CN106279058A - The preparation of 3,4-diaryl-1,2,5-diazole oxide and purposes - Google Patents
The preparation of 3,4-diaryl-1,2,5-diazole oxide and purposes Download PDFInfo
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- CN106279058A CN106279058A CN201510309617.6A CN201510309617A CN106279058A CN 106279058 A CN106279058 A CN 106279058A CN 201510309617 A CN201510309617 A CN 201510309617A CN 106279058 A CN106279058 A CN 106279058A
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- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
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Abstract
The invention belongs to pharmaceutical technology field, relate to one 3,4-diaryl-1, preparation of 2,5-diazole oxides and application thereof, exactly, relate to this compounds and as tumor cell proliferation inhibitor application in terms of preparing anti-tumor drug.Compound of the present invention is as shown in formula I or formula II: wherein R1-R5As described in claims and description.
Description
Technical field
The invention belongs to pharmaceutical technology field, relate to a kind of 3,4-diaryl-1, preparation of 2,5-diazole oxides and application thereof, really
Say with cutting, relate to this compounds and as tumor cell proliferation inhibitor application in terms of preparing anti-tumor drug.
Background technology
Malignant tumor is the serious disease threatening human health with life, is the first lethal cause of disease in China.Find and find treatment
It is the key subjects currently faced with the new drug of prophylaxis of tumours.
Combretastatin A-4 (CA-4) is the cis-stilbene class natural product of isolated from the willow of South Africa, and it is changed
Formal name used at school is referred to as (Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenol.CA-4 is tubulin polymerization inhibitor, presents
The strongest suppression proliferative activity o f tumor, its prodrug CA-4 phosphate (CA-4P) enters three phases clinical research rank in the U.S.
Section.The research designing, synthesizing new active compound for anti tumor with CA-4 for lead compound is reported the most in a large number, but most
CA-4 analog exists or activity is not high enough or toxicity is relatively big or synthesizes the shortcomings such as more complicated.Relevant report sees Pettit G.
R.,et al.Experientia,1989,45,209；Nam N.H.Current Medicinal Chemistry,2003,10,1697；Tron
G.C.,et al.Journal of Medicinal Chemistry,2006,49(11),3033-3044.
3,4-diaryl-1,2,5-diazole oxide antitumor activity has not yet to see report.
Summary of the invention
Technical problem solved by the invention is to provide compound shown in below formula I or formula II:
Wherein, R1～R5Each stand alone as hydrogen, C1-C4Alkyl, hydroxyl, C1-C4Alkyl oxy, C7-C10Phenylalkyl epoxide,
Amino, C1-C4Alkyl amino, C1-C4Dialkyl amido, halogen atom, nitro；Its precondition is: work as R1、R5Simultaneously
During for hydrogen, R2、R3、R4It it is asynchronously methoxyl group.
Preferred compound feature of the present invention is as follows:
R2、R3、R4Each stand alone as C1-C4Alkyl, hydroxyl, C1-C4Alkyl oxy, C7-C10Phenylalkyl epoxide, amino,
C1-C4Alkyl amino, C1-C4Dialkyl amido, halogen atom, nitro；R1、R5It is hydrogen simultaneously；Its precondition is: R2、
R3、R4It it is asynchronously methoxyl group.
The present invention more preferably compound characteristic is as follows:
R2、R3、R4Each stand alone as hydroxyl, C1-C3Alkyl oxy, C7-C9Phenylalkyl epoxide, amino, C1-C3Alkyl
Amino, C1-C3Dialkyl amido, halogen atom, nitro；R1、R5It is hydrogen simultaneously；Its precondition is: R2、R3、R4
It it is asynchronously methoxyl group.
The present invention more preferably compound characteristic is as follows:
R2、R3、R4Each stand alone as hydroxyl, C1-C2Alkyl oxy, C7-C8Phenylalkyl epoxide, amino, C1-C2Alkyl
Amino, C1-C2Dialkyl amido, halogen atom, nitro；R1、R5It is hydrogen simultaneously；Its precondition is: R2、R3、R4
It it is asynchronously methoxyl group.
The present invention more preferably compound characteristic is as follows:
R2、R3、R4Each stand alone as hydroxyl, methoxyl group, ethyoxyl, benzyloxy, amino, methylamino, dimethylamino,
F, Cl, Br, nitro；R1、R5It is hydrogen simultaneously；Its precondition is: R2、R3、R4It it is asynchronously methoxyl group.
The compound of the present invention also includes the most acceptable nontoxic salts and the water thereof that derivant shown in structure above formed
Compound, these pharmaceutically acceptable nontoxic salts include the salt that this derivant is formed with acid.Described acid can be hydrochloric acid, sulfur
Acid, hydrobromic acid, the mineral acid of phosphoric acid or selected from acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, the organic acid of malic acid.
The hydration number of described hydrate is any real number in 0～16.
Currently preferred part of compounds structure and name are as follows:
Compound 1:
3-(3,4,5-trimethoxyphenyl)-4-(3-benzyloxy-4-methoxyphenyl)-1,2,5-diazole-5-oxide
Compound 2:
3-(3,4,5-trimethoxyphenyl)-4-(3-benzyloxy-4-methoxyphenyl)-1,2,5-diazole-2-oxide
Compound 3:
3-(3,4,5-trimethoxyphenyl)-4-(3-hydroxyl-4-methoxyphenyl)-1,2,5-diazole-5-oxide
Compound 4:
3-(3,4,5-trimethoxyphenyl)-4-(3-hydroxyl-4-methoxyphenyl)-1,2,5-diazole-2-oxide
Compound 5:
3-(3,4,5-trimethoxyphenyl)-4-(4-methoxyphenyl)-1,2,5-diazole-5-oxide
Compound 6:
3-(3,4,5-trimethoxyphenyl)-4-(4-methoxyphenyl)-1,2,5-diazole-2-oxide
Compound 7:
3-(3,4,5-trimethoxyphenyl)-4-(4-ethoxyl phenenyl)-1,2,5-diazole-5-oxide
Compound 8:
3-(3,4,5-trimethoxyphenyl)-4-(4-ethoxyl phenenyl)-1,2,5-diazole-2-oxide
Compound 9:
3-(3,4,5-trimethoxyphenyl)-4-(3-benzyloxy-phenyl)-1,2,5-diazole-5-oxide
Compound 10:
3-(3,4,5-trimethoxyphenyl)-4-(3-benzyloxy-phenyl)-1,2,5-diazole-2-oxide
Compound 11:
3-(3,4,5-trimethoxyphenyl)-4-(3-hydroxy phenyl)-1,2,5-diazole-5-oxide
Compound 12:
3-(3,4,5-trimethoxyphenyl)-4-(3-hydroxy phenyl)-1,2,5-diazole-2-oxide
Compound 13:
3-(3,4,5-trimethoxyphenyl)-4-(4-benzyloxy-phenyl)-1,2,5-diazole-5-oxide
Compound 14:
3-(3,4,5-trimethoxyphenyl)-4-(4-benzyloxy-phenyl)-1,2,5-diazole-2-oxide
Compound 15:
3-(3,4,5-trimethoxyphenyl)-4-(4-hydroxy phenyl)-1,2,5-diazole-5-oxide
Compound 16:
3-(3,4,5-trimethoxyphenyl)-4-(4-hydroxy phenyl)-1,2,5-diazole-2-oxide
Compound 17:
3-(3,4,5-trimethoxyphenyl)-4-(3-bromo-4-benzyloxy-phenyl)-1,2,5-diazole-5-oxide
Compound 18:
3-(3,4,5-trimethoxyphenyl)-4-(3-bromo-4-benzyloxy-phenyl)-1,2,5-diazole-2-oxide
Compound 19:
3-(3,4,5-trimethoxyphenyl)-4-(3-bromo-4-hydroxy phenyl)-1,2,5-diazole-5-oxide
Compound 20:
3-(3,4,5-trimethoxyphenyl)-4-(3-bromo-4-hydroxy phenyl)-1,2,5-diazole-2-oxide
Compound 21:
3-(3,4,5-trimethoxyphenyl)-4-(4-nitrobenzophenone)-1,2,5-diazole-5-oxide
Compound 22:
3-(3,4,5-trimethoxyphenyl)-4-(4-nitrobenzophenone)-1,2,5-diazole-2-oxide
Compound 23:
3-(3,4,5-trimethoxyphenyl)-4-(4-chlorphenyl)-1,2,5-diazole-5-oxide
Compound 24:
3-(3,4,5-trimethoxyphenyl)-4-(4-chlorphenyl)-1,2,5-diazole-2-oxide
Compound 25:
3-(3,4,5-trimethoxyphenyl)-4-(3-fluoro-4-methoxyphenyl)-1,2,5-diazole-5-oxide
Compound 26:
3-(3,4,5-trimethoxyphenyl)-4-(3-fluoro-4-methoxyphenyl)-1,2,5-diazole-2-oxide
Compound 27:
3-(3,4,5-trimethoxyphenyl)-4-(naphthalene-2-base)-1,2,5-diazole-5-oxide
Compound 28:
3-(3,4,5-trimethoxyphenyl)-4-(naphthalene-2-base)-1,2,5-diazole-2-oxide
3,4-bis-replacement of the present invention-[1,2,5] diazole oxide can be synthesized by route and prepare:
Reagents and conditions:a:NaOMe,MeOH,50℃；b:TsOH,3,4-Dihydro-2H-pyran,Anhydrous toluene,
Nitrogen protection,50℃；c:(i)n-BuLi,-55℃；(ii)Aromatic aldehydes/Anhydrous THF；D:HCl (18%), MeOH,
rt；e:SeO2,DMSO,MW(1000W),2min；f:NH2OH·HCl,Pyridine,AcOEt,MW(800W),90℃；g:NaOCl,
CH3OH,0℃.；H:HPLC (60%CH3OH).
Detailed description of the invention
Be will assist in by following example and understand the present invention, but present disclosure is not limited to example.Used by the present invention
To solvent except not elsewhere specified be all analytical pure, petroleum ether boiling range is 60-90 DEG C.The nuclear magnetic resonance, NMR of compound1H-NMR
Analyze and measure (Bruker company of Switzerland, TMS is internal standard) with Bruker ARX-300 type magnetic nuclear resonance analyzer；Mass spectral analysis
Measure and use 1100 series SL type ion trap mass spectrometers to measure (Agilent company of the U.S.)；Tlc analysis uses thin-layer silicon offset plate
Detection (TLC, GF254Silica gel plate, Qingdao Haiyang chemical industry)；Column chromatography used silica gel is 200～300 mesh and 100～200 mesh (green grass or young crops
Island marine chemical industry)；Circulation preparative liquid chromatograph (LC-9103 type, JAI company of Japan).
Embodiment 1:3-(3,4,5-trimethoxyphenyl)-4-(3-benzyloxy-4-methoxyphenyl)-1,2,5-diazole-5-oxide and
The preparation of 3-(3,4,5-trimethoxyphenyl)-4-(3-benzyloxy-4-methoxyphenyl)-1,2,5-diazole-2-oxide
Feldalat NM (0.40g, 7.60mmol) is dissolved in absolute methanol (20mL), and addition dimethylphosphite (6.73g, 61.17
And 3,4,5-Trimethoxybenzaldehyde (10g, 51.0mmol) mmol), stir under the conditions of 50 DEG C, complete through TLC detection reaction,
Remove under reduced pressure during solvent is fallen back and extract three times with dichloromethane, merge organic layer and wash with saturated aqueous common salt, anhydrous sulfur
Acid sodium removes organic solvent after drying under reduced pressure, with ethyl acetate and petroleum ether recrystallization, obtains white solid 14.96g, yield
96.5%.
Dissolve above-claimed cpd (2.0g, 4.73mmol) with a small amount of DMSO, add SeO2(1.06g, 9.47mmol) is solid
Body, reacts 2min under the microwave condition of 1000W, complete through TLC detection reaction, and filtrate is poured in trash ice by filtered while hot,
After ice-out, having a large amount of solid to separate out, reduce pressure sucking filtration, and filter cake MeOH recrystallization obtains purer intermediate 1-(3-
Benzyloxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl) second diketone (1.29g sepia solid), yield is 63.8%.
Above-mentioned gained intermediate (1.0g, 2.29mmol) is dissolved in the mixed solvent of ethyl acetate and pyridine, adds oxammonium hydrochloride.
(1.63g, 22.91mmol) solid, uses diluted ethyl acetate reactant liquor by 90 DEG C, react 2h under the microwave condition of 800W,
Then washing organic layer three times with dilute hydrochloric acid, then wash organic layer with saturated aqueous common salt, anhydrous sodium sulfate is dried, and removes under reduced pressure molten
Agent, obtains intermediate 1-(3-benzyloxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl) glyoxime (0.49g grease),
Yield is 45.4%.
Above-claimed cpd (1.0g, 2.14mmol) is dissolved in a small amount of methanol, under the conditions of ice-water bath, drips 20% sodium hypochlorite
Aqueous solution, stirring can separate out solid, sucking filtration washing after reacting about 20min, obtains target compound 3-(3-benzyloxy-4-
Methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,2,5-diazole oxide 2-1 (0.93g white solid), yield is 93.7%.
Through circulation preparation liquid phase separation purification (flowing is 60% methanol aqueous solution mutually), obtain compound 1 (0.36g white solid) respectively,
Yield is 48.6%.Compound 2 (0.33g white solid), yield is 44.6%.Its structural formula, 1H-NMR and MS number
According to being listed in the table below in-1.
Embodiment 2:3-(3,4,5-trimethoxyphenyl)-4-(3-hydroxyl-4-methoxyphenyl)-1,2,5-diazole-5-oxide and
The preparation of 3-(3,4,5-trimethoxyphenyl)-4-(3-hydroxyl-4-methoxyphenyl)-1,2,5-diazole-2-oxide
In addition to using corresponding raw material, prepare example 2 with the method that embodiment 1 is identical, by compound 3-(3-benzyloxy-4-first
Phenyl)-4-(3,4,5-trimethoxyphenyl)-1,2,5-diazole oxide (1.0g, 2.15mmol) is dissolved in the most anhydrous two
Chloromethanes, adds TiCl under-20 DEG C of stirring conditions4React complete through TLC detection after (1.1ml, 10.76mmol), about 30min,
Being poured into water by reactant liquor, extract three times with dichloromethane, and wash with saturated aqueous common salt, anhydrous sodium sulfate is dried organic layer,
Remove solvent under reduced pressure.Through circulation preparation liquid phase separation purification (flowing is 60% methanol aqueous solution mutually), obtain compound 3 yield 45.7%,
Compound 4 yield 42.6%.Its structural formula, 1H-NMR and MS data are listed in the table below in-1.
Embodiment 3:3-(3,4,5-trimethoxyphenyl)-4-(4-methoxyphenyl)-1,2,5-diazole-5-oxide and 3-(3,4,5-tri-
Methoxyphenyl) preparation of-4-(4-methoxyphenyl)-1,2,5-diazole-2-oxide
In addition to using corresponding raw material, complete example 3, compound 5 yield 49.5%, chemical combination with the method that embodiment 1 is identical
Thing 6 yield 42.3%.Its structural formula, 1H-NMR and MS data are listed in the table below in-1.
Embodiment 4:3-(3,4,5-trimethoxyphenyl)-4-(4-ethoxyl phenenyl)-1,2,5-diazole-5-oxide and 3-(3,4,5-tri-
Methoxyphenyl) preparation of-4-(4-ethoxyl phenenyl)-1,2,5-diazole-2-oxide
In addition to using corresponding raw material, complete example 4, compound 7 yield 48.5%, chemical combination with the method that embodiment 1 is identical
Thing 8 yield 43.3%.Its structural formula, 1H-NMR and MS data are listed in the table below in-1.
Embodiment 5:3-(3,4,5-trimethoxyphenyl)-4-(3-benzyloxy-phenyl)-1,2,5-diazole-5-oxide and 3-(3,4,5-tri-
Methoxyphenyl) preparation of-4-(3-benzyloxy-phenyl)-1,2,5-diazole-2-oxide
In addition to using corresponding raw material, complete example 5, compound 9 yield 49.1%, chemical combination with the method that embodiment 1 is identical
Thing 10 yield 44.9%.Its structural formula, 1H-NMR and MS data are listed in the table below in-1.
Embodiment 6:3-(3,4,5-trimethoxyphenyl)-4-(3-hydroxy phenyl)-1,2,5-diazole-5-oxide and 3-(3,4,5-front three
Phenyl) preparation of-4-(3-hydroxy phenyl)-1,2,5-diazole-2-oxide
In addition to using corresponding raw material, complete example 6, compound 11 yield 44.4% with the method that embodiment 2 is identical, change
Compound 12 yield 42.1%.Its structural formula, 1H-NMR and MS data are listed in the table below in-1.
Embodiment 7:3-(3,4,5-trimethoxyphenyl)-4-(4-benzyloxy-phenyl)-1,2,5-diazole-5-oxide and 3-(3,4,5-tri-
Methoxyphenyl) preparation of-4-(4-benzyloxy-phenyl)-1,2,5-diazole-2-oxide
In addition to using corresponding raw material, complete example 7, compound 13 yield 48.1% with the method that embodiment 1 is identical, change
Compound 14 yield 44.4%.Its structural formula, 1H-NMR and MS data are listed in the table below in-1.
Embodiment 8:3-(3,4,5-trimethoxyphenyl)-4-(4-hydroxy phenyl)-1,2,5-diazole-5-oxide and 3-(3,4,5-front three
Phenyl) preparation of-4-(4-hydroxy phenyl)-1,2,5-diazole-2-oxide
In addition to using corresponding raw material, complete example 8, compound 15 yield 43.1% with the method that embodiment 2 is identical, change
Compound 16 yield 42.3%.Its structural formula, 1H-NMR and MS data are listed in the table below in-1.
Embodiment 9:3-(3,4,5-trimethoxyphenyl)-4-(3-bromo-4-benzyloxy-phenyl)-1,2,5-diazole-5-oxide and
The preparation of 3-(3,4,5-trimethoxyphenyl)-4-(3-bromo-4-benzyloxy-phenyl)-1,2,5-diazole-2-oxide
In addition to using corresponding raw material, complete example 9, compound 17 yield 46.4% with the method that embodiment 1 is identical, change
Compound 18 yield 45.2%.Its structural formula, 1H-NMR and MS data are listed in the table below in-1.
Embodiment 10:3-(3,4,5-trimethoxyphenyl)-4-(3-bromo-4-hydroxy phenyl)-1,2,5-diazole-5-oxide and 3-(3,4,5-
Trimethoxyphenyl) preparation of-4-(3-bromo-4-hydroxy phenyl)-1,2,5-diazole-2-oxide
In addition to using corresponding raw material, complete example 10, compound 19 yield 42.2% with the method that embodiment 2 is identical, change
Compound 20 yield 41.3%.Its structural formula, 1H-NMR and MS data are listed in the table below in-1.
Embodiment 11:3-(3,4,5-trimethoxyphenyl)-4-(4-nitrobenzophenone)-1,2,5-diazole-5-oxide and 3-(3,4,5-front three
Phenyl) preparation of-4-(4-nitrobenzophenone)-1,2,5-diazole-2-oxide
In addition to using corresponding raw material, complete example 11, compound 21 yield 45.6% with the method that embodiment 1 is identical, change
Compound 22 yield 41.3%.Its structural formula, 1H-NMR and MS data are listed in the table below in-1.
Embodiment 12:3-(3,4,5-trimethoxyphenyl)-4-(4-chlorphenyl)-1,2,5-diazole-5-oxide and 3-(3,4,5-trimethoxy
Base phenyl) preparation of-4-(4-chlorphenyl)-1,2,5-diazole-2-oxide
In addition to using corresponding raw material, complete example 12, compound 23 yield 46.7% with the method that embodiment 1 is identical, change
Compound 24 yield 43.8%.Its structural formula, 1H-NMR and MS data are listed in the table below in-1.
Embodiment 13:3-(3,4,5-trimethoxyphenyl)-4-(3-fluoro-4-methoxyphenyl)-1,2,5-diazole-5-oxide and
The preparation of 3-(3,4,5-trimethoxyphenyl)-4-(3-fluoro-4-methoxyphenyl)-1,2,5-diazole-2-oxide
In addition to using corresponding raw material, complete example 13, compound 25 yield 47.8% with the method that embodiment 1 is identical, change
Compound 26 yield 43.7%.Its structural formula, 1H-NMR and MS data are listed in the table below in-1.
Embodiment 14:3-(3,4,5-trimethoxyphenyl)-4-(naphthalene-2-base)-1,2,5-diazole-5-oxide and 3-(3,4,5-trimethoxy
Base phenyl) preparation of-4-(naphthalene-2-base)-1,2,5-diazole-2-oxide
In addition to using corresponding raw material, complete example 14, compound 27 yield 47.7% with the method that embodiment 1 is identical, change
Compound 28 yield 44.3%.Its structural formula, 1H-NMR and MS data are listed in the table below in-1.
Embodiment 15: the external pharmacology test of the compound of the present invention
(1) experimental principle: tetrazolium (micoculture tetrozolium, MTT) reducing process.The positive used is with reference to medicine
Thing is clinical conventional amycin.
(2) cell strain: human stomach cancer cell line SGC-7901, human fibrosarcoma cell strain HT-1080 and human lung adenocarcinoma cell line
A549
(3) experimental technique:
1. preparation concentration is 1 × 105μ g/mL cell suspension, adds in 96 orifice plates, every hole 100 μ L, puts 37 DEG C, 5%CO2
Incubator is hatched 24h.
2., in 96 orifice plates of the tumor cell that the tested material of variable concentrations is added to cultivation, continue to cultivate 24h, under inverted microscope
Observe.
3. discarding culture fluid, every hole adds 0.05%MTT application liquid 100 μ L, cultivates 4h.
4. discarding culture fluid, every hole adds 100 μ L DMSO, vibration 5min makes the crystallization of first a ceremonial jade-ladle, used in libation dissolve, and measures at 490nm
Cell absorbance (OD value).
Processing for Data Analysis in Physics is as follows:
Using the absorbance of non-medicine feeding hole cell as blank group absorbance (OD value), computing formula is as follows:
Suppression ratio (%)=(blank group OD meansigma methods-sample sets OD meansigma methods degree)/blank OD meansigma methods × 100%,
It is shown in Table-2.
Embodiment 16: anti-tumor activity test in the animal body of the compound of the present invention
Selecting the preferable compound of external activity 5 to carry out anti-tumor activity test in animal body, model used is mice S-180
Sarcoma model, positive control medicine is clinical conventional antitumor drug fluorouracil (Fluorouracil).
Experimental technique: select the S-180 tumor kind of 18-22 gram of female KM mice and well-grown 7-11 days, by tumor tissue system
Become cell suspension, be seeded to right side of mice armpit subcutaneous, about 1.0-2.0 × 106Cell/only, random point of cage after inoculating 24 hours,
Continuous 7 days of intraperitoneal injection.Within after drug withdrawal 24 hours, put to death animal, weigh, tumor weight, calculate each group of average tumor weight, by such as
Lower formula is obtained tumor control rate and carries out t inspection.
Tumor control rate=[(blank group average tumor weight-treatment group average tumor weight)/(blank group average tumor weight)] × 100%
Experimental result is shown in Table-3.
Table-1
Table-2
Table-3
Claims (10)
1. the 3,4-diaryl-1,2,5-diazole oxide shown in formula I or formula II:
Wherein,
R1～R5Each stand alone as hydrogen, C1-C4Alkyl, hydroxyl, C1-C4Alkyl oxy, C7-C10Phenylalkyl
Epoxide, amino, C1-C4Alkyl amino, C1-C4Dialkyl amido, halogen atom, nitro；Its precondition
It is: work as R1、R5When being hydrogen simultaneously, R2、R3、R4It it is asynchronously methoxyl group.
2. compound as claimed in claim 1 and salt thereof and hydrate, it is characterised in that:
R2、R3、R4Each stand alone as C1-C4Alkyl, hydroxyl, C1-C4Alkyl oxy, C7-C10Octadecyloxy phenyl
Base epoxide, amino, C1-C4Alkyl amino, C1-C4Dialkyl amido, halogen atom, nitro；R1、R5
It is hydrogen simultaneously；Its precondition is: R2、R3、R4It it is asynchronously methoxyl group.
3. compound as claimed in claim 1 or 2 and salt thereof and hydrate, it is characterised in that:
R2、R3、R4Each stand alone as hydroxyl, C1-C3Alkyl oxy, C7-C9Phenylalkyl epoxide, amino,
C1-C3Alkyl amino, C1-C3Dialkyl amido, halogen atom, nitro；R1、R5It is hydrogen simultaneously；Before it
The condition of carrying is: R2、R3、R4It it is asynchronously methoxyl group.
4. compound as described in claim 1-3 any one and salt thereof and hydrate, it is characterised in that:
R2、R3、R4Each stand alone as hydroxyl, C1-C2Alkyl oxy, C7-C8Phenylalkyl epoxide, amino,
C1-C2Alkyl amino, C1-C2Dialkyl amido, halogen atom, nitro；R1、R5It is hydrogen simultaneously；Before it
The condition of carrying is: R2、R3、R4It it is asynchronously methoxyl group.
5. compound as described in claim 1-4 any one and salt thereof and hydrate, it is characterised in that:
R2、R3、R4Each stand alone as hydroxyl, methoxyl group, ethyoxyl, benzyloxy, amino, methylamino,
Dimethylamino, F, Cl, Br, nitro；R1、R5It is hydrogen simultaneously；Its precondition is: R2、R3、R4
It it is asynchronously methoxyl group.
6. compound as described in as any in Claims 1 to 5 one and salt thereof and hydrate, it is characterised in that:
Described salt is this compound and the salt that formed of acid, described acid selected from hydrochloric acid, sulphuric acid, hydrobromic acid,
Phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid；The crystallization water number of described hydrate
Mesh is any real number in 0～16.
7. one kind as claimed in claim 13,4-diaryl-1, the preparation method of 2,5-diazole oxides, its feature
It is:
Reagents and conditions:a:NaOMe,MeOH,50℃；b:TsOH,3,4-Dihydro-2H-pyran,Anhydrous
toluene,Nitrogen protection,50℃；c:(i)n-BuLi,-55℃；(ii)Aromatic aldehydes/Anhydrous THF；
D:HCl (18%), MeOH, rt；e:SeO2,DMSO,MW(1000W),2min；f:NH2OH·HCl,Pyridine,
AcOEt,MW(800W),90℃；g:NaOCl,CH3OH,0℃.；H:HPLC (60%CH3OH)。
8. a pharmaceutical composition, it is characterised in that comprise the chemical combination described in claim 1-6 any one
Thing and salt thereof and hydrate and pharmaceutically acceptable carrier.
9. described in compound described in claim 1-6 any one and salt thereof and hydrate or claim 8
Pharmaceutical composition application in preparing antitumor drug.
Apply the most as claimed in claim 9, it is characterised in that described tumor be gastric cancer, fibrosarcoma,
Adenocarcinoma of lung.
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| CN106883266A (en) * | 2017-01-23 | 2017-06-23 | 江苏七洲绿色化工股份有限公司 | A kind of 1（4 chlorphenyls）The Preparation Method And Their Intermediate of the acetone of 2 cyclopropyl 1 |
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