CN117164531A - 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series, preparation method and application thereof - Google Patents
2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series, preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- KGWNRZLPXLBMPS-UHFFFAOYSA-N 2h-1,3-oxazine Chemical class C1OC=CC=N1 KGWNRZLPXLBMPS-UHFFFAOYSA-N 0.000 title claims abstract description 18
- -1 [1,3] oxazine series compound Chemical class 0.000 claims abstract description 59
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 239000003814 drug Substances 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 49
- 239000012043 crude product Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 7
- 125000003944 tolyl group Chemical group 0.000 claims description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- QCCRJBGXYNIAPO-UHFFFAOYSA-N (5-chloro-2-isocyanatophenyl)-phenylmethanone Chemical compound ClC1=CC=C(N=C=O)C(C(=O)C=2C=CC=CC=2)=C1 QCCRJBGXYNIAPO-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- HSOSFVSBJKBBHW-UHFFFAOYSA-N (2-isocyanatophenyl)-phenylmethanone Chemical group O=C=NC1=CC=CC=C1C(=O)C1=CC=CC=C1 HSOSFVSBJKBBHW-UHFFFAOYSA-N 0.000 claims description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- 150000003254 radicals Chemical class 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000003999 initiator Substances 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000004071 biological effect Effects 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- 229910052786 argon Inorganic materials 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- 239000007789 gas Substances 0.000 description 12
- 230000005311 nuclear magnetism Effects 0.000 description 12
- 238000001819 mass spectrum Methods 0.000 description 11
- 238000007789 sealing Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 2
- 150000005130 benzoxazines Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 2
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- PZWQSPGETWGKPS-UHFFFAOYSA-N (2-isocyanophenyl)-phenylmethanone Chemical compound C=1C=CC=C([N+]#[C-])C=1C(=O)C1=CC=CC=C1 PZWQSPGETWGKPS-UHFFFAOYSA-N 0.000 description 1
- KIEKZKLQIRABBK-UHFFFAOYSA-N 1-(2-isocyanatophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1N=C=O KIEKZKLQIRABBK-UHFFFAOYSA-N 0.000 description 1
- GVOYKJPMUUJXBS-UHFFFAOYSA-N 2-(aminomethyl)aniline Chemical compound NCC1=CC=CC=C1N GVOYKJPMUUJXBS-UHFFFAOYSA-N 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical compound C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012777 electrically insulating material Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- BSASAHDKONAXQX-UHFFFAOYSA-N n-(2-methylphenyl)benzamide Chemical compound CC1=CC=CC=C1NC(=O)C1=CC=CC=C1 BSASAHDKONAXQX-UHFFFAOYSA-N 0.000 description 1
- 150000004893 oxazines Chemical class 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The application belongs to the field of chemical drugs, and particularly relates to a 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series compound, and a preparation method and application thereof. The application adopts a preparation method for synthesizing 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series by directly reacting an ortho-acyl aryl isonitrile compound with a free radical initiator azo diisobutyronitrile (AIBN) under the conditions of no metal, no catalyst and no alkali. The preparation method has the advantages of simple and mild reaction conditions, high safety, high product yield, low raw material cost, no need of any catalyst or alkali liquor, and suitability for industrial production. The 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series prepared by the application has potential biological activity and medicinal value, and can be subjected to gram-scale reaction.
Description
Technical Field
The application belongs to the field of chemical drugs, and particularly relates to a 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series compound, and a preparation method and application thereof.
Background
Benzoxazine compounds have antifungal, antimalarial, and other biological and medicinal values and are widely used for synthesizing various drug molecules. In 2012, zhang's topic reported oneCopper-catalyzed fluorine-mediated selective C-O cyclization reaction of N-O-tolylbenzamide to successfully synthesize 4H-benzo [ d ]][1,3]Oxazine; in 2017, the Shen topic group was in 9-azabicyclo [3.3.1 ]]Catalytic reaction of nonane-N-oxyl radical (ABNO) with 2-aminobenzyl alcohol and 2-aminobenzylamine to give 2-substituted 4H-benzo [ d ]][1,3]A method of oxazine. In recent years, a number of benzoxazine drug intermediates have been published, and the Kushwaha subject group has 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]Oxazines. In addition, benzoxazine compounds have also been found to be useful as electrically insulating materials (laobuthe, a.; chirachachi, s.; ishida, h.; tashiro, K).J.Am. Chem. Soc.2001,123, 9947-9955.). Therefore, the method for synthesizing the benzoxazine compound by developing a simple and efficient method has a certain research significance.
Disclosure of Invention
The application aims to solve the defects in the prior art and provides a 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series and a preparation method and application thereof, wherein the preparation method specifically adopts the following technical scheme:
according to a first aspect of the present application there is provided a 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series having the structure shown in formula I:
a formula I; r is R 1 Selected from hydrogen, fluorine, chlorine, bromine or methyl, R 2 Selected from alkyl, aryl or methoxy.
The 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series prepared by the application has good yield, wide substrate applicability, potential bioactivity and medicinal value, and can perform gram-scale reaction.
According to a second aspect of the present application, there is also provided a process for the preparation of the above 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series comprising the steps of:
o-acyl aryl isonitrile and Azobisisobutyronitrile (AIBN) are dissolved in an organic solvent to react 14H-24H to obtain 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series.
The reaction equation is as follows:
；
r1 of the substrate ortho-acyl aryl isonitrile is selected from hydrogen, methyl, fluorine, chlorine or bromine groups, and R2 is selected from alkyl, aryl or methoxy groups.
The application adopts a preparation method for synthesizing 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series by directly reacting an ortho-acyl aryl isonitrile compound with a free radical initiator AIBN under the conditions of no metal, no catalyst and no alkali. The preparation method has the advantages of simple and mild reaction conditions, high safety, high product yield, low raw material cost, no need of any catalyst or alkali liquor, and suitability for industrial production.
Preferably, the ortho-acyl aryl isonitrile is (2-isocyanatophenyl) (phenyl) methanone, (5-bromo-2-isocyanatophenyl) (phenyl) methanone, (2-isocyanatophenyl-5-methylphenyl) (phenyl) methanone, (4-fluoro-2-isocyanatophenyl) (phenyl) methanone, (2-isocyanato-4-methylphenyl) (phenyl) methanone, (3-bromo-2-isocyanatophenyl) (phenyl) methanone, (3-chloro-2-isocyanatophenyl) (phenyl) methanone, (5-chloro-2-isocyanatophenyl) (phenyl) methanone, (4-bromophenyl) (2-isocyanatophenyl) methanone, (2-isocyanatophenyl) (m-tolyl) methanone, (2-isocyanatophenyl) (2-methoxyphenyl) methanone, 1- (2-isocyanatophenyl) ethan-1-one.
Preferably, the molar ratio of ortho-acyl aryl isonitriles to azobisisobutyronitrile is 1:3. when the molar ratio is below this range, the substrate reaction is incomplete, and the yield of the produced target product is low.
Preferably, the organic solvent is toluene, fluorobenzene, benzotrifluoride, chlorobenzene, 1, 2-dichloroethane. More preferably, the organic solvent is toluene. When the organic solvent is toluene, the solubility of the reactant is good, the reaction efficiency is high, and the yield of the prepared 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series is highest.
Preferably, the reaction temperature is 100 ℃. When the system temperature is lower than 100 ℃, the reaction is incomplete, and the yield is low; when the temperature of the system is higher than 100 ℃, the yield is not changed obviously.
Preferably, the reaction system is required to be carried out under an inert gas atmosphere. After the reaction is finished, the crude product is separated and purified by decompression and concentration.
According to a third aspect of the present application there is also provided the use of the 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series described above in the manufacture of a medicament.
The synthesized product prepared by the application has the same parent ring skeleton with a plurality of drug molecules, so the product has potential bioactivity and medicinal value.
The beneficial effects of the application are as follows: the application adopts a preparation method for synthesizing 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series by directly reacting an ortho-acyl aryl isonitrile compound with a free radical initiator AIBN under the conditions of no metal, no catalyst and no alkali. The preparation method has the advantages of simple and mild reaction conditions, high safety, high product yield, low raw material cost, no need of any catalyst or alkali liquor, and suitability for industrial production. The 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series prepared by the application has potential biological activity and medicinal value, and can be subjected to gram-scale reaction.
Detailed Description
The following is a clear and complete description of the conception and technical effects produced by the embodiment of the present application to fully understand the objects, aspects, and effects of the present application. It should be noted that, without conflict, the embodiments of the present application and features of the embodiments may be combined with each other.
Example 1
A2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series compound has a structure shown in a formula 3 a:
3a；
the preparation method comprises the following steps: a clean reaction tube was taken, and after (2-isocyanophenyl) (phenyl) methanone (0.2 mmol,1.0 equiv) and AIBN (0.6mmol,3.0 equiv) were added and sealed, the gas was purged three times, and after argon was terminated, toluene (2 mL) was added by syringe and allowed to react at 100℃for 14 h until complete reaction was detected by TLC. The crude product was purified by flash column chromatography (PE: ea=30:1) by reduced pressure, concentration to give 2,2' - (4-phenyl-4H-benzo [ d ] [1,3] oxazine-2, 4-diyl) bis (2-methylpropanenitrile), 3a,57.5 mg, 84% yield.
3a, the results of the nuclear magnetism and mass spectrometry test are: 1 H NMR(400 MHz, CDCl 3 ) 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, CDCl 3 )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 for C 22 H 21 N 3 ONa + : ([M+Na] + ), 366.1577,found, 366.1575。
example 2
A2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series compound has a structure shown in a formula 3 b:
3b；
the preparation method comprises the following steps: a clean reaction tube was taken, and after sealing with (5-bromo-2-isocyanatophenyl) (phenyl) methanone (0.2 mmol,1.0 equiv) and AIBN (0.6 mmol,3.0 equiv), the gas was purged three times, and after argon was terminated, toluene (2 mL) was added by syringe and allowed to react at 100℃for 14 h until complete reaction was detected by TLC. The crude product was purified by flash column chromatography (PE: ea=30:1) by reduced pressure, concentration to give 2,2' - (6-bromo-4-phenyl-4H-benzo [ d ] [1,3] oxazine-2, 4-diyl) bis (2-methacrylonitrile), 3b,46.3mg, 55% yield.
3b, the results of the nuclear magnetic resonance and mass spectrometry test are: 1 H NMR (400 MHz, CDCl 3 ) δ 8.01(d,J= 1.7 Hz, 1H), 7.65 – 7.58 (m, 2H), 7.48 (dd,J= 8.4, 2.0Hz, 1H), 7.45 – 7.32 (m, 3H), 7.09 (d,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, CDCl 3 ) 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 BrN 3 ONa + : ([M + Na] + ), 444.0682,found, 444.0672。
example 3
A2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series compound has a structure shown in a formula 3 c:
3c；
the preparation method comprises the following steps: a clean reaction tube was taken, and after sealing with (2-isocyano-5-methylphenyl) (phenyl) methanone (0.2 mmol,1.0 equiv) and AIBN (0.6 mmol,3.0 equiv), the gas was purged three times, and after argon was terminated, toluene (2 mL) was added by syringe and allowed to react at 100℃for 14 h until complete reaction was detected by TLC. The crude product was purified by flash column chromatography (PE: ea=30:1) by reduced pressure, concentration to give 2,2' - (6-methyl-4-phenyl-4H-benzo [ d ] [1,3] oxazine-2, 4-diyl) bis (2-methacrylonitrile), 3c,33.8 mg, 47% yield.
The nuclear magnetism and mass spectrum test results of 3c are: 1 H NMR (400 MHz, CDCl 3 ) 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 CNMR (100 MHz, CDCl 3 ) 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 N 3 ONa + : ([M + Na] + ), 380.1733,found, 380.1741。
example 4
A2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series compound has a structure shown in a formula 3 d:
3d；
the preparation method comprises the following steps: a clean reaction tube was taken, and after sealing with (4-fluoro-2-isocyanatophenyl) (phenyl) methanone (0.2 mmol,1.0equiv) and AIBN (0.6 mmol,3.0 equiv), the gas was purged three times, and after argon was terminated, toluene (2 mL) was added by syringe and allowed to react at 100℃for 20 h until complete reaction was detected by TLC. The crude product was purified by flash column chromatography (PE: ea=30:1) by reduced pressure, concentration to give 2,2' - (7-fluoro-4-phenyl-4H-benzo [ d ] [1,3] oxazine-2, 4-diyl) bis (2-methacrylonitrile), 3d,40.7mg, 56% yield.
The nuclear magnetism and mass spectrum test results of 3d are: 1 H NMR (400 MHz, CDCl 3 ) δ 7.90(d,J= 6.0 Hz, 1H), 7.62 (d,J= 7.5 Hz, 2H), 7.46 – 7.33 (m, 3H), 7.06 (t,J= 8.4 Hz,1H), 6.95 (d,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, CDCl 3 ) δ 163.0 (d,J= 247.9 Hz), 158.4, 139.9 (d,J= 11.1 Hz), 138.7, 128.9, 128.4, 127.5(d,J= 9.1 Hz), 127.0, 123.6, 121.4, 120.4 (d,J= 3.4 Hz),114.4 (d,J= 21.7 Hz), 113.2 (d,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 FN 3 ONa + : ([M + Na] + ), 384.1483,found, 384.1484。
example 5
A2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series compound has a structure shown in a formula 3 e:
3e；
the preparation method comprises the following steps: a clean reaction tube was taken, and after sealing with (2-isocyano-4-methylphenyl) (phenyl) methanone (0.2mmol,1.0 equiv) and AIBN (0.6 mmol,3.0equiv), the gas was purged three times, and after argon was terminated, toluene (2 mL) was added by syringe and allowed to react at 100℃for 13 h until complete reaction was detected by TLC. The crude product was purified by flash column chromatography (PE: ea=20:1) by reduced pressure, concentration operation to give 2,2' - (7-methyl-4-phenyl-4H-benzo [ d ] [1,3] oxazine-2, 4-diyl) bis (2-methacrylonitrile), 3e,47.2mg, 66% yield.
3e, nuclear magnetism and mass spectrum test results are: 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (d,J= 8.0 Hz,1H), 7.65 – 7.59 (m, 2H), 7.40 – 7.28 (m, 3H), 7.14 (dd,J= 8.0, 1.0Hz, 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, CDCl 3 ) 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 N 3 ONa + : ([M + Na] + ), 380.1733,found, 380.1733。
example 6
A2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series compound has a structure shown in a formula 3 f:
3f；
the preparation method comprises the following steps: a clean reaction tube was taken, and after sealing with (3-bromo-2-isocyanatophenyl) (phenyl) methanone (0.2 mmol,1.0equiv) and AIBN (0.6 mmol,3.0 equiv), the gas was purged three times, and after argon was terminated, toluene (2 mL) was added by syringe and allowed to react at 100℃for 14 h until complete reaction was detected by TLC. The crude product was purified by flash column chromatography (PE: ea=30:1) by reduced pressure, concentration to give 2,2' - (8-bromo-4-phenyl-4H-benzo [ d ] [1,3] oxazine-2, 4-diyl) bis (2-methacrylonitrile), 3f,64.8mg, 77% yield.
The nuclear magnetism and mass spectrum test results of 3f are: 1 H NMR(400 MHz, CDCl 3 ) 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, CDCl 3 )δ 158.4, 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 BrN 3 ONa + :([M + Na] + ), 444.0682, found, 444.0689。
example 7
A2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series compound has a structure shown in a formula 3 g:
3g；
the preparation method comprises the following steps: a clean reaction tube was taken, and after sealing with (3-chloro-2-isocyanatophenyl) (phenyl) methanone (0.2mmol,1.0 equiv) and AIBN (0.6 mmol,3.0equiv), the gas was purged three times, and after argon was terminated, toluene (2 mL) was added by syringe and allowed to react at 100℃for 14 h until complete reaction was detected by TLC. The crude product was purified by flash column chromatography (PE: ea=30:1) by reduced pressure, concentration to give 2,2' - (8-chloro-4-phenyl-4H-benzo [ d ] [1,3] oxazine-2, 4-diyl) bis (2-methacrylonitrile), 3g,53.5mg, 71% yield.
The nuclear magnetism and mass spectrum test result of 3g is: 1 H NMR (400 MHz, CDCl 3 ) δ 7.80(d,J= 7.8 Hz, 1H), 7.53 (d,J= 7.2 Hz, 2H), 7.38 – 7.24 (m,4H), 7.18 (t,J= 8.0 Hz, 1H), 1.72 (s, 3H), 1.69 (s, 3H), 1.56 (s, 3H), 1.51 (s, 3H). 13 CNMR (100 MHz, CDCl 3 ) 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 ClN 3 ONa + : ([M + Na] + ), 400.1187, found,400.1194。
example 8
A2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series compound has a structure shown in a formula 3H:
3h；
the preparation method comprises the following steps: a clean reaction tube was taken, and after sealing with (5-chloro-2-isocyanatophenyl) (phenyl) methanone (0.2 mmol,1.0 equiv) and AIBN (0.6 mmol,3.0 equiv), the gas was purged three times, and after argon was terminated, toluene (2 mL) was added by syringe and allowed to react at 100℃for 13 h until complete reaction was detected by TLC. The crude product was purified by flash column chromatography (PE: ea=30:1) by reduced pressure, concentration to give 2,2' - (6-chloro-4-phenyl-4H-benzo [ d ] [1,3] oxazine-2, 4-diyl) bis (2-methacrylonitrile), 3H,39.6mg, 52% yield.
The nuclear magnetism and mass spectrum test results of 3h are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.90(d,J= 2.0 Hz, 1H), 7.67 – 7.61 (m, 2H), 7.47 – 7.37 (m, 3H), 7.35 (dd,J= 8.4, 2.2 Hz, 1H), 7.18 (d,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, CDCl 3 )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 ClN 3 ONa + : ([M + Na] + ), 400.1187, found,400.1179。
example 9
A2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series compound has a structure shown in a formula 3 i:
3i；
the preparation method comprises the following steps: a clean reaction tube was taken, and after sealing with (4-bromophenyl) (2-isocyanatophenyl) methanone (0.2 mmol,1.0 equiv) and AIBN (0.6mmol,3.0 equiv), the gas was purged three times, and after argon was terminated, toluene (2 mL) was added by syringe and allowed to react at 100℃for 20 h until complete reaction was detected by TLC. The crude product was purified by flash column chromatography (PE: ea=40:1) by reduced pressure, concentration to give 2,2' - (4- (4-bromophenyl) -4H-benzo [ d ] [1,3] oxazine-2, 4-diyl) bis (2-methacrylonitrile), 3i,54.7 mg, 65% yield.
The nuclear magnetism and mass spectrum test results of 3i are: 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 (dd,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, CDCl 3 )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): Calcdfor C 22 H 20 BrN 3 ONa + :([M + Na] + ), 444.0682, found, 444.0678.
example 10
A2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series compound has a structure shown in a formula 3 j:
3j；
the preparation method comprises the following steps: a clean reaction tube was taken, and after (2-isocyanophenyl) (p-tolyl) methanone (0.2 mmol,1.0equiv) and AIBN (0.6 mmol,3.0 equiv) were added and sealed, the gas was purged three times, and after argon was terminated, toluene (2 mL) was added by syringe and allowed to react at 100℃for 21 h until complete reaction was detected by TLC. The crude product was purified by flash column chromatography (PE: ea=30:1) by a reduced pressure, concentration operation to give 2,2' - (4- (p-tolyl) -4H-benzo [ d ] [1,3] oxazine-2, 4-diyl) bis (2-methacrylonitrile), 3j,37.7mg, 53% yield.
The nuclear magnetism and mass spectrum test results of 3j are: 1 H NMR (400 MHz, CDCl 3 ) δ 7.91(d,J= 7.6 Hz, 1H), 7.49 (d,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, CDCl 3 ) 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 N 3 ONa + : ([M + Na] + ), 380.1733,found, 380.1741。
example 11
A2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series compound has a structure shown in a formula 3 k:
3k；
the preparation method comprises the following steps: a clean reaction tube was taken, and after (2-isocyanatophenyl) (m-tolyl) methanone (0.2 mmol,1.0equiv) and AIBN (0.6 mmol,3.0 equiv) were added and sealed, the gas was purged three times, and after argon was terminated, toluene (2 mL) was added by syringe and allowed to react at 100℃for 21 h until complete reaction was detected by TLC. The crude product was purified by flash column chromatography (PE: ea=40:1) by reduced pressure, concentration operation to give 2,2' - (4- (m-tolyl) -4H-benzo [ d ] [1,3] oxazine-2, 4-diyl) bis (2-methacrylonitrile), 3k,43.3mg, 61% yield.
The nuclear magnetism and mass spectrum test results of 3k are: 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 )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): Calcd for C 23 H 23 N 3 ONa + : ([M + Na] + ), 380.1733,found, 380.1723。
example 12
A2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series compound has a structure shown in a formula 3 l:
3l；
the preparation method comprises the following steps: a clean reaction tube was taken, and after (2-isocyanophenyl) (2-methoxyphenyl) methanone (0.2 mmol,1.0 equiv) and AIBN (0.6 mmol,3.0 equiv) were added and sealed, the gas was purged three times, and after argon was terminated, toluene (2 mL) was added by syringe and allowed to react at 100℃for 17 h until completion of the reaction by TLC. The crude product was purified by flash column chromatography (PE: ea=40:1) by a reduced pressure, concentration operation to give 2,2' - (4- (2-methoxyphenyl) -4H-benzo [ d ] [1,3] oxazine-2, 4-diyl) bis (2-methacrylonitrile). 3l,30.6mg, 41% yield.
The nuclear magnetism and mass spectrum test results of 3l are: 1 H NMR (400 MHz, CDCl 3 ) δ 8.08(d,J= 7.9 Hz, 1H), 7.37 (t,J= 8.0 Hz, 1H), 7.27 – 7.16 (m,2H), 7.09 – 7.00 (m, 3H), 6.89 (d,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,CDCl 3 ) 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 N 3 O 2 Na + : ([M + Na] + ), 396.1682,found, 396.1675。
example 13
A2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series compound has a structure shown in a formula 3 m:
3m；
the preparation method comprises the following steps: a clean reaction tube was taken, 1- (2-isocyanophenyl) ethyl-1-ketone (0.2 mmol,1.0 equiv) and AIBN (0.6mmol,3.0 equiv) were added and sealed, the air was purged three times, and after argon was terminated, toluene (2 mL) was added by syringe and allowed to react at 100℃for 14 h until complete reaction was detected by TLC. The crude product was purified by flash column chromatography (PE: ea=30:1) by reduced pressure, concentration to give 2,2' - (4-methyl-4H-benzo [ d ] [1,3] oxazine-2, 4-diyl) bis (2-methylpropanenitrile), 3m,44.5 mg, 79% yield.
The nuclear magnetism and mass spectrum test result of 3m is: 1 H NMR (400 MHz, CDCl 3 ) δ 7.26(t,J= 8.0 Hz, 2H), 7.21 – 7.16 (m, 1H), 7.14 (d,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, CDCl 3 )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 N 3 ONa + : ([M + Na] + ), 304.1420,found, 304.1429。
while the present application has been described in considerable detail and with particularity with respect to several described embodiments, it is not intended to be limited to any such detail or embodiments or any particular embodiment, but is to be construed as providing broad interpretation of such claims by reference to the appended claims in view of the prior art so as to effectively encompass the intended scope of the application. Furthermore, the foregoing description of the application has been presented in its embodiments contemplated by the inventors for the purpose of providing a useful description, and for the purposes of providing a non-essential modification of the application that may not be presently contemplated, may represent an equivalent modification of the application.
Claims (10)
1. The 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series is characterized in that the structure is shown as a formula I:
a formula I; r is R 1 Selected from hydrogen, fluorine, chlorine, bromine or methyl, R 2 Selected from alkyl, aryl or methoxy.
2. A process for the preparation of the 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series of claim 1 comprising the steps of:
o-acyl aryl isonitrile and Azobisisobutyronitrile (AIBN) are dissolved in an organic solvent to react 14H-24H to obtain 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series.
3. The process according to claim 2, wherein the ortho-acyl aryl isonitrile is (2-isocyanatophenyl) (phenyl) methanone, (5-bromo-2-isocyanatophenyl) (phenyl) methanone, (4-fluoro-2-isocyanatophenyl) (phenyl) methanone, (2-isocyanato-4-methylphenyl) (phenyl) methanone, (3-bromo-2-isocyanatophenyl) (phenyl) methanone, (3-chloro-2-isocyanatophenyl) (phenyl) methanone, (5-chloro-2-isocyanatophenyl) (phenyl) methanone, (4-bromophenyl) (2-isocyanatophenyl) methanone, (2-isocyanatophenyl) (p-tolyl) methanone, (2-isocyanatophenyl) (m-tolyl) methanone, (2-isocyanatophenyl) (2-methoxyphenyl) methanone, 1- (2-isocyanatophenyl) ethano-1-ketone.
4. The method according to claim 2, wherein the molar ratio of the ortho-acyl aryl isonitrile to the azobisisobutyronitrile is 1:3.
5. the preparation method according to claim 2, wherein the organic solvent is toluene, fluorobenzene, benzotrifluoride, chlorobenzene, 1, 2-dichloroethane.
6. The method according to claim 2, wherein the organic solvent is toluene.
7. The method of claim 2, wherein the reaction temperature is 100 ℃.
8. The preparation method according to claim 2, wherein the reaction system is carried out under an inert gas atmosphere.
9. The preparation method according to claim 2, wherein after the reaction is completed, the crude product is further separated and purified by decompression and concentration.
10. Use of a 2, 4-disubstituted 4H-benzo [ d ] [1,3] oxazine series according to claim 1 for the preparation of a medicament.
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