CN105820132B - N- aryl benzotriazole nitrogen oxygen derivatives and its synthetic method - Google Patents

N- aryl benzotriazole nitrogen oxygen derivatives and its synthetic method Download PDF

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CN105820132B
CN105820132B CN201610315960.6A CN201610315960A CN105820132B CN 105820132 B CN105820132 B CN 105820132B CN 201610315960 A CN201610315960 A CN 201610315960A CN 105820132 B CN105820132 B CN 105820132B
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copper
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CN105820132A (en
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莫冬亮
石维敏
马小盼
闭红艳
苏桂发
陈春华
邹宁
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Guangxi Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention discloses a series of N- aryl benzotriazole nitrogen oxygen derivatives and its synthetic methods.N- aryl benzotriazole nitrogen oxygen derivative of the present invention have structure, preparation method as shown in following formula (I) be：Organoboron reagent, mantoquita and the alkaline matter for taking structure shown in the N- hydroxybenzotriazoles derivative of structure shown in following formula (II), formula (III), are placed in organic solvent, react in the presence of oxygen, and object crude product is made.The method of the invention is simple and easy to control, and the period is short；Part N- aryl benzotriazole nitrogen oxygen derivative obtained has good antitumor activity.The compound difference of structure shown in the formula (I), formula (II) and formula (III) is as follows：

Description

N- aryl benzotriazole nitrogen oxygen derivatives and its synthetic method
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of N- aryl benzotriazole nitrogen oxygen derivative and its synthesis Method.
Background technology
Benzotriazole nitrogen oxygen derivative is widely present in many drug molecules, is important physiological activity unit, Antibacterial, anticancer aspect have important application.Currently, many research workers are dedicated to the research of this respect, but it is existing The synthetic method step of triazole type nitrogen oxygen derivative is long, and substrate and reagent be there are limitation or experimental operating conditions are complicated, Limit the further further investigation of such compound.
Invention content
The technical problem to be solved in the present invention is to provide a series of N- aryl benzotriazole nitrogen oxygen of structure novels derivatives Object and their synthetic method.
The present invention relates to compound shown in lower formula (I) or its pharmaceutically acceptable salts：
Wherein：
X indicates carbon or nitrogen-atoms；
Ar1Indicate the unsubstituted naphthalene of unsubstituted thienyl or unsubstituted, monosubstituted or two substitutions Phenyl, wherein substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, halogen atom, unsubstituted phenyl, Nitro or carbomethoxy；
R1Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution or disubstituted phenyl, wherein substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl or halogen atom；
R2Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution or disubstituted phenyl, wherein substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl or halogen atom；
R3Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution or disubstituted phenyl, wherein substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl or halogen atom；
R4Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution or disubstituted phenyl, wherein substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl hydrogen atoms.
In above compound：
Ar1Further preferably unsubstituted, monosubstituted or disubstituted phenyl, wherein substituent group C1~4Alkoxy, C1~4Alkyl, halogen atom, unsubstituted phenyl, nitro or carbomethoxy；
R1Further preferably hydrogen, C1-C4Alkyl, halogen atom or C1~4Alkoxy；
R2Further preferably hydrogen, C1-C4Alkyl, halogen atom or C1~4Alkoxy；
R3Further preferably hydrogen, C1-C4Alkyl, halogen atom or C1~4Alkoxy；
R4Further preferably hydrogen, C1-C4Alkyl, halogen atom or C1~4Alkoxy.
The synthetic method of compound, mainly includes the following steps that shown in above-mentioned formula (I)：N- hydroxybenzotriazoles are taken to derive Object, organoboron reagent, mantoquita and alkaline matter, are placed in organic solvent, react in the presence of oxygen, and object is made Crude product；Wherein：
The N- hydroxybenzotriazole derivatives have structure shown in following (II)：
Wherein,
X indicates carbon or nitrogen-atoms；
R1Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution or disubstituted phenyl, wherein substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl or halogen atom；
R2Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution or disubstituted phenyl, wherein substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl or halogen atom；
R3Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution or disubstituted phenyl, wherein substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl or halogen atom；
R4Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution or disubstituted phenyl, wherein substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl hydrogen atoms；
The organoboron reagent has structure shown in following (III)：
Ar1B(OH)2(III)；Wherein, Ar1Indicate unsubstituted thienyl or unsubstituted naphthalene, or not Substitution, monosubstituted or disubstituted phenyl, wherein substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, Halogen atom, unsubstituted phenyl, nitro or carbomethoxy.
In above-mentioned synthetic method, the raw material N- hydroxybenzotriazole derivatives that are related to can refer to existing literature (B.X.Yu, Z.Huang, M.Zhang, D.Dillard, and H.T.Ji, Acs Chem.Biol, 2013,8,524-529 or N.J.Leonard, K.Colankiewice, J.Org.Chem.1969,34,359-365) it is synthesized, it also can free design conjunction It is synthesized at route, this will not be detailed here.The raw material organoboron reagent being related to directly can commercially obtain (such as benzene Ylboronic acid, to methyl-boric acid, P-Trifluoromethyl boronic acid, 2- naphthalenylboronic acids etc.).
In above-mentioned synthetic method, the mantoquita can be selected from copper bromide, cupric iodide, copper chloride, copper sulphate, acetic acid The combination of one or more of ketone, copper nitrate, copper trifluoromethanesulfcomposite, cuprous bromide, cuprous iodide and stannous chloride.When When the combination for being selected as the above substance of above two of mantoquita, their proportioning can be arbitrary proportioning.
In above-mentioned synthetic method, the alkaline matter can be the alkaloids containing hydroxyl, can be specifically to be selected from Tripotassium phosphate, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, Potassium fluoride, pyridine, triethylamine and N, the combination of one or more of N- diisopropyl ethyl amines.When alkaline matter When being selected as the combination of the above substance of above two, their proportioning can be arbitrary proportioning.
In above-mentioned synthetic method, the organic solvent can be selected from benzene, toluene, hexamethylene, petroleum ether, four chlorinations It is a kind of in carbon, tetrahydrofuran, ethyl acetate, acetonitrile, ether, dichloromethane, acetone, chloroform, n-hexane and dioxane Or two or more combination.When the combination for being selected as the above substance of above two of organic solvent, their proportioning can be Arbitrary proportioning.
In above-mentioned synthetic method, reaction, which is typically chosen under air conditions, to be carried out, and simultaneous reactions are preferably less than 80 DEG C Under conditions of carry out, be further preferred that under conditions of room temperature is to 60 DEG C and carry out, more preferably the condition in room temperature to 40 DEG C Lower progress.Whether reaction can be used TLC tracing detections completely.According to the experience of applicant, when reaction is in room temperature to 60 DEG C of conditions When lower progress, reaction time control 10~it is more suitable for 24 hours.
In order to make reaction more advantageously carry out, the yield of target product is further increased, is preferably added before the reaction Enter additive, the additive can be divided selected from sodium sulphate, magnesium sulfate, calcium chloride, phosphorus pentoxide, 3A molecular sieves, 4A The combination of son sieve and one or more of 5A molecular sieves.When the combination for being selected as the above substance of above two of additive When, their proportioning can be arbitrary proportioning.
In synthetic method of the present invention, the consumption proportion of each raw material is stoichiometric ratio, in practical operation, N- hydroxyls Base benzotriazole derivatives, organoboron reagent, mantoquita and alkaline matter molar ratio be usually 1.0：1.0~5.0：0.1~ 1.0.The dosage of the organic solvent is advisable with that can dissolve the raw material participated in and reacted, it is generally the case that with the N- hydroxyls of 1mmol On the basis of benzotriazole derivatives, all raw materials for participating in reaction are usually dissolved with the organic solvent of 1~10mL.When reaction needs When additive is added, the addition of additive is usually 4.0-10.0 times of the amount of N- hydroxybenzotriazole derivative substances.
It is the crude product of formula (I) compound made from the above method, existing conventional purification process can be used, it is carried out Purifying is to improve the purity of formula (I) compound.Generally use silica gel thin-layer chromatography or silica gel column chromatography, or recrystallization side Formula is purified, and the eluant, eluent in chromatography is identical with solvent when recrystallization, can be by petroleum ether and ethyl acetate By 10：1~1：The mixed solvent of 1 volume ratio composition can also be by n-hexane and ethyl acetate by 10:1~1:1 volume Than the mixed solvent of composition, can also be by petroleum ether and methanol by 100:1~10:The mixed solvent of 1 volume ratio composition, again Either 100 are pressed by dichloromethane and methanol:1~10:The mixed solvent of 1 volume ratio composition.
Compared with prior art, the present invention provides a series of N- aryl benzotriazole nitrogen oxygen of structure novels derivatives Object and their synthetic method.Synthetic method provided by the invention is simple and easy to control, and the period is short, the certain compounds pair of gained Hepg2 tumor lines have preferable activity.
Specific implementation mode
With reference to specific embodiment, the present invention is described in further detail, to more fully understand present disclosure, but The present invention is not limited to following embodiments.
N- hydroxybenzotriazoles derivative involved in following embodiment is synthesized with reference to following synthetic routes：
Reactant S1 (11.655mmol) and ethyl alcohol (40mL) are added in 100mL round-bottomed flasks, is injected after stirring evenly Hydrazine hydrate S2 (116.6mmol, 10equiv), which, which is stirred to react under reflux conditions after 20h, stops reaction and is allowed to cool To room temperature；The ethyl alcohol removed in reaction solution is concentrated under reduced pressure, 20mL methanol is added into Liquid Residue, has precipitation after being acidified with concentrated hydrochloric acid Object is precipitated, and filtrate is collected in filtering, and product S3 (i.e. N- hydroxybenzotriazoles derivative) is obtained after filtrate decompression is concentrated.
Organoboron reagent involved in following embodiment is to be bought directly from the market.
Embodiment 1
N- aryl benzotriazole nitrogen oxygen derivative of the present invention is synthesized by following synthetic routes.
By Cu (OAc)2(0.3mmol, 54mg), N- hydroxybenzotriazoles substrate (0.3mmol), aryl boric acid (0.9mmol) is placed in reaction tube, and 3mL dioxane is added, and pyridine (3mmol, 0.24mL) is added at room temperature；It is stirred at 40 DEG C Reaction 12-24h is mixed, water (10mL) is added in gained reactant, extracts (2 × 10mL) with dichloromethane, merges organic phase, use is anhydrous It is filtered after sodium sulphate drying, solvent is removed under reduced pressure, silica gel column chromatography detaches (petrol ether/ethyl acetate=10：1~1：1, volume Than), obtain target product 3.It different target product and its is characterized as below：
3aa:Solid, 49mg, 77%yield；mp 115-116℃.1H NMR(400MHz,CDCl3):δ 8.03 (d, J= 8.5Hz, 1H), 7.75 (d, J=8.6Hz, 1H), 7.70-7.61 (m, 3H), 7.56 (t, J=7.9Hz, 2H), 7.44 (td, J= 7.6,4.6Hz,2H)；13C NMR(100MHz,CDCl3):δ135.8,132.9,131.2,131.1,130.0,128.5, 124.8,122.4,115.9,111.4.IR(neat):3046,1593,1502,1459,1417,1123,750cm-1；MS(ESI) m/z[M+H]+calcd for[C12H10N3O]+:212.0824；found:212.0813. its structural formula is as follows：
3ab:Solid, 69mg, 95%yield；mp 150-151℃.1H NMR(400MHz,CDCl3):δ 8.03 (d, J= 8.5Hz,1H),7.67–7.55(m,4H),7.45–7.40(m,1H),7.08–7.03(m,2H),3.87(s,3H)；13C NMR (100MHz,CDCl3):δ=159.8,133.2,130.9,130.8,128.6,124.7,124.4,115.8,115.1, 111.3,55.6；IR(neat):3070,1602,1514,1460,1412,1251,744cm-1.MS(ESI)m/z(M+H)+ calcd for[C12H12N3O]+:242.0930；found:242.0919. its structural formula is as follows：
3ac:Solid, 31mg, 43%yield；mp 195-196℃.1H NMR(400MHz,CDCl3):δ10.07(s, 1H), 8.12-8.04 (m, 3H), 7.95-7.86 (m, 3H), 7.73 (ddd, J=8.4,7.1,0.9Hz, 1H), 7.54-7.48 (m,1H).13C NMR(100MHz,CDCl3):δ190.4,140.4,135.2,132.7,131.9,131.8,131.5,125.4, 121.7,116.3,111.6；IR(neat):3096,2755,1690,1597,1417,1210,739cm-1；MS(ESI)m/z(M+ H)+calcd for[C13H10N3O2]+:240.0773；found:240.0761. its structural formula is as follows：
3ad:Solid, 31mg, 43%yield；mp 195-196℃.1H NMR(400MHz,CDCl3):δ10.07(s, 1H), 8.12-8.04 (m, 3H), 7.95-7.86 (m, 3H), 7.73 (ddd, J=8.4,7.1,0.9Hz, 1H), 7.54-7.48 (m,1H)；13C NMR(100MHz,CDCl3):δ190.4,140.4,135.2,132.7,131.9,131.8,131.5,125.4, 121.7,116.3,111.6；IR(neat):3096,2755,1690,1597,1417,1210,739cm-1；MS(ESI)m/z(M+ H)+calcd for[C13H10N3O2]+:240.0773；found:240.0761. its structural formula is as follows：
3ae:Solid, 57mg, 79%yield；mp 143-144℃.1H NMR(400MHz,CDCl3):δ 8.03 (d, J= 8.5Hz, 1H), 7.75 (d, J=8.6Hz, 1H), 7.65-7.60 (m, 1H), 7.45-7.40 (m, 1H), 7.29 (s, 2H), 7.08 (s,1H),2.40(s,6H)；13C NMR(100MHz,CDCl3):δ140.0,135.6,132.9,131.1,130.9,130.3, 124.7,120.2,115.8,111.6,21.3；IR(neat):3063,1601,1495,1468,1414,1362,764cm-1；MS (ESI)m/z(M+H)+calcd for[C14H14N3O]+:240.1137；found:240.1125. its structural formula is as follows：
3af:Solid, 58mg, 80%yield；mp 141-142℃.1H NMR(400MHz,CDCl3):δ 7.99 (d, J= 8.5Hz, 1H), 7.73 (d, J=8.6Hz, 1H), 7.59 (t, J=7.8Hz, 1H), 7.40 (td, J=8.0,3.6Hz, 2H), 7.24-7.16 (m, 2H), 6.93 (dd, J=8.4,2.3Hz, 1H), 3.81 (s, 3H)；13C NMR(100MHz,CDCl3):δ 160.7,136.8,132.9,131.2,131.1,130.6,124.8,115.9,114.4,114.0,111.6,108.2,55.6； IR(neat):3070,1597,1498,1460,1417,1212,752cm-1；MS(ESI)m/z(M+H)+calcd for [C13H12N3O2]+:242.0930；found:242.0917. its structural formula is as follows：
3ag:Solid, 53mg, 68%yield；mp 163-164℃.1H NMR(400MHz,CDCl3):δ 8.11 (d, J= 1.9Hz, 1H), 8.05 (dd, J=17.9,8.6Hz, 2H), 7.93-7.88 (m, 2H), 7.85 (d, J=8.6Hz, 1H), 7.80 (dd, J=8.8,2.1Hz, 1H), 7.67 (dd, J=11.6,4.0Hz, 1H), 7.61-7.53 (m, 2H), 7.49-7.44 (m, 1H)；13C NMR(100MHz,CDCl3):δ133.2,133.1,133.0,132.5,131.3,131.1,130.3,128.0, 127.9,127.5,127.1,124.9,120.5,120.4,116.0,111.5.IR(neat):3032,1591,1464,1417, 1356,1155,747cm-1；MS(ESI)m/z(M+H)+calcd for[C16H12N3O]+:262.0980；found:262.0968. Its structural formula is as follows：
3ah:Solid, 70mg, 77%yield；mp 116-117℃.1H NMR(400MHz,CDCl3):δ 8.07 (d, J= 8.5Hz, 1H), 7.71 (d, J=8.6Hz, 1H), 7.67-7.61 (m, 3H), 7.48-7.38 (m, 3H), 7.21-7.15 (m, 3H), 7.09 (dt, J=9.1,1.9Hz, 2H)；13C NMR(100MHz,CDCl3):δ157.9,156.0,133.1,131.1, 131.0,130.5,130.1,124.8,124.3,119.6,119.3,116.0,111.3.IR(neat):3060,1590, 1501,1416,1386,1242,751cm-1；MS(ESI)m/z(M+H)+calcd for[C18H14N3O2]+:304.1086； found:304.1073. its structural formula is as follows：
3ai:Solid, 70mg, 77%yield；mp 116-117℃.1H NMR(400MHz,CDCl3):δ 8.07 (d, J= 8.5Hz, 1H), 7.71 (d, J=8.6Hz, 1H), 7.67-7.61 (m, 3H), 7.48-7.38 (m, 3H), 7.21-7.15 (m, 3H), 7.09 (dt, J=9.1,1.9Hz, 2H)；13C NMR(100MHz,CDCl3):δ157.9,156.0,133.1,131.1, 131.0,130.5,130.1,124.8,124.3,119.6,119.3,116.0,111.3；IR(neat):3060,1590, 1501,1416,1386,1242,751cm-1；MS(ESI)m/z(M+H)+calcd for[C18H14N3O2]+:304.1086； found:304.1073. its structural formula is as follows：
3ba:Solid, 44mg, 60%yield；mp 129-130℃.1H NMR(500MHz,CDCl3):δ 7.68 (d, J= 7.9Hz, 2H), 7.63 (d, J=9.2Hz, 1H), 7.56 (t, J=7.9Hz, 2H), 7.45 (t, J=7.4Hz, 1H), 7.32 (s, 1H), 7.27 (dd, J=8.9,1.9Hz, 1H), 3.90 (s, 3H)；13C NMR(125MHz,CDCl3):δ157.8,135.8, 131.9,123.0,128.5,128.3,124.1,122.1,112.3,94.4,56.0；IR(neat):3036,1595,1508, 1446,1417,1268,767cm-1；MS(ESI)m/z(M+H)+calcd for[C13H12N3O2]+:242.0930；found: 242.0920. its structural formula is as follows：
3ea:Solid, 18mg, 28%yield；mp 178-179℃.1H NMR(400MHz,CDCl3):δ 8.72 (d, J= 3.0Hz, 1H), 8.23 (dd, J=8.6,1.2Hz, 1H), 7.67 (dd, J=11.2,6.3Hz, 3H), 7.60 (t, J=7.9Hz, 2H), 7.49 (t, J=7.4Hz, 1H)；13C NMR(100MHz,CDCl3):δ148.1,141.7,135.6,130.2,129.0, 125.9,125.8,122.0,121.0；IR(neat):3052,1588,1503,1448,1402,1134,757cm-1；MS(ESI) m/z(M+H)+calcd for[C11H9N4O]+:213.0776；found:213.0765. its structural formula is as follows：
3fa:Solid, 47mg, 56%yield；mp 130-131℃.1H NMR(400MHz,CDCl3):δ8.39(s,1H), 7.90-7.83 (m, 2H), 7.71-7.67 (m, 2H), 7.62 (dd, J=10.6,5.1Hz, 2H), 7.52 (dd, J=8.2, 6.5Hz,1H)；13C NMR(100MHz,CDCl3):δ135.3,134.0,130.8,130.2,129.3,127.7,127.7, 127.2,124.6,122.7,114.7,114.6,112.6；IR(neat):3076,1601,1505,1454,1325,1126, 749cm-1；MS(ESI)m/z(M+H)+calcd for[C13H9FN3O]+:280.0698；found:280.0685. its structural formula is such as Under：
3dj:Solid, 54mg, 60%yield；mp 162-163℃.1H NMR(500MHz,CDCl3):δ7.80-7.73 (m, 6H), 7.58 (d, J=15.0Hz, 1H), 7.55-7.47 (m, 2H), 7.46-7.38 (m, 2H), 7.30 (dd, J=15.0, 2.9Hz,1H),2.31(s,3H)；13C NMR(125MHz,CDCl3):δ140.5,138.2,136.6,136.2,135.8, 132.8,129.2,128.1,127.8,123.4,120.5,117.2,21.3；IR(neat):3050,1601,1545,1460, 1427,1278,768cm-1；MS(ESI)m/z(M+H)+calcd for[C19H16N3O]+:302.1293；found:302.1282. Its structural formula is as follows：
Embodiment 2：
N- aryl benzotriazole nitrogen oxygen derivative of the present invention is synthesized by following synthetic routes.
By CuCl2(0.3mmol), N- hydroxybenzotriazoles substrate (0.3mmol), aryl boric acid (0.9mmol) are placed in instead Ying Guanzhong, is added 3mL1, and potassium carbonate (3mmol) is added in 2- dichloroethanes at room temperature；12-24h, institute are stirred to react at 25 DEG C It obtains reactant and water (10mL) is added, extract (2 × 10mL) with dichloromethane, merge organic phase, mistake after being dried with anhydrous sodium sulfate Filter, is removed under reduced pressure solvent, and silica gel column chromatography detaches (n-hexane/ethyl acetate=10：1~1：1, volume ratio), obtain target production Object 3.It different target product and its is characterized as below：
3ga:Solid, 43mg, 55%yield；mp 125-126℃.1H NMR(500MHz,CDCl3):δ7.68-7.62 (m, 2H), 7.60-7.48 (m, 3H), 7.34 (d, J=2.9,1H), 7.33 (d, J=3.1Hz, 1H), 2.31 (s, 3H)；13C NMR(125MHz,CDCl3):δ140.0,137.8,132.5,131.8,128.2,127.0,125.4,122.0,118.8, 21.9；IR(neat):3046,1600,1497,1443,1423,1286,746cm-1；MS(ESI)m/z(M+H)+calcd for [C13H11ClN3O]+:260.0591；found:260.0583. its structural formula is as follows：
3ha:Solid, 38mg, 47%yield；mp 134-135℃.1H NMR(500MHz,CDCl3):δ=7.67 (dt, J =3.7,1.9Hz, 2H), 7.59 (t, J=7.0Hz, 2H), 7.56-7.51 (m, 1H), 7.23 (s, 1H), 2.36 (s, 3H), 2.31(s,3H)；13C NMR(125MHz,CDCl3):δ=140.9,140.6,138.8,128.4,127.5,126.4,122.3, 120.4,119.0,21.0,18.8；IR(neat):3064,1612,1535,1450,1414,1292,743cm-1；MS(ESI)m/ z(M+H)+calcd for[C14H13ClN3O]+:274.0747；found:274.0741. its structural formula is as follows：
3ia:Solid, 32mg, 36%yield；mp 151-152℃.1H NMR(500MHz,CDCl3):δ7.70-7.64 (m,2H),7.61-7.47(m,3H),7.41(s,1H),3.92(s,3H),2.15(s,3H)；13C NMR(125MHz,CDCl3): δ147.5,138.2,137.0,128.5,127.2,122.8,122.0,118.0,110.9,61.0,17.0；IR(neat): 3064,1597,1525,1468,1432,1250,763cm-1；MS(ESI)m/z(M+H)+calcd for[C14H13ClN3O2]+: 290.0696；found:290.0687. its structural formula is as follows：
3gk:Solid, 16mg, 20%yield；mp 178-179℃.1H NMR(500MHz,CDCl3):δ7.62-7.55 (m, 1H), 7.51-7.46 (m, 1H), 7.40 (td, J=14.7,3.4Hz, 1H), 7.35 (d, J=2.9Hz, 1H), 7.40 (td, J=14.7,3.4Hz, 1H), 7.35 (d, J=2.9Hz, 1H), 7.34-7.29 (m, 2H), 2.32 (s, 3H), 1.85 (s, 3H)；13C NMR(125MHz,CDCl3):δ138.0,137.2,135.3,132.4,131.8,127.6,126.5,125.2,124.0, 118.0,21.8,17.5；IR(neat):3065,1601,1496,1468,1424,1354,767cm-1；MS(ESI)m/z(M+H )+calcd for[C14H13ClN3O]+:274.0747；found:274.0735. its structural formula is as follows：
3gl:Solid, 51mg, 52%yield；mp 178-179℃.1H NMR(500MHz,CDCl3):δ7.54(s,4H), 7.35 (d, J=3.1Hz, 1H), 7.32 (d, J=3.1Hz, 1H), 2.31 (s, 3H)13C NMR(125MHz,CDCl3):δ 144.1,138.3,132.0,131.1,126.6,125.0,121.8,118.2,118.1,21.83.IR(neat):3109, 1608,1468,1436,1322,1114,743cm-1；MS(ESI)m/z(M+H)+calcd for[C14H10ClF3N3O]+: 328.0465；found:328.0453. its structural formula is as follows：
3gm:Solid, 17mg, 19%yield；mp 153-154℃.1H NMR(500MHz,CDCl3):δ 7.34 (d, J= 1.4Hz, 1H), 7.31 (d, J=1.4Hz, 1H), 6.72 (s, 2H), 2.50 (s, 6H), 2.32 (s, 3H), 2.27 (s, 3H)；13C NMR(125MHz,CDCl3):δ=138.3,138.0,137.4,133.1,132.9,133.1,131.0,124.5,117.6, 22.3,19.3；IR(neat):3068,1618,1521,1468,1438,1352,767cm-1；MS(ESI)m/z(M+H)+calcd for[C16H17ClN3O]+:302.1060；found:302.1058. its structural formula is as follows：
3gn:Solid, 62mg, 65%yield；mp 135-136℃.1H NMR(500MHz,CDCl3):δ7.64-7.62 (m, 1H), 7.61-7.58 (m, 1H), 7.37-7.35 (m, 1H), 7.34 (q, J=3.2Hz, 2H), 7.31 (d, J=3.1Hz, 1H), 2.65 (t, J=14.1Hz, 2H), 2.31 (s, 3H), 1.63-1.49 (m, 2H), 1.40-1.25 (m, 2H), 0.89 (t, J =13.0Hz, 3H)；13C NMR(125MHz,CDCl3):δ141.4,138.3,136.4,132.0,131.1,130.2,125.7, 122.0,118.2,36.3,32.7,22.7,14.0；IR(neat):3076,1605,1524,1462,1425,1256,746cm-1；MS(ESI)m/z(M+H)+calcd for[C17H19ClN3O]+:316.1217；found:316.1208. its structural formula is as follows：
3go:Solid, 50mg, 67%yield；mp 106-107℃.1H NMR(500MHz,CDCl3):δ 7.46 (dd, J= 7.3,1.6Hz, 1H), 7.35 (d, J=1.4Hz, 1H), 7.32 (d, J=1.4Hz, 1H), 6.37 (t, J=7.4Hz, 1H), 6.33 (dd, J=7.5,1.6Hz, 1H), 2.32 (s, 3H)；13C NMR(125MHz,CDCl3):δ142.7,140.5,137.1, 134.3,129.4,122.4,117.4,108.6,100.1,22.3；IR(neat):3056,1587,1501,1408,1386, 1241,748cm-1；MS(ESI)m/z(M+H)+calcd for[C11H9ClN3O2]+:250.0383；found:250.0376. its Structural formula is as follows：
3gp:Solid, 66mg, 70%yield；mp 146-147℃.1H NMR(500MHz,CDCl3):δ7.80-7.97 (m, 1H), 7.94-7.92 (m, 1H), 7.76-7.75 (m, 1H), 7.72-7.69 (m, 1H), 7.35 (d, J=3.1Hz, 1H), 7.32 (d, J=2.9Hz, 1H), 3.92 (s, 3H), 2.31 (s, 3H)；13C NMR(125MHz,CDCl3):δ167.7,140.7, 138.3,132.3,132.0,131.2,125.7,120.0,118.2,52.3,22.3；IR(neat):3062,1705,1640, 1545,1346,1134,767cm-1；MS(ESI)m/z(M+H)+calcd for[C15H13ClN3O3]+:318.0645；found: 318.0632. its structural formula is as follows：
3ia:Solid, 23mg, 30%yield；mp 189-190℃.1H NMR(500MHz,CDCl3):δ 7.68 (dt, J= 3.7,1.9Hz 2H), 7.59 (t, J=7.0Hz, 2H), 7.56-7.52 (m, 1H), 2.58 (s, 3H), 2.50 (s, 3H), 2.42 (s,3H)；13C NMR(125MHz,CDCl3):δ153.2,138.2,137.6,131.2,128.2,127.8,122.3,22.2, 16.2,15.6；IR(neat):3050,1586,1502,1446,1340,1135,767cm-1；MS(ESI)m/z(M+H)+calcd for[C14H15N4O]+:255.1246；found:255.1235. its structural formula is as follows：
Experimental example 1：N- aryl benzotriazole nitrogen oxygen derivative of the present invention presses down a variety of human tumour strains in vitro Activity experiment processed：
(1) cell culture：By 7404, H460,7702, Hepg2, T24 cell culture in containing 10% (volume ratio) tire ox blood The DMEM culture mediums of cleer and peaceful 1% (volume ratio) dual anti-(containing penicillin and streptomysin), in 37 DEG C of temperature, 5%CO2And 95% air Incubator in cultivate, change liquid every other day.It is passed on, is frozen after cell covers with.
(2) plate is planted：The cell in exponential phase is taken, removes old culture medium, is washed twice with PBS, trypsase disappears Change cell, new culture medium is added after cell rounding and terminates cell dissociation and blows and beats suspension cell, individual cells suspension is made. Suitable cell suspension is taken, a certain amount of culture medium dilution is added, is inoculated into 96 orifice plates, per 180 μ L of hole, is per hole cell number 20000-40000。
(3) dosing：Sample to be tested is added in 96 orifice plates that kind has tumour cell, per 20 μ L of hole, makes the final dense of sample Degree is 10 μM, carries out primary dcreening operation.According to being screened as a result, different concentration gradients is arranged to compound for primary dcreening operation, every group of setting 5 A multiple holes.CO is put after adding compound2The MTT solution that 10 μ L are prepared is added per hole, puts CO by incubator culture 48h2Incubator continues Cultivate 4~6h.
(4) it tests：The culture medium abandoned in 96 orifice plates is inhaled, the DMSO of 100 μ L is added, 5~10min of concussion on shaking table is put, makes The first a ceremonial jade-ladle, used in libation of crystallization is completely dissolved.With microplate reader with the absorbing wavelength of 570nm, the reference wavelength dual wavelength of 630nm measures absorbance (OD) value calculates inhibiting rate.Inhibiting rate=(1- sample sets OD values/blank group OD values) × 100%, is calculated separately with SPSS softwares IC of each compound to different tumor cell lines50Value.Test result is as follows for it shown in table 1：
Table 1：

Claims (10)

1. compound or its pharmaceutically acceptable salt shown in lower formula (I)：
Wherein：
X indicates carbon atom；
Ar1Indicate phenyl；
R1Indicate hydrogen；
R2Indicate trifluoromethyl；
R3Indicate hydrogen；
R4Indicate hydrogen.
2. the synthetic method of compound described in claim 1, it is characterised in that：Take N- hydroxybenzotriazoles derivative, organic boron Reagent, mantoquita and alkaline matter, are placed in organic solvent, react in the presence of oxygen, and object crude product is made；Its In：
The N- hydroxybenzotriazole derivatives have structure shown in following (II)：
Wherein,
X indicates carbon atom；
R1Indicate hydrogen；
R2Indicate trifluoromethyl；
R3Indicate hydrogen；
R4Indicate hydrogen；
The organoboron reagent has structure shown in following (III)：
Ar1B(OH)2(III)；Wherein, Ar1Indicate phenyl.
3. synthetic method according to claim 2, it is characterised in that：The mantoquita is selected from copper bromide, cupric iodide, chlorine Change copper, copper sulphate, cupric acetate, copper nitrate, copper trifluoromethanesulfcomposite, cuprous bromide, cuprous iodide and one kind in stannous chloride or Two or more combinations.
4. synthetic method according to claim 2, it is characterised in that：The alkaline matter is selected from tripotassium phosphate, hydrogen Sodium oxide molybdena, potassium hydroxide, calcium hydroxide, cesium hydroxide, cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, pyrrole Pyridine, triethylamine and N, the combination of one or more of N- diisopropyl ethyl amines.
5. synthetic method according to claim 2, it is characterised in that：The organic solvent is selected from benzene, toluene, hexamethylene Alkane, petroleum ether, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, ether, dichloromethane, acetone, chloroform, n-hexane With a combination of one or more in dioxane.
6. synthetic method according to claim 2, it is characterised in that：Reaction carries out under conditions of less than 80 DEG C.
7. synthetic method according to claim 2, it is characterised in that：Reaction carries out under conditions of room temperature is to 60 DEG C.
8. the synthetic method according to any one of claim 2~7, it is characterised in that：It is added and adds before the reaction It is selected from sodium sulphate, magnesium sulfate, calcium chloride, phosphorus pentoxide, 3A molecular sieves, 4A molecular sieves and 5A to add agent, the additive The combination of one or more of molecular sieve.
9. the synthetic method according to any one of claim 2~7, it is characterised in that：It further include purification step：Specifically Object crude product obtained is subjected to silica gel thin-layer chromatography or silica gel column chromatography, or recrystallization, obtains target after purification Object.
10. compound described in claim 1 or its pharmaceutically acceptable salt application in preparation of anti-tumor drugs.
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