1, 123.5,122.3, 121.3, 85.9, 41.5, 38.3, 26.2, 25.2, 24.1, 22.8. HRMS (ESI, m / z):Calcd for C 22 H 20 BrN3ONa + :([M + Na] + ), 444.0682, found, 444.0689。

[0052] Example 7

[0053] A series of 2,4-disubstituted 4H-benzo[d][1,3]oxazines, the structure of which is shown in Formula 3g:

[0054] 3g;

[0055] The specific preparation method is as follows: Take a clean reaction test tube, add (3-chloro-2-isocyanatophenyl)(phenyl)methanone (0.2 mmol, 1.0 equiv) and AIBN (0.6 mmol, 3.0 equiv), seal it, evacuate and replace the gas three times, end with argon, add toluene (2 mL) with a syringe, and react at 100 °C for 14 h until the reaction is complete as detected by TLC. The crude product was purified by flash column chromatography (PE:EA = 30:1) through reduced pressure and concentration operations to obtain 2,2'-(8-chloro-4-phenyl-4H-benzo[d][1,3]oxazine-2,4-diyl)bis(2-methylacrylonitrile), 3g, 53.5 mg, with a yield of 71%.

[0056] The NMR and mass spectrometry test results of 3g are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J J = 7.8 Hz, 1H), 7.53 (d, J J = 7.2 Hz, 2H), 7.38 – 7.24 (m, 4H), 7.18 (t, J J = 8.0 Hz, 1H), 1.72 (s, 3H), 1.69 (s, 3H), 1.56 (s, 3H), 1.51 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 158.3, 138.3, 135.0, 131.5, 130.7, 129.0, 128.4, 127.6, 127.1, 126.4, 124.4, 123.5, 121.4, 85.8, 41.6, 38.4, 26.2, 25.3, 24.1, 22.8. HRMS (ESI, m / z): Calcd for C 22 H 20 ClN3ONa + : ([M + Na] + ), 400.1187, found, 400.1194.

[0057] Example 8

[0058] A series of 2,4-disubstituted 4H-benzo[d][1,3]oxazines, the structure of which is shown in Formula 3h:

[0059] 3 h;

[0060] The specific preparation method is as follows: Take a clean reaction test tube, add (5-chloro-2-isocyanatophenyl)(phenyl)methanone (0.2 mmol, 1.0 equiv) and AIBN (0.6 mmol, 3.0 equiv), seal it, evacuate and refill with gas three times, and end with argon. After adding toluene (2 mL) with a syringe, react at 100 °C for 13 h until the reaction is complete as detected by TLC. The crude product is separated and purified by flash column chromatography (PE:EA = 30:1) through reduced pressure and concentration operations to obtain 2,2'-(6-chloro-4-phenyl-4H-benzo[d][1,3]oxazine-2,4-diyl)bis(2-methylacrylonitrile), 3 h, 39.6 mg, with a yield of 52%.

[0061] The NMR and mass spectrometry test results for 3 h are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J J = 2.0 Hz, 1H), 7.67 – 7.61 (m, 2H), 7.47 – 7.37 (m, 3H), 7.35 (dd, J J = 8.4, 2.2 Hz, 1H), 7.18 (d, J J = 8.4 Hz, 1H), 1.77 (s, 3H), 1.76 (s, 3H), 1.64 (s, 3H), 1.61 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 157.5, 138.3, 136.5, 133.0, 129.9, 129.0, 128.5, 127.6, 127.0, 125.9, 125.9, 123.3, 121.4, 85.5, 41.7, 38.3, 26.0, 25.2, 24.0, 22.7. HRMS (ESI, m / z): Calcd for C 22 H 20 ClN3ONa + : ([M + Na] + ), 400.1187, found, 400.1179.

[0062] Example 9

[0063] A 2,4-disubstituted 4H-benzo[d][1,3]oxazine series compound, whose structure is shown in Formula 3i:

[0064] 3i;

[0065] The specific preparation method is as follows: Take a clean reaction test tube, add (4-bromophenyl)(2-isocyanatophenyl)methanone (0.2 mmol, 1.0 equiv) and AIBN (0.6 mmol, 3.0 equiv), seal it, evacuate and refill with gas three times, and end with argon. After adding toluene (2 mL) with a syringe, react at 100 °C for 20 h until the reaction is complete as detected by TLC. The crude product was purified by flash column chromatography (PE:EA = 40:1) through reduced pressure and concentration operations to obtain 2,2'-(4-(4-bromophenyl)-4H-benzo[d][1,3]oxazine-2,4-diyl)bis(2-methylacrylonitrile), 3i, 54.7 mg, with a yield of 65%.

[0066] The NMR and mass spectrometry test results of 3i are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.96 (dd, J J = 6.4, 3.5 Hz, 1H), 7.53 (s, 4H), 7.41 – 7.35 (m, 2H), 7.26 – 7.21 (m, 1H), 1.77 (s, 3H), 1.75 (s, 3H), 1.63 (s, 3H), 1.60 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 157.0, 137.9, 137.8, 131.5, 130.0, 128.9, 127.8, 126.6, 125.6, 124.1, 123.5, 123.3, 121.6, 85.3, 41.5, 38.2, 26.1, 25.1, 23.9, 22.7. HRMS (ESI, m / z): Calcd for C 22 H 20 BrN3ONa + :([M + Na] + ), 444.0682, found, 444.0678.

[0067] Example 10

[0068] A 2,4-disubstituted 4H-benzo[d][1,3]oxazine series compound, whose structure is shown in Formula 3j:

[0069] 3j;

[0070] The specific preparation method is as follows: Take a clean reaction test tube, add (2-isocyanatophenyl)(p-tolyl)methanone (0.2 mmol, 1.0 equiv) and AIBN (0.6 mmol, 3.0 equiv), seal it, evacuate and refill with gas three times, and end with argon. After adding toluene (2 mL) with a syringe, react at 100 °C for 21 h until the reaction is complete as detected by TLC. The crude product is separated and purified by flash column chromatography (PE:EA = 30:1) through reduced pressure and concentration operations to obtain 2,2'-(4-(p-tolyl)-4H-benzo[d][1,3]oxazine-2,4-diyl)bis(2-methylacrylonitrile), 3j, 37.7 mg, with a yield of 53%.

[0071] The NMR and mass spectrometry test results of 3j are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.91 (d, J J = 7.6 Hz, 1H), 7.49 (d, J J = 8.2 Hz, 2H), 7.37 – 7.29 (m, 2H), 7.20 – 7.14 (m, 3H), 2.32 (s, 3H), 1.75 (s, 3H), 1.73 (s, 3H), 1.62 (s, 3H), 1.57 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 157.3, 138.7, 137.9, 135.9, 129.6, 128.9, 127.5, 127.1, 126.3, 125.8, 124.7, 123.9, 121.7, 85.7, 41.6, 38.3, 26.0, 25.2, 24.0, 22.8, 21.0. HRMS (ESI, m / z): Calcd for C 23 H 23 N3ONa + : ([M + Na] + +), 380.1733, found, 380.1741。

[0072] Example 11

[0073] A series of 2,4-disubstituted 4H-benzo[d][1,3]oxazine compounds, whose structures are shown in Formula 3k:

[0074] 3k;

[0075] The specific preparation method is as follows: Take a clean reaction test tube, add (2-isocyanatophenyl)(m-tolyl)methanone (0.2 mmol, 1.0 equiv) and AIBN (0.6 mmol, 3.0 equiv), seal it, evacuate and refill with gas three times, and end with argon. After adding toluene (2 mL) with a syringe, react at 100 °C for 21 h until the reaction is complete as detected by TLC. The crude product is separated and purified by flash column chromatography (PE:EA = 40:1) through reduced pressure and concentration operations to obtain 2,2'-(4-(m-tolyl)-4H-benzo[d][1,3]oxazine-2,4-diyl)bis(2-methylacrylonitrile), 3k, 43.3 mg, with a yield of 61%.

[0076] The NMR and mass spectrometry test results of 3k are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.97 –7.88 (m, 1H),7.42 (d, J = 9.2 Hz, 2H), 7.36 – 7.30 (m, 2H), 7.25 (t, J = 7.6 Hz, 1H), 7.22 –7.16 (m, 1H), 7.13 (d, J = 7.4 Hz, 1H), 2.35(s, 3H), 1.76 (s, 3H), 1.74(s, 3H),1.62 (s, 3H), 1.58 (s, 3H). 13 C NMR (100 MHz, CDCl3)δ 157.3, 138.8, 138.0,137.8, 129.6, 129.5, 128.1, 127.7, 127.5, 126.3, 125.9,124.7, 124.3, 123.8,121.7, 85.7, 41.6, 38.2, 26.0, 25.2, 24.1, 22.8, 21.6.HRMS (ESI, m / z): Calcdfor C 23 H 23 N3ONa + : ([M + Na] + ), 380.1733,found, 380.1723。

[0077] Example 12

[0078] A series of 2,4-disubstituted 4H-benzo[d][1,3]oxazines, the structure of which is shown in Formula 3l:

[0079] 3l;

[0080] The specific preparation method is as follows: Take a clean reaction test tube, add (2-isocyanatophenyl)(2-methoxyphenyl)methanone (0.2 mmol, 1.0 equiv) and AIBN (0.6 mmol, 3.0 equiv), seal it, evacuate and refill with gas three times, and end with argon. After adding toluene (2 mL) with a syringe, react at 100 °C for 17 h until the reaction is complete as detected by TLC. The crude product was separated and purified by flash column chromatography (PE:EA = 40:1) through reduced pressure and concentration operations to obtain 2,2'-(4-(2-methoxyphenyl)-4H-benzo[d][1,3]oxazine-2,4-diyl)bis(2-methylacrylonitrile). 3l, 30.6 mg, yield 41%.

[0081] The NMR and mass spectrometry test results of 3l are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.08 (d, J J = 7.9 Hz, 1H), 7.37 (t, J J = 8.0 Hz, 1H), 7.27 – 7.16 (m, 2H), 7.09 – 7.00 (m, 3H), 6.89 (d, J J = 8.2 Hz, 1H), 3.40 (s, 3H), 1.79 (s, 3H), 1.70 (s, 3H), 1.67 (s, 3H), 1.42 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 158.9, 157.1, 137.9, 130.6, 129.1, 128.9, 126.9, 126.8, 125.3, 124.8, 124.1, 123.9, 121.8, 119.5, 113.3, 85.0, 55.4, 41.6, 38.3, 25.4, 24.8, 23.8, 22.2. HRMS (ESI, m / z): Calcd for C 23 H 23 N3O2Na + : ([M + Na] + +), 396.1682, found, 396.1675.

[0082] Example 13

[0083] A 2,4-disubstituted 4H-benzo[d][1,3]oxazine series compound, the structure of which is shown in Formula 3m:

[0084] 3m;

[0085] The specific preparation method is as follows: Take a clean reaction test tube, add 1-(2-isocyanophenyl)ethan-1-one (0.2 mmol, 1.0 equiv) and AIBN (0.6 mmol, 3.0 equiv), seal it, evacuate and refill with gas three times, end with argon, add toluene (2 mL) with a syringe, then place it in a reaction at 100 °C for 14 h until the reaction is complete as detected by TLC. The crude product is separated and purified by flash column chromatography (PE:EA = 30:1) through decompression and concentration operations to obtain 2,2'-(4-methyl-4H-benzo[d][1,3]oxazine-2,4-diyl)bis(2-methylpropanenitrile), 3m, 44.5 mg, with a yield of 79%.

[0086] The NMR and mass spectrometry test results of 3m are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.26 (t, J J = 8.0 Hz, 2H), 7.21 – 7.16 (m, 1H), 7.14 (d, J J = 7.8 Hz, 1H), 1.85 (s, 3H), 1.63 (s, 3H), 1.62 (s, 3H), 1.42 (s, 3H), 1.26 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 157.7, 137.6, 129.8, 127.8, 126.0, 125.1, 124.0, 123.0, 121.5, 83.2, 43.9, 38.2, 25.4, 25.4, 24.8, 22.2, 21.4. HRMS (ESI, m / z): Calcd for C 17 H 19 N3ONa + : ([M + Na] + ), 304.1420, found, 304.1429.

[0087] Although the description of the present invention has been quite detailed and particularly describes several of the described embodiments, it is not intended to be limited to any of these details or embodiments or any particular embodiment, but rather should be regarded as providing a broad interpretation of these claims in light of the prior art by reference to the appended claims, thereby effectively covering the intended scope of the present invention. In addition, the present invention is described above in terms of embodiments foreseeable by the inventors for the purpose of providing a useful description, and non-substantive modifications to the present invention that are not currently foreseeable may still represent equivalent modifications of the present invention.

Claims

1. A preparation method of a benzod[d][1,3]oxazine series compound, characterized in that, It includes the following steps: Dissolve o-acylaryl isocyanide and azobisisobutyronitrile in an organic solvent, and react for 14 h - 24 h under an inert gas atmosphere to obtain a series of benzod[d][1,3]oxazine compounds; The o-acylaryl isocyanide is (2-isocyanophenyl)(phenyl)methanone, (5-bromo-2-isocyanophenyl)(phenyl)methanone, (2-isocyano-5-methylphenyl)(phenyl)methanone, (4-fluoro-2-isocyanophenyl)(phenyl)methanone, (2-isocyano-4-methylphenyl)(phenyl)methanone, (3-bromo-2-isocyanophenyl)(phenyl)methanone, (3-chloro-2-isocyanophenyl)(phenyl)methanone, (5-chloro-2-isocyanophenyl)(phenyl)methanone, (4-bromophenyl)(2-isocyanophenyl)methanone, (2-isocyanophenyl)(p-tolyl)methanone, (2-isocyanophenyl)(m-tolyl)methanone, (2-isocyanophenyl)(2-methoxyphenyl)methanone, 1-(2-isocyanophenyl)ethan-1-one; The structure of the series of benzod[d][1,3]oxazine compounds is shown as follows: 、 、 、 、 、 、 、 、 、 、 、 、 。 2. The preparation method according to claim 1, characterized in that, The molar ratio of the o-acylaryl isocyanide to azobisisobutyronitrile is 1:

3.

3. The preparation method according to claim 1, wherein, The organic solvent is toluene, fluorobenzene, trifluorotoluene, chlorobenzene, 1,2-dichloroethane.

4. The preparation method according to claim 1, characterized in that, The organic solvent is toluene.

5. The preparation method according to claim 1, wherein The reaction temperature is 100 °C.

6. The preparation method according to claim 1, wherein After the reaction is completed, the crude product needs to be separated and purified by decompression and concentration.

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