CN1824657A - 3-substituted-2-aryl substituted-5-(3,4,5-tri alkoxy phenyl)-1,-3,4-oxidazole derivative, its preparation method and use - Google Patents
3-substituted-2-aryl substituted-5-(3,4,5-tri alkoxy phenyl)-1,-3,4-oxidazole derivative, its preparation method and use Download PDFInfo
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- CN1824657A CN1824657A CN 200610050996 CN200610050996A CN1824657A CN 1824657 A CN1824657 A CN 1824657A CN 200610050996 CN200610050996 CN 200610050996 CN 200610050996 A CN200610050996 A CN 200610050996A CN 1824657 A CN1824657 A CN 1824657A
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Abstract
The present invention uses 3,4,5-trialkoxybenzoyl hydrazine, aromatic aldehyde and acid anhydride as raw material, uses methyl alcohol, ethyl alcohol, isopropanol, absolute alcohole, benzene, toluene, xylene, N,N-dimethylformamide, dioxane, methyl-sulfoxide, cyclohexane, n-hexane or their mixture as solvent and adopts two-step synthesis process to obtain the invented compound 3-substituted-2-aryl substituted -5-(3,4,5-trialkoxyphenyl)-1,3,4-oxdiazole derivative. Said invention provides the general formula of said compound. Said compound can be used as a medicine for resisting tumor, the tests show that said compound has good activity for inhibiting cancer cell of prostate.
Description
Technical field
The present invention is the medicine 3-replacement-2-aryl replacement-5-(3,4, the 5-tri-alkoxy phenyl)-1,3 with antitumor action, 4-oxadiazole derivative and preparation method thereof.
Background technology
In recent years 1,3,4-oxadiazole compounds is because of having wide biological activity such as desinsection, sterilization, anticancer, anti-inflammatory etc., thus enjoy people's attention [as document: 1.Chai, B.; Cao, S.; Liu, H.D.; Song, G.H.; Qian X H.Heterocyclic Communications, 2002,8 (6), 601; 2.Hui, X.P.; Chu, C.H.; Zhang, Z..; Wang, Q.; Zhang, Q.India J Chem Soc, 2003,41B, 2176.3.Abdel, K.M.; Mohga, M.E.; Nasser, S.A.Molecules, 2003,8,744; 4.Burbuliene, M.M.; Udrenaite, E.; Gaidelis, P.; Vainlavicius, P.Polish JChem, 2002,76,557; 5. Li Qian post, Song Baoan, Chen Jiang, Liu Jie, Yang Song, Hu Deyu, Jin Linhong, agricultural chemicals .2005,44 (12), 538.].
With the gallic acid be in addition raw material synthesize the osajin derivative more existing as report anticancer, antioxidant.For example: Sedoxazin and 3,4, the basic amine of 5-trimethoxy benzoyl eggplant can treat heart trouble, anticancer and antiulcer agent etc. [document: 1. Zhao Jin, Song Jinyong. applied chemistry 2003,20 (1), 95; 2.Sopalvida-Boza, S.; Walizei, G.H.; Rezendo, M.C.; Vasquez, Y.; Mascayano C.; Mejias L.Synth.Commun.2001,31,1933.].
Human 5-pyrazole carboxylic acid and 5-pyrazoles formyl hydrazines such as Chen Han pine in 1998 adopt one kettle way, reflux to get two compounds in 6 hours, and yield is 55%～60%.Adopt the little strain method of live body to make bactericidal assay, the result shows: (X=Cl, X '=H) inhibiting rate to Rhizoctonia solani Kuhn (Rhizoctonia solani) is 70% to 1b under 0.05% concentration.2000, again pyrazolyl, alkylthio are introduced 1,3, the 4-oxadiazole has synthesized novel cpd 2, and synthesis yield is 70%～80%.(Carbendazim) compares medicament with derosal, carried out the bacteriostatic activity test under 100ppm concentration, and the result shows: substituting group changes the influence of compound biological activity bigger.Wherein, (R=Me, X=Cl) inhibiting rate to rice sheath blight disease (ricesheath blight) is 80% to compound 2.[document: 1. Chen Han pine, Li Zhengming .2,5-two pyrazolyls-1,3, the synthetic and biological activity [J] of the method for the treatment of different things alike of 4-oxadiazole. SCI, 1998,19 (4): 572-573; 2.Chen H S, Li Z M, Han Y F.Synthesis and fungicidalactivity against Rhizoctonia solani of 2-alkyl (alkylthio)-5-pyrazolyl-1,3,4-oxadiazoles (thiadiazoles) [J] .J.Agric Food Chem, 2000,48:5312-5315.]
People such as Hu Guoqiang were starting raw material with nicotinic acid in 2004, through over-churning, hydrazineization, again with CS
25-(pyridin-3-yl) 1,3 has been synthesized in/KOH effect, closed loop, 4-oxadiazole-2-mercaptan.Under the suitably excessive condition of pH=6 and Mono Chloro Acetic Acid, this compound is easy to react in the alcoholic solution of sodium bicarbonate with Mono Chloro Acetic Acid, at POCl
3Effect gets target compound with fragrant hydrazides cyclization down again.Under the 0.1mg/L drug concentration, compound j (Ar=p-CH
3C
6H
4) active and suitable with reference to medicament norfloxicin (NF) to the inhibition of streptococcus aureus (S.aureus).Compound f (Ar=m-O
2NC
6H
4), i (Ar=4-pyridyl) is active suitable with norfloxicin to the inhibition of Gram colon bacillus (E.coli).[Liu's treasured waits .2-(3-pyridine)-5-{[(5-aryl-1,3,4-oxadiazole-2-yl for document: Hu Guoqiang, Xu Qiuju) methylene radical] sulfo-)-1,3, the synthetic and anti-microbial activity [J] of 4-oxadiazole. Acta Pharmaceutica Sinica, 2004,39 (4): 263-265.]
E1-masry in 2000 etc. have synthesized and have contained 1,3 of benzoglyoxaline parent nucleus, and 4-oxadiazole new compound, synthesis yield are 86%.(disk diffusion method) carried out the bacteriostatic activity test with the filter paper method.The result shows: when 600 μ g/disk, new compound is suitable to the inhibiting rate of streptococcus aureus (B.cereus) and contrast medicine ammonia benzyl cyanogen (Ampicelline), gentamicin (Gentamycine), and bacteriostatic diameter is greater than 12 millimeters.[document: Afaf H, Fahmy H H, Ali Abdelwahed S H.Synthesis andantimicrobial activity of some new benzimidazole derivatives[J] .Molecules, 2000,5:1429-1438]
Maslat in 2002 etc. are starting raw material with the dihydrazide compound, in the ethanolic soln of potassium hydroxide with the dithiocarbonic anhydride effect, generate the new compound of Han Shuan oxadiazole ring, it has carried out the bacteriostatic activity test under 450 μ g/ml concentration, the result shows: this compound has activity to Bacillus subtilus (B.subtilis), Candida albicans (C.albicans), to Gram colon bacillus (E.coli) non-activity.[document: Ahmed O Maslat, Mahmud Abussaud, Hasan Tashtoush, et al.Synthesis, antibacterial, antifungal and genotoxic activity of bis-1,3,4-oxadiazolederivatives[J] .Pol.J.Pharmacol, 2002,54:55-59]
Khan in 2003 etc. are respectively with salicylic aldehyde, 1, and the 3-dihydroxy-benzene is a starting raw material, has synthesized through two lines and has contained 1,3 of pyrone, 4-oxadiazole new compound.The synthesis yield of target compound is 40%～60%.Adopt cup-plate method (cup-plate method) under 100 μ g/ml concentration, to carry out the bacteriostatic activity test, the result shows: part of compounds has stronger activity to Gram colon bacillus (E.coli), and bacteriostatic diameter is 18～19mm (contrast medicine Norfloxacin is 28mm).[Khan?M?S?Y，Akhtar?M.Synthesis?of?some?new?2，5-disubsituted?1，3，4-oxadiazolederivatives?and?their?biological?activity[J].Indian?Journal?of?Chemistry，42B(4)：900-904]
Yan Zhang etc. have synthesized series and have contained 1,3 of 1,2,3-triazoles ring from the 1,2,3-triazoles formyl hydrazine in water (not adding PTC), 4-oxadiazole compounds, synthesis yield are 72%～75%.Adopt cup-plate method (cup-plate method), under 100 μ g/mL concentration, carried out the bacteriostatic activity test.The result shows: to Gram colon bacillus (E.coli), the bacteriostatic diameter of two compounds is greater than 17mm; To Pseudomonas aeruginosa (P.aeruginosa), the bacteriostatic diameter of four compounds is greater than 17mm; To streptococcus aureus (S.aureus), the bacteriostatic diameter of a compound is greater than 17mm.[document: ZhangY, Qiao R Z, Xu P F, et al.Synthesis and antibacterial activities of2-(1-aryl-5-methyl-1,2,3-triazol-4-yl)-1,3,4-oxadiazole derivatives[J] .Journalof the Chinese Chemical Society, 2002,49:369-373]
It is 1,3 of fragrant formyl sulfo-that serial 2-position has been synthesized in designs such as Sandeep Jain, and 4-oxadiazole compound, synthesis yield are 81%～85%.With norfloxicin (Norfloxacin) is contrast, target compound is to colon bacillus (E.coli), Shigella dysenteriae (S.dysenteriae), streptococcus aureus (S.aureas) and Bacillus subtilus (B.subtilis) have carried out the bacteriostatic activity test, and the result shows: wherein a compound has better bacteriostatic activity.[document: Sandeep Jain, Pradeep Mishra.Synthesis and antibacterial activity of 5-aryl-2-acyl thio-1,3,4-oxadiazoles[J] .Indian Journal of Heterocyclic Chemistry, 2004,13:April-June:307-310]
In recent years, inventor research group is in order to seek efficient antitumour activity new compound, the working foundation that synthesizes with original gallic acid derivatize, Yin Ru oxadiazole group in the molecule designs and has synthesized 3-replacement-2-aryl replacement-5-(3,4, the 5-tri-alkoxy phenyl)-1,3,4-oxadiazole compounds, carry out have antitumour activity heterocycle new compound design, synthetic and biological screening.
Summary of the invention
Based on original work, derive design and the synthetic novel 3-replacement-2-of class aryl replacement-5-(3,4, the 5-tri-alkoxy phenyl)-1,3,4-oxadiazole compounds carries out cancer therapy drug initiative research.Its general structure is as follows:
In the formula
R
1Be the C1-6 alkyl;
R
2Aromatic group for C5-14; contain 1 or a plurality of N of being selected from; O; S; the heteroatomic C5-14 hetero-aromatic ring group of SO and SO2; and can independently be selected from following substituent group by one or more on the above-mentioned cyclic group replaces: (1) hydroxyl; (2) halogen atom; (3) itrile group; (4) nitro; (5) C1-6 alkyl; C2-6 alkenyl or C2-6 alkynyl group; wherein each group all can be replaced by at least one or a plurality of halogen atom substituting group; (6) C1-6 alkoxyl group; C2-6 alkenyloxy or C2-6 chain oxy-acetylene; wherein each group all can be replaced by at least one or a plurality of halogen atom substituting group; (7) C1-6 alkylthio; C2-6 alkenyl thio or C2-6 alkynes sulfenyl; wherein each group all can be replaced by at least one or a plurality of halogen atom substituting group; (8) substituted carbonyl; described substituting group is selected from (i) C1-6 alkyl; (ii) amino; (iii) C1-6 alkylamino; (iv) C1-6 alkyl oxy; (v) C1-6 alkyl sulfenyl; (vi) C3-8 cycloalkyl; (9) can be by the amino of 1 or 2 each substituting groups replacement; described substituting group is selected from (i) C1-6 alkyl; (ii) C2-6 alkenyl; (iii) C2-6 alkynyl group; (iv) C1-6 alkyl sulphonyl; (v) C2-6 alkenyl alkylsulfonyl; (vi) C2-6 alkynyl group alkylsulfonyl; (vii) C1-6 alkyl-carbonyl; (viii) C2-6 alkenyl carbonyl (ix) C2-6 alkynyl group carbonyl, (10) C1-6 alkyl sulphonyl, (11) C2-6 alkenyl alkylsulfonyl; (12) C2-6 alkynyl group alkylsulfonyl; (13) C1-6 alkyl sulphinyl, (14) C2-6 alkenyl sulfinyl, (15) C2-6 alkynyl group sulfinyl; (16) formyl radical, (17) C3-8 cycloalkyl or C3-8 cycloalkenyl group.
R
3Be substituted carbonyl; thiocarbonyl group; sulfuryl; sulfoxide group; alkylsulfonyl; sulfinyl; wherein be substituted the part substituting group and be selected from (i) C1-10 alkyl; (ii) amino; (iii) C1-10 alkylamino; (iv) C1-10 alkyl oxy; (v) C1-10 alkyl sulfenyl; (vi) C3-8 cycloalkyl or C3-8 cycloalkenyl group; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (vii) hydrogen; (viii) C3-8 cycloalkyloxy or C3-8 cyclenes oxygen base, wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces.
Above-described a kind of medicine that is used for antitumor action, R in its compound general formula
1Be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl.
Above-described a kind of medicine that is used for antitumor action, R in its compound general formula
2Be phenyl, pyrryl, furyl, tetrahydrofuran base, thienyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl oxazolyl isoxazolyl, triazolyl, tetrazyl, thiadiazolyl group, pyridyl, morpholinyl, piperazinyl, triazinyl, piperidyl, pyridazinyl, pyrimidyl, purine radicals, pyrazinyl, naphthyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, indyl, draw the azoles base, benzofuryl, benzimidazolyl-, benzothiazolyl, benzisothiazole base benzoxazolyl, the benzoisoxazole base, the benzopyrazoles base, quinazolyl, different quinazolyl, dibenzofuran group, the dibenzothiophene base, the bisbenzimidazole base, the dibenzo pyrimidyl, the dibenzopyridine base, carbazyl, and above-mentioned cyclic group can independently be selected from following substituent group by one or more and replace: (1) halogen atom, (2) itrile group, (3) nitro, (4) C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl group, wherein each group all can be replaced by at least one or a plurality of halogen atom substituting group, (5) C1-6 alkoxyl group, C2-6 alkenyloxy or C2-6 chain oxy-acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom substituting group.
Above-described a kind of medicine that is used for antitumor action, R in its compound general formula
2Be 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 3,4-dichlorophenyl, 2,5-Dimethoxyphenyl, 3,4-difluorophenyl, 2,3-Dimethoxyphenyl, 4-chloro-3-nitrophenyl, 3,5-dichlorophenyl, 2,4-Dimethoxyphenyl, 2,6-dichlorophenyl, 3,4, the 5-trimethoxyphenyl.
Above-described a kind of medicine that is used for antitumor action, R in its compound general formula
3Be ethanoyl, propionyl, different propionyl, ethanethioyl, sulfo-propionyl, the different propionyl of sulfo-.
In the content of the present invention, the C1-6 alkyl can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, neo-pentyl, n-hexyl, isohexyl, uncle's hexyl, new hexyl.
In the content of the present invention, the C2-6 alkenyl can be vinyl, propenyl, allyl group, butenyl (two keys are 1, two or three-digit), isobutenyl (two keys are at 1 or 2), pentenyl (two keys are at 1,2,3 or 4), isopentene group (two keys are 1, two or three-digit), new pentenyl (two keys are at 1 or 2), hexenyl (two keys are at 1,2,3,4 or 5), dissident's thiazolinyl (two keys are at 1,2,3 or 4), neohexene base (two keys are 1, two or three-digit).
In the content of the present invention, the C2-6 alkynyl group can be ethynyl, proyl, propargyl, butynyl (three key is 1, two or three-digit), isobutyl alkynyl (three key is at 1 or 2), pentynyl (three key is at 1,2,3 or 4), isoamyl alkynyl (three key is 1, two or three-digit), new pentynyl (three key is at 1 or 2), hexin base (three key is at 1,2,3,4 or 5), dissident's alkynyl (three key is at 1,2,3 or 4), new hexin base (three key is 1, two or three-digit).
In the content of the present invention, halogen atom can be fluorine, chlorine, bromine, iodine.
In the content of the present invention, can be a kind of pharmaceutical composition, it is characterized in that comprising formula (I) compound of significant quantity, its purposes is also to can be used as treatment and prevent various optimum or malignant tumours as activeconstituents.Wherein said tumour comprises prostate cancer, leukemia, skin carcinoma, cancer of the stomach, mammary cancer, liver cancer, lung cancer, ovarian cancer, cervical cancer, lymphatic cancer, large bowel cancer, nasopharyngeal carcinoma, oral carcinoma, wherein is meant prostate cancer, cancer of the stomach and mammary cancer especially.
The present invention is with 3,4, and 5-tri-alkoxy benzoyl hydrazine, aromatic aldehyde, acid anhydrides are raw material, and synthetic through two steps, synthetic route is as follows:
R wherein
1, R
2, R
3As previously mentioned, reaction solvent is methyl alcohol, ethanol, Virahol, dehydrated alcohol, benzene,toluene,xylene, N, dinethylformamide, dioxane, methyl-sulphoxide, hexanaphthene, normal hexane or its mixture.
The first step: replace aromatic aldehyde-3,4,5-tri-alkoxy benzoyl hydrazone synthetic
At the bottom of having three mouthfuls of gardens of reflux, drop into 3,4 in the flask, 5-tri-alkoxy benzoyl hydrazine, aromatic aldehyde, solvent, reflux, the 0.5-5h reaction finishes, and is replacement aromatic aldehyde-3,4,5-tri-alkoxy benzoyl hydrazone.
This step is applicable to all above-mentioned replacement aromatic aldehydes-3,4,5-tri-alkoxy benzoyl hydrazone synthetic.
Second step: the 3-replacements-2-aryl replacement-5-(3,4, the 5-tri-alkoxy phenyl)-1,3, the synthesizing of 4-oxadiazole
The product of the first step is dissolved in the acid anhydrides, reacts 0.5-5h under the stirring and refluxing condition, pour in the trash ice, spend the night suction filtration, washing, drying, thick product acetone-water recrystallization gets white solid, is 3-replacement-2-aryl replacement-5-(3,4, the 5-tri-alkoxy phenyl)-1,3, the 4-oxadiazole.
This step is applicable to all above-mentioned 3-replacement-2-aryl replacement-5-(3,4, the 5-tri-alkoxy phenyl)-1,3,4-oxadiazole synthetic.
Embodiment
Embodiment one, 3-ethanoyl-2-(2-fluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, (compound number is a) for 4-oxadiazole synthetic
(1) 2-fluorobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone synthetic
Drop into 3,4 in the flask at the bottom of three mouthfuls of gardens of the 50mL that has reflux, 5-trimethoxy benzoyl hydrazine 2mmol and 10mL dehydrated alcohol, stir, heating adds 2mmol 2-phenyl aldehyde after whole dissolvings, reflux 30min, cooling back suction filtration, ethanol～DMF recrystallization obtains intermediate 2-fluorobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone: clear crystal, productive rate 81.4%, m.p.173～174 ℃;
1H NMR (DMSO-d
6) δ: 3.722 (s, 3H, OCH
3), 3.860 (s, 6H, 2OCH
3), 7.250～7.973 (m, 6H, Ar-H), 8.705 (s, 1H, N=CH), 11.847 (s, 1H, NH);
13C NMR (DMSO-d
6) δ: 162.8,162.3,153.9,140.8,132.3,128.5,126.6,125.3,122.2,116.4,105.5,60.4,56.4; IR (KBr) v:3200,3040,1645,1558,1120cm
-1.Anal.calcd for C
17H
17FN
2O
4: C 61.44, and H 5.16, and N 8.43; Found C 61.22, H 5.14, N8.36.
(2) 3-ethanoyl-2-(2-fluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole synthetic
With the product 1mmol of the first step, add the 5mL diacetyl oxide, react 2h under the stirring and refluxing condition, pour in the trash ice, spend the night, suction filtration, washing, drying, thick product acetone-water recrystallization, get white solid, be 3-ethanoyl-2-(2-fluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole: white solid, productive rate 71.5%, m.p.138～140 ℃;
1H NMR (DMSO-d
6) δ: 2.253 (s, 1H, CH
3), 3.775 (s, 3H, OCH
3), 3.858 (s, 6H, 2OCH
3), 7.134 (s, 1H, CH), 7.194～7.522 (m, 6H, Ar-H);
13C NMR (DMSO-d
6) δ: 167.4,155.6,142.1,132.9,132.8,130.0,129.9,125.4,125.4,124.9,124.8,120.4,116.8,104.8,89.3,21.2; IR (KBr) v:3010,1658,1581,977cm
-1Anal.calcd forC
19H
19FN
2O
5: C 60.96, and H 5.12, and N 7.48; Found C 60.74, H 4.95, N 7.37..
Embodiment two, 3-ethanoyl-2-(3-fluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, synthetic (compound number is b) of 4-oxadiazole
(1) 3-fluorobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone synthetic
Synthetic as embodiment one (1) method and condition, only the 2-fluorobenzaldehyde is changed to the 3-fluorobenzaldehyde, obtain intermediate 3-fluorobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone: clear crystal, productive rate 69.4%, m.p.147～149 ℃;
1H NMR (DMSO-d
6) δ: 3.720 (s, 3H, OCH
3), 3.856 (s, 6H, 2OCH
3), 7.234～7.582 (m, 6H, Ar-H), 8.465 (s, 1H, N=CH), 11.833 (s, 1H, NH);
13C NMR (DMSO-d
6) δ: 168.6,152.7,146.3,140.5,136.9,136.8,131.0,130.9,128.3,123.4,116.9,116.7,113.1,112.8,105.2,60.1,56.0; IR (KBr) v:3184,3024,1645,1568,1120cm
-1Anal.calcd for C
17H
17FN
2O
4: C 61.44, H5.16, and N 8.43; Found C 61.30, H 5.13, N 8.34.
(2) 3-ethanoyl-2-(3-fluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole synthetic
Synthetic as embodiment one (2) method and condition, obtain 3-ethanoyl-2-(3-fluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole: white solid, productive rate 62.9%, m.p.140～141 ℃;
1HNMR (DMSO-d
6) δ: 2.266 (s, 1H, CH
3), 3.709 (s, 3H, OCH
3), 3.814 (s, 6H, 2OCH
3), 7.061 (s, 1H, CH), 7.183～7.504 (m, 6H, Ar-H);
13C NMR (DMSO-d
6) δ: 166.9,154.5,140.6,139.2,139.2,131.1,122.7,119.0,116.9,116.7,113.8,113.5,103.8,91.0,60.2,56.0,21.2; IR (KBr) v:3001,1664,1583,1006cm
-1Anal.calcd for C
19H
19FN
2O
5: C 60.96, and H 5.12, and N 7.48; Found C 61.09, H 5.12, N 7.46.
Embodiment three, 3-ethanoyl-2-(4-fluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, synthetic (compound number is c) of 4-oxadiazole
(1) 4-fluorobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone synthetic
Synthetic as embodiment one (1) method and condition, only the 2-fluorobenzaldehyde is changed to the 4-fluorobenzaldehyde, obtain intermediate 4-fluorobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone: clear crystal, productive rate 71.4%, m.p.179～181C;
1H NMR (DMSO-d
6) δ: 3.769 (s, 3H, OCH
3), 3.864 (s, 6H, 2OCH
3), 7.157～7.791 (m, 6H, Ar-H), 8.461 (s, 1H, N=CH), 11.247 (s, 1H, NH);
13C NMR (DMSO-d
6) δ: 165.7,163.2,154.1,147.1,132.1,130.1,130.0,129.5,116.5,116.3,105.9,60.5,56.4; IR (KBr) v:3200,3010,1643,1546,1128cm
-1Anal.calcd for C
17H
17FN
2O
4: C 61.44, and H 5.16, and N 8.43; Found C61.21, H 5.03, N 8.33.
(2) 3-ethanoyl-2-(4-fluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole synthetic
Synthetic as embodiment one (2) method and condition, obtain 3-ethanoyl-2-(4-fluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole: white solid, productive rate 67.5%, m.p.134～136 ℃;
1HNMR (DMSO-d
6) δ: 2.253 (s, 3H, CH
3), 3.709 (s, 3H, OCH
3), 3.810 (s, 6H, 2OCH
3), 7.052 (s, 1H, CH), 7.173～7.541 (m, 6H, Ar-H);
13C NMR (DMSO-d
6) δ: 166.7,154.5,153.2,140.6,133.0,129.1,129.0,119.0,115.9,115.6,103.8,91.3,60.2,56.0,21.2; IR (KBr) v:3064,1660,1585,1004cm
-1Anal.calcdfor C
19H
19FN
2O
5: C 60.96, and H 5.12, and N 7.48; Found C 60.82, H 5.14, N 7.45.
Embodiment four, 3-ethanoyl-2-(2-trifluoromethyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, synthetic (compound number is d) of 4-oxadiazole
(1) 2-trifluoromethylated benzaldehyde-3,4,5-trimethoxy benzoyl hydrazone synthetic
Synthetic as embodiment one (1) method and condition, only the 2-fluorobenzaldehyde is changed to the 2-trifluoromethylated benzaldehyde, obtain intermediate 2-trifluoromethylated benzaldehyde-3,4,5-trimethoxy benzoyl hydrazone: clear crystal, productive rate 81.3%, m.p.214～216 ℃;
1H NMR (DMSO-d
6) δ: 3.777 (s, 3H, OCH
3), 3.867 (s, 6H, 2OCH
3), 7.331～8.319 (m, 6H, Ar-H), 8.777 (s, 1H, N=CH), 11.547 (s, 1H, NH);
13C NMR (DMSO-d
6) δ: 154.2,143.3,133.5,133.3,130.6,129.2,128.5,128.2,127.9,126.6,126.5,123.9,106.1,60.5,56.5; IR (KBr) v:3180,3040,1647,1548,1124cm
-1Anal.calcd for C
18H
17F
3N
2O
4: C 56.55, H4.48, and N 7.33; Found C 56.52, H 4.22, N 7.30.
(2) 3-ethanoyl-2-(2-trifluoromethyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole synthetic
Synthetic as embodiment one (2) method and condition, obtain 3-ethanoyl-2-(2-trifluoromethyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole: white solid, productive rate 66.5%, m.p.226～227 ℃;
1H NMR (DMSO-d
6) δ: 2.317 (s, 3H, CH
3), 3.762 (s, 3H, OCH
3), 3.845 (s, 6H, 2OCH
3), 7.107 (s, 1H, CH), 7.402～7.874 (m, 6H, Ar-H);
13C NMR (DMSO-d
6) δ: 167.7,155.4,154.5,135.7,134.0,131.1,128.5,127.2,127.1,126.4,126.2,104.9,89.6,60.6,56.4,21.2; IR (KBr) v:3010,1662,1583,983cm
-1Anal.calcd for C
20H
19F
3N
2O
5: C 56.60, and H 4.51, and N 6.60; Found C 56.43, H 4.30, N6.51.
Embodiment five, 3-ethanoyl-2-(3-trifluoromethyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, synthetic (compound number is e) of 4-oxadiazole
(1) 3-trifluoromethylated benzaldehyde-3,4,5-trimethoxy benzoyl hydrazone synthetic
Synthetic as embodiment one (1) method and condition, only the 2-fluorobenzaldehyde is changed to the 3-trifluoromethylated benzaldehyde, obtain intermediate 3-trifluoromethylated benzaldehyde-3,4,5-trimethoxy benzoyl hydrazone: clear crystal, productive rate 63.0%, m.p.190～191 ℃;
1H NMR (DMSO-d
6) δ: 3.772 (s, 3H, OCH
3), 3.868 (s, 6H, 2OCH
3), 7.336～8.049 (m, 6H, Ar-H), 8.572 (s, 1H, N=CH), 11.447 (s, 1H, NH);
13C NMR (DMSO-d
6) δ: 154.1,146.5,136.8,131.5,131.1,130.5,129.3,127.0,126.3,124.1,106.0,60.5,56.0; IR (KBr) v:3180,3010,1647,1558,1124cm
-1Anal.calcd for C
18H
17F
3N
2O
4: C 56.55, and H 4.48, and N 7.33; Found C 56.51, H 4.24, N 7.23.
(2) 3-ethanoyl-2-(3-trifluoromethyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole synthetic
Synthetic as embodiment one (2) method and condition, obtain 3-ethanoyl-2-(3-trifluoromethyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole: white solid, productive rate 57.5%, m.p.119～120 ℃;
1H NMR (DMSO-d
6) δ: 2.269 (s, 3H, CH
3), 3.711 (s, 3H, OCH
3), 3.815 (s, 6H, 2OCH
3), 7.074 (s, 1H, CH), 7.288～7.859 (m, 6H, Ar-H);
13C NMR (DMSO-d
6) δ: 167.0,154.6,153.2,140.6,137.9,130.7,130.3,126.7,123.6,118.9,109.3,103.8,91.1,60.2,56.1,21.2; IR (KBr) v:3001,1664,1583,999cm
-1Anal.calcd for C
20H
19F
3N
2O
5: C 56.60, and H 4.51, and N 6.60; Found C 56.87, H 4.38, N6.64.
Embodiment six, 3-ethanoyl-2-(4-trifluoromethyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, synthetic (compound number is f) of 4-oxadiazole
(1) 4-trifluoromethylated benzaldehyde-3,4,5-trimethoxy benzoyl hydrazone synthetic
Synthetic as embodiment one (1) method and condition, only the 2-fluorobenzaldehyde is changed to the 4-trifluoromethylated benzaldehyde, obtain intermediate 4-trifluoromethylated benzaldehyde-3,4,5-trimethoxy benzoyl hydrazone: clear crystal, productive rate 77.9%, m.p.200～202 ℃;
1H NMR (DMSO-d
6) δ: 3.776 (s, 3H, OCH
3), 3.872 (s, 6H, 2OCH
3), 7.320～7.945 (m, 6H, Ar-H), 8.549 (s, 1H, N=CH), 11.447 (s, 1H, NH);
13C NMR (DMSO-d
6) δ: 162.4,154.2,146.5,139.5,131.6,131.2,129.3,129.3,128.4,126.4,126.4,126.3,123.7,106.1,60.5,56.5; IR (KBr) v:3221,3010,1649,1543,1120cm
-1Anal.calcd for C
18H
17F
3N
2O
4: C56.55, H 4.48, and N 7.33; Found C 56.41, H 4.29, N 7.27.
(2) 3-ethanoyl-2-(4-trifluoromethyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole synthetic
Synthetic as embodiment one (2) method and condition, obtain 3-ethanoyl-2-(4-trifluoromethyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole: white solid, productive rate 59.4%, m.p.120～122 ℃;
1H NMR (DMSO-d
6) δ: 2.069 (s, 3H, CH
3), 3.714 (s, 3H, OCH
3), 3.814 (s, 6H, 2OCH
3), 7.073 (s, 1H, CH), 7.273～7.829 (m, 6H, Ar-H);
13C NMR (DMSO-d
6) δ: 166.9,154.6,153.2,140.8,140.6,127.7,125.9,125.8,118.9,103.8,91.0,60.2,56.0,21.2; IR (KBr) v:3010,1660,1581,999cm
-1Anal.calcd forC
20H
19F
3N
2O
5: C 56.60, and H 4.51, and N 6.60; Found C 56.96, H 4.51, N 6.58.
Embodiment seven, 3-ethanoyl-2-(3, the 4-dichlorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, synthetic (compound number is g) of 4-oxadiazole
(1) 3,4-dichlorobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone synthetic
Synthetic as embodiment one (1) method and condition, only the 2-fluorobenzaldehyde is changed to 3, the 4-dichlorobenzaldehyde obtains intermediate 3,4-dichlorobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone: clear crystal, productive rate 67.0%, m.p.193～194 ℃;
1H NMR (DMSO-d
6) δ: 3.538 (s, 3H, OCH
3), 3.895 (s, 6H, 2OCH
3), 7.191～7.795 (m, 5H, Ar-H), 8.229 (s, 1H, N=CH), 10.955 (s, 1H, NH);
13C NMR (DMSO-d
6) δ: 164.4,152.8,146.2,141.1,134.0,133.8,130.4,128.9,127.4,126.2,104.9,60.7,56.0; IR (KBr) v:3170,3003,1651,1566,1121cm
-1Anal.calcd for C
17H
16Cl
2N
2O
4: C 53.28, and H 4.21, and N 7.31; Found C53.55, H 4.23, N 7.37.
(2) 3-ethanoyl-2-(3, the 4-dichlorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole synthetic
Synthetic as embodiment one (2) method and condition, obtain 3-ethanoyl-2-(3, the 4-dichlorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole: white solid, productive rate 58.8%, m.p.157～159 ℃;
1H NMR (CDCl
3-d
1) δ: 2.372 (s, 3H, CH
3), 3.911 (s, 3H, OCH
3), 3.919 (s, 6H, 2OCH
3), 6.998 (s, 1H, CH), 7.098～7.566 (m, 5H, Ar-H);
13C NMR (DMSO-d
6) δ: 168.0,155.6,153.5,141.3,136.5,134.3,133.2,130.9,128.7,126.1,119.1,104.2,91.1,61.1,56.4,21.5; IR (KBr) v:3080,1660,1587,997cm
-1Anal.calcd for C
19H
18Cl
2N
2O
5: C 53.61, and H 4.27, and N 6.59; Found C 53.57, H 4.20, N6.58.
Embodiment eight, 3-ethanoyl-2-(2, the 5-Dimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, synthetic (compound number is h) of 4-oxadiazole
(1) 2,5-dimethoxy benzaldehyde-3,4,5-trimethoxy benzoyl hydrazone synthetic
Synthetic as embodiment one (1) method and condition, only the 2-fluorobenzaldehyde is changed to 2, the 5-dimethoxy benzaldehyde obtains intermediate 2,5-dimethoxy benzaldehyde-3,4,5-trimethoxy benzoyl hydrazone: faint yellow solid, productive rate 63.2%, m.p.216～218 ℃;
1H NMR (DMSO-d
6) δ: 3.734 (s, 3H, OCH
3), 3.768 (s, 3H, OCH
3), 3.829 (s, 3H, OCH
3), 3.871 (s, 6H, 2OCH
3), 7.191～7.795 (m, 5H, Ar-H), 8.229 (s, 1H, N=CH), 11.773 (s, 1H, NH);
13C NMR (DMSO-d
6) δ: 162.8,153.7,153.2,152.8,143.4,140.9,128.7,123.3,118.2,113.8,109.7,105.6,60.6,56.6,56.5; IR (KBr) v:3170,3003,1651,1566,1126cm
-1Anal.calcd for C
19H
22N
2O
6: C 60.95, and H 5.92, N, 7.48; Found C60.96, H 5.90, N 7.60.
(2) 3-ethanoyl-2-(2, the 5-Dimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole synthetic
Synthetic as embodiment one (2) method and condition, obtain 3-ethanoyl-2-(2, the 5-Dimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole: faint yellow solid, productive rate 60.0%, m.p.151～153 ℃;
1H NMR (DMSO-d
6) δ: 2.383 (s, 3H, CH
3), 3.734 (s, 3H, OCH
3), 3.768 (s, 3H, OCH
3), 3.829 (s, 3H, OCH
3), 3.871 (s, 6H, 2OCH
3), 6.863～7.324 (m, 6H, CH and Ar-H);
13C NMR (DMSO-d
6) δ: 167.4,155.7,153.7,153.3,152.0,140.9,140.2,125.0,120.0,115.8,113.9,113.4,112.9,89.1,61.0,56.6,56.3,55.8,21.5; IR (KBr) v:3020,1662,1583,979cm
-1Anal.calcd forC
21H
24N
2O
7: C 60.57, and H 5.81, and N 6.73; Found C 60.48, H 5.74, N 6.67.
Embodiment nine, 3-ethanoyl-2-(3, the 4-difluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, synthetic (compound number is i) of 4-oxadiazole
(1) 3,4-difluorobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone synthetic
Synthetic as embodiment one (1) method and condition, only the 2-fluorobenzaldehyde is changed to 3, the 4-difluorobenzaldehyde obtains intermediate 3,4-difluorobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone: faint yellow solid, productive rate 85.6%, m.p.172～174 ℃;
1H NMR (DMSO-d
6) δ: 3.819 (s, 3H, OCH
3), 3.876 (s, 6H, 2OCH
3), 7.025～7.407 (m, 5H, Ar-H), 8.343 (s, 1H, N=CH), 11.012 (s, 1H, NH);
13C NMR (DMSO-d
6) δ: 164.7,141.5,130.9,127.4,124.2,117.4,117.2,115.3,115.1,105.1,60.8,56.0; IR (KBr) v:3207,3020,1643,1554,1128cm
-1Anal.calcd for C
17H
16F
2N
2O
4: C 58.28, and H 4.60, N, 8.00; Found C58.26, H 4.41, N, 8.06.
(2) 3-ethanoyl-2-(3, the 4-difluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole synthetic
Synthetic as embodiment one (2) method and condition, obtain 3-ethanoyl-2-(3, the 4-difluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole: white solid, productive rate 68.0%, m.p.151～153 ℃;
1HNMR (DMSO-d
6) δ: 2.368 (s, 3H, CH
3), 3.848 (s, 3H, OCH
3), 3.917 (s, 6H, 2OCH
3), 7.014 (s, 1H, CH), 7.064～7.266 (m, 5H, Ar-H);
13C NMR (DMSO-d
6) δ: 168.0,155.6,153.5,153.2,141.6,133.4,123.2,119.2,117.8,117.7,116.0,115.9,104.6,104.2,91.1,61.1,56.4,21.5; IR (KBr) v:3045,1660,1587,993cm
-1Anal.calcd for C
19H
18F
2N
2O
5: C 58.16, and H 4.62, and N 7.14; Found C 58.33, H4.71, N 7.07.
Embodiment ten, 3-ethanoyl-2-(2, the 3-Dimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, synthetic (compound number is j) of 4-oxadiazole
(1) 2,3-dimethoxy benzaldehyde-3,4, the synthetic of 5-trimethoxy benzoyl hydrazone synthesized as embodiment one (1) method and condition, only the 2-fluorobenzaldehyde is changed to 2, the 3-dimethoxy benzaldehyde obtains intermediate 2,3-dimethoxy benzaldehyde-3,4,5-trimethoxy benzoyl hydrazone: clear crystal, productive rate 80.1%, m.p.204～207 ℃;
1H NMR (DMSO-d
6) δ: 3.818 (s, 3H, OCH
3), 3.849 (s, 6H, 2OCH
3), 3.878 (s, 6H, 2OCH
3), 6.882～7.670 (m, 5H, Ar-H), 8.574 (s, 1H, N=CH), 11.012 (s, 1H, NH);
13C NMR (DMSO-d
6) δ: 164.2,152.8,152.3,148.2,144.4,140.8,127.9,127.4,124.4,118.1,113.8,104.8,61.4,60.7,56.0,55.5; IR (KBr) v:3180,1645,1571,1126cm
-1Anal.calcdfor C
19H
22N
2O
6: C 60.95, and H 5.92, N, 7.48; Found C 60.95, H 5.74, N 7.57.
(2) 3-ethanoyl-2-(2, the 3-Dimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole synthetic
Synthetic as embodiment one (2) method and condition, obtain 3-ethanoyl-2-(2, the 3-Dimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole: faint yellow solid, productive rate 60.0%, m.p.154～156 ℃; 1H NMR (DMSO-d
6) δ: 2.376 (s, 3H, CH
3), 3.450 (s, 3H, OCH
3), 3.772 (s, 3H, OCH
3), 3.813 (s, 3H, OCH
3), 3.849 (s, 6H, 2OCH
3), 6.930～7.291 (m, 6H, CH and Ar-H);
13C NMR (DMSO-d
6) δ: 167.3,155.8,153.3,152.9,147.7,129.9,124.4,120.0,119.4,114.1,104.6,104.1,89.4,61.6,56.3,55.9,21.5; IR (KBr) v:3045,1662,1579,983cm
-1Anal.calcd for C
21H
24N
2O
7: C 60.57, H5.81, and N 6.73; Found C 60.55, H 5.98, N 6.74.
Embodiment 11,3-ethanoyl-2-(4-chloro-3-nitrophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, synthetic (compound number is k) of 4-oxadiazole
(1) 4-chloro-3-nitrobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone synthetic
Synthetic as embodiment one (1) method and condition, only the 2-fluorobenzaldehyde is changed to 4-chloro-3-nitrobenzaldehyde, obtain intermediate 4-chloro-3-nitrobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone: faint yellow solid, productive rate 81.3%, m.p.214～216 ℃;
1H NMR (DMSO-d
6) δ: 3.818 (s, 3H, OCH
3), 3.849 (s, 6H, 2OCH
3), 6.882～7.670 (m, 5H, Ar-H), 8.574 (s, 1H, N=CH), 11.012 (s, 1H, NH);
13C NMR (DMSO-d
6) δ: 164.5,152.9,147.9,144.4,140.8,131.3,132.1,130.9,127.8,127.4,124.2,105.0,60.7,56.0; IR (KBr) v:3180,1645), 1571,1126cm
-1Anal.calcd for C
17H
16C1N
3O
6: C 51.85, and H 4.10, N10.67; Found C 51.96, H 4.23, N 10.70.
(2) 3-ethanoyl-2-(4-chloro-3-nitrophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole synthetic
Synthetic as embodiment one (2) method and condition, obtain 3-ethanoyl-2-(4-chloro-3-nitrophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole: faint yellow solid, productive rate 57.4%, m.p.176～177 ℃;
1H NMR (DMSO-d
6) δ: 2.378 (s, 3H, CH
3), 3.917 (s, 3H, OCH
3), 3.925 (s, 6H, 2OCH
3), 7.079 (s, 1H, CH), 7.101～7.996 (m, 5H, Ar-H);
13C NMR (DMSO-d
6) δ: 168.3,155.6,153.4,148.1,141.5,136.8,132.5,131.5,128.6,124.0,118.8,104.2,90.4,61.1,56.4,21.5; IR (KBr) v:3140,1656,1587,997cm
-1Anal.calcd for C
19H
18ClN
3O
7: C 52.36, and H 4.16, and N 9.64; Found C 52.35, H 4.11, N 9.92.
Embodiment 12,3-ethanoyl-2-(3, the 5-dichlorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, synthetic (compound number is 1) of 4-oxadiazole
(1) 3,5-dichlorobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone synthetic
Synthetic as embodiment one (1) method and condition, only the 2-fluorobenzaldehyde is changed to 3, the 5-dichlorobenzaldehyde obtains intermediate 3,5-dichlorobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone: clear crystal, productive rate 94.7%, m.p.224～226 ℃;
1H NMR (DMSO-d
6) δ: 3.898 (s, 3H, OCH
3) 3.919 (s, 6H, 2OCH
3), 7.091～7.600 (m, 5H, Ar-H), 8.374 (s, 1H, N=CH), 11.512 (s, 1H, NH);
13C NMR (DMSO-d
6) δ: 163.3,153.2,145.0,141.1,138.5,135.1,129.6,128.5,125.8,105.7,60.6,56.6; IR (KBr) v:3172,3007,1649,1583,1128cm
-1Anal.calcd for C
17H
16Cl
2N
2O
4: C 53.28, and H 4.21, and N 7.31; Found C 53.20, H4.51, N 7.34.
(2) 3-ethanoyl-2-(3, the 5-dichlorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole synthetic
Synthetic as embodiment one (2) method and condition, obtain 3-ethanoyl-2-(3, the 5-dichlorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole: clear crystal, productive rate 70.5%, m.p.169～170 ℃;
1H NMR (DMSO-d
6) δ: 2.384 (s, 3H, CH
3), 3.913 (s, 3H, OCH
3), 3.923 (s, 6H, 2OCH
3), 6.979 (s, 1H, CH), 7.102～7.385 (m, 5H, Ar-H);
13C NMR (DMSO-d
6) δ: 168.1,155.6,153.5,141.3,139.5,135.6,130.1,125.3,119.0,104.2,90.9,61.1,56.3,21.5; IR (KBr) v:3078,1664,1585,1010cm
-1Anal.calcd for C
19H
18Cl
2N
2O
5: C 53.66, and H 4.27, and N 6.59; Found C 53.59, H 4.17, N6.53.
Embodiment 13,3-ethanoyl-2-(2, the 4-Dimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, synthetic (compound number is m) of 4-oxadiazole
(1) 2,4-dimethoxy benzaldehyde-3,4,5-trimethoxy benzoyl hydrazone synthetic
Synthetic as embodiment one (1) method and condition, only the 2-fluorobenzaldehyde is changed to 2, the 4-dimethoxy benzaldehyde obtains intermediate 2,4-dimethoxy benzaldehyde-3,4,5-trimethoxy benzoyl hydrazone: faint yellow solid, productive rate 70.0%, m.p.206～208 ℃;
1H NMR (DMSO-d
6) δ: 3.840 (s, 3H, OCH
3), 3.888 (s, 6H, 2OCH
3), 3.917 (s, 6H, 2OCH
3), 6.418～7.270 (m, 5H, Ar-H), 8.039 (s, 1H, N=CH), 11.561 (s, 1H, NH);
13C NMR (DMSO-d
6) δ: 163.0,159.6,153.1,143.6,140.7,128.9,127.2,115.5,106.9,105.5,98.7,60.6,56.5,56.2,55.9; IR (KBr) v:3176,3001,1643,1583,1128cm
-1Anal.calcdfor C
19H
22N
2O
6: C 60.95, and H 5.92, N, 7.48; Found C 61.07, H 6.06, N 7.55.
(2) 3-ethanoyl-2-(2, the 4-Dimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole synthetic
Synthetic as embodiment one (2) method and condition, obtain 3-ethanoyl-2-(2, the 4-Dimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole: white solid, productive rate 72.0%, m.p.172～175 ℃; 1H NMR (DMSO-d
6) δ: 2.369 (s, 3H, CH
3), 3.728 (s, 3H, OCH
3), 3.827 (s, 3H, OCH
3), 3.866 (s, 9H, 3OCH
3), 6.448～7.276 (m, 6H, CH and Ar-H);
13CNMR (DMSO-d
6) δ: 167.3,162.4,159.0,155.7,153.3,130.8,129.2,120.2,116.7,105.7,104.6,104.1,90.0,89.6,61.0,56.3,55.8,21.6; IR (KBr) v:3060,1660,1585,979cm
-1Anal.calcd for C
21H
24N
2O
7: C 60.57, and H 5.81, and N 6.73; Found C 60.60, H 5.81, N 6.71.
Embodiment 14,3-ethanoyl-2-(2, the 6-dichlorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, synthetic (compound number is n) of 4-oxadiazole
(1) 2,6-dichlorobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone synthetic
Synthetic as embodiment one (1) method and condition, only the 2-fluorobenzaldehyde is changed to 2, the 6-dichlorobenzaldehyde obtains intermediate 2,6-dichlorobenzaldehyde-3,4,5-trimethoxy benzoyl hydrazone: clear crystal, productive rate 80.0%, m.p.232～234 ℃;
1H NMR (DMSO-d
6) δ: 3.902 (s, 3H, OCH
3), 3.933 (s, 6H, 2OCH
3), 7.261～7.437 (m, 5H, Ar-H), 8.474 (s, 1H, N=CH), 11.583 (s, 1H, NH);
13C NMR (DMSO-d
6) δ: 163.5,152.7,147.9,143.4,142.8,134.7,130.1,128.3,128.2,127.5,127.2,104.9,60.4,55.8; IR (KBr) v:3194,3068,1651,1544,1126cm
-1Anal.calcd for C
17H
16Cl
2N
2O
4: C 53.28, and H 4.21, N7.31; Found C 53.33, H 4.42, N 7.27.
(2) 3-ethanoyl-2-(2, the 6-dichlorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole synthetic
Synthetic as embodiment one (2) method and condition, obtain 3-ethanoyl-2-(2, the 6-dichlorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole: white solid, productive rate 78.3%, m.p.211-213 ℃;
1HNMR (DMSO-d
6) δ: 2.384 (s, 3H, CH
3), 3.906 (s, 3H, OCH
3), 3.912 (s, 6H, 2OCH
3), 7.104 (s, 1H, CH), 7.251～7.691 (m, 5H, Ar-H);
13C NMR (DMSO-d
6) δ: 167.4,155.3,153.4,141.0,136.1,131.2,129.5,119.5,104.1,89.4,61.0,56.3,21.3; IR (KBr) v:3078,1656,1583,997cm
-1Anal.calcd forC
19H
18Cl
2N
2O
5: C 53.66, and H 4.27, and N 6.59; Found C 53.53, H 4.21, N 6.48.
Embodiment 15,3-ethanoyl-2-(3,4, the 5-trimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, synthetic (compound number is o) of 4-oxadiazole
(1) 3,4,5-TMB-3,4,5-trimethoxy benzoyl hydrazone synthetic
Synthetic as embodiment one (1) method and condition, only the 2-fluorobenzaldehyde is changed to 3,4, the 5-TMB obtains intermediate 3,4,5-TMB-3,4,5-trimethoxy benzoyl hydrazone: white solid, productive rate 80.0%, m.p.240～242 ℃;
1H NMR (DMSO-d
6) δ: 3.717 (s, 3H, OCH
3), 3.734 (s, 3H, OCH
3), 3.847 (s, 6H, OCH
3), 3.869 (s, 6H, 2OCH
3), 7.261～7.437 (m, 4H, Ar-H), 8.474 (s, 1H, N=CH), 11.745 (s, 1H, NH);
13CNMR (DMSO-d
6) δ: 163.1,153.7,153.2,148.4,140.9,139.7,130.3,128.9,105.6,104.8,60.6,56.5,56.4; IR (KBr) v:3200,1641,1577,1122cm
-1Anal.calcd for C
20H
24N
2O
7: C 59.40, and H 5.98, and N 6.93; Found C 59.30, H 6.02, N 6.92.
(2) 3-ethanoyl-2-(3,4, the 5-trimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3,4-oxadiazole synthetic
Synthetic as embodiment one (2) method and condition, obtain 3-ethanoyl-2-(3,4, the 5-trimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole: clear crystal, productive rate 67.3%, m.p.124～126 ℃;
1H NMR (DMSO-d
6) δ: 2.398 (s, 3H, CH
3), 3.717 (s, 3H, OCH
3), 3.734 (s, 3H, OCH
3), 3.847 (s, 6H, 2OCH
3), 3.869 (s, 6H, 2OCH
3), 6.707～7.136 (m, 5H, CH and Ar-H);
13C NMR (DMSO-d
6) δ: 168.0,155.6,153.6,153.4,141.1,139.3,131.8,119.5,106.7,104.4,103.7,92.7,61.0,60.8,56.3,56.2,21.6; IR (KBr) v:3050,1670,1597,1001cm
-1Anal.calcd forC
22H
26N
2O
8: C 59.19, and H 5.87, and N 6.27; Found C 59.49, H 5.79, N 6.14.
Embodiment 16, mtt assay are measured Compound I to the inhibition of proliferation experiment in 72 hours of prostate cancer cell strain PC3 cell
The MTT test method
With the PC3 cell inoculation in 96 porocyte culture plates, 2200 cells in every hole, at 37 ℃, 5%CO
2, cultivate 24h under the condition of saturated humidity, add and contain 1640 substratum (200 μ L/ hole) of handling the factor, establish the contrast of blank and solvent, 4 every group are parallel, continue to cultivate 72h, add 5mg/mL MTT 20 μ L and cultivate 4h, measure OD on microplate reader
570Value is made reference with the solvent control group at last and is calculated inhibiting rate.
Test-results
After tested, compound l is 93.9% to the PC3 cell inhibitory rate when drug concentration 5 μ g/mL, shows the good anticancer activity.
Embodiment 17, mtt assay are measured compound m to the inhibition of proliferation experiment in 72 hours of prostate cancer cell strain PC3 cell
Test method is with embodiment 16.
Test-results
After tested, compound m is 92.0% to the PC3 cell inhibitory rate when drug concentration 5 μ g/mL, shows the good anticancer activity.
Embodiment 18, mtt assay are measured compound n to the inhibition of proliferation experiment in 72 hours of stomach cancer cell line BGC823 cell
Test method is with embodiment 16.
Test-results
After tested, compound n is 45.8% to show certain antitumour activity to the BGC823 cell inhibitory rate when drug concentration 5 μ g/mL.
Embodiment 19, mtt assay are measured the intermediate 2-fluorobenzaldehyde-3,4 of compound a, and 5-trimethoxy benzoyl hydrazone is to prostate cancer cell strain PC3 cell, breast carcinoma cell strain Bcap37 cell, the inhibition of proliferation experiment in 72 hours of stomach cancer cell line BGC823 cell
Test method is with embodiment 16.
Test-results
After tested, the intermediate 2-fluorobenzaldehyde-3,4 of compound a, 5-trimethoxy benzoyl hydrazone is respectively 70.6%, 51.6% and 58.9% to PC3, Bcap37, BGC823 cell inhibitory rate when drug concentration 1 μ g/mL, show the good anticancer activity.
Embodiment 20, mtt assay are measured the intermediate 4-fluorobenzaldehyde-3,4 of compound c, and 5-trimethoxy benzoyl hydrazone is to prostate cancer cell strain PC3 cell, breast carcinoma cell strain Bcap37 cell, the inhibition of proliferation experiment in 72 hours of stomach cancer cell line BGC823 cell
Test method is with embodiment 16.
Test-results
After tested, the intermediate 4-fluorobenzaldehyde-3,4 of compound c, 5-trimethoxy benzoyl hydrazone is respectively 76.0%, 50.9% and 50.2% to PC3, Bcap37, BGC823 cell inhibitory rate when drug concentration 1 μ g/mL, show the good anticancer activity.
Embodiment 21, mtt assay are measured the intermediate 4-trifluoromethylated benzaldehyde-3 of compound f, 4,5-trimethoxy benzoyl hydrazone is to prostate cancer cell strain PC3 cell, breast carcinoma cell strain Bcap37 cell, the inhibition of proliferation experiment in 72 hours of stomach cancer cell line BGC823 cell
Test method is with embodiment 16.
Test-results
After tested, the intermediate 4-trifluoromethylated benzaldehyde-3 of compound f, 4,5-trimethoxy benzoyl hydrazone is respectively 59.9%, 47.4% and 61.8% to PC3, Bcap37, BGC823 cell inhibitory rate when drug concentration 1 μ g/mL, show the good anticancer activity.
Embodiment 22, mtt assay are measured the intermediate 2 of compound j, 3-dimethoxy benzaldehyde-3,4, and 5-trimethoxy benzoyl hydrazone is to prostate cancer cell strain PC3 born of the same parents inhibition of proliferation experiment in 72 hours
Test method is with embodiment 16.
Test-results
After tested, the intermediate 2 of compound j, 3-dimethoxy benzaldehyde-3,4,5-trimethoxy benzoyl hydrazone are 53.2% to the PC3 cell inhibitory rate when drug concentration 1 μ g/mL, show the good anticancer activity.
The embodiment of the invention is aided with explanation technical scheme of the present invention, but the content of embodiment is not limited thereto.
Claims (8)
1, a kind of compound with anti-tumor activity is characterized in that described compound is 3-replacement-2-aryl replacement-5-(3,4, the 5-tri-alkoxy phenyl)-1,3,4-oxadiazole analog derivative, and wherein said compound has following general formula:
Wherein
R
1Be the C1-6 alkyl;
R
2Aromatic group for C5-14; contain 1 or a plurality of N of being selected from; O; S; the heteroatomic C5-14 hetero-aromatic ring group of SO and SO2; and can independently be selected from following substituent group by one or more on the above-mentioned cyclic group replaces: (1) hydroxyl; (2) halogen atom; (3) itrile group; (4) nitro; (5) C1-6 alkyl; C2-6 alkenyl or C2-6 alkynyl group; wherein each group all can be replaced by at least one or a plurality of halogen atom substituting group; (6) C1-6 alkoxyl group; C2-6 alkenyloxy or C2-6 chain oxy-acetylene; wherein each group all can be replaced by at least one or a plurality of halogen atom substituting group; (7) C1-6 alkylthio; C2-6 alkenyl thio or C2-6 alkynes sulfenyl; wherein each group all can be replaced by at least one or a plurality of halogen atom substituting group; (8) substituted carbonyl; described substituting group is selected from (i) C1-6 alkyl; (ii) amino; (iii) C1-6 alkylamino; (iv) C1-6 alkyl oxy; (v) C1-6 alkyl sulfenyl; (vi) C3-8 cycloalkyl; (9) can be by the amino of 1 or 2 each substituting groups replacement; described substituting group is selected from (i) C1-6 alkyl; (ii) C2-6 alkenyl; (iii) C2-6 alkynyl group; (iv) C1-6 alkyl sulphonyl; (v) C2-6 alkenyl alkylsulfonyl; (vi) C2-6 alkynyl group alkylsulfonyl; (vii) C1-6 alkyl-carbonyl; (viii) C2-6 alkenyl carbonyl (ix) C2-6 alkynyl group carbonyl, (10) C1-6 alkyl sulphonyl, (11) C2-6 alkenyl alkylsulfonyl; (12) C2-6 alkynyl group alkylsulfonyl; (13) C1-6 alkyl sulphinyl, (14) C2-6 alkenyl sulfinyl, (15) C2-6 alkynyl group sulfinyl; (16) formyl radical, (17) C3-8 cycloalkyl or C3-8 cycloalkenyl group.
R
3Be substituted carbonyl; thiocarbonyl group; sulfuryl; sulfoxide group; alkylsulfonyl; sulfinyl; wherein be substituted the part substituting group and be selected from (i) C1-10 alkyl; (ii) amino; (iii) C1-10 alkylamino; (iv) C1-10 alkyl oxy; (v) C1-10 alkyl sulfenyl; (vi) C3-8 cycloalkyl or C3-8 cycloalkenyl group; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (vii) hydrogen; (viii) C3-8 cycloalkyloxy or C3-8 cyclenes oxygen base, wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces.
2, compound according to claim 1, wherein R
1Be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl.
3, compound according to claim 1, wherein R
2Be phenyl, pyrryl, furyl, tetrahydrofuran base, thienyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl oxazolyl isoxazolyl, triazolyl, tetrazyl, thiadiazolyl group, pyridyl, morpholinyl, piperazinyl, triazinyl, piperidyl, pyridazinyl, pyrimidyl, purine radicals, pyrazinyl, naphthyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, indyl, draw the azoles base, benzofuryl, benzimidazolyl-, benzothiazolyl, benzisothiazole base benzoxazolyl, the benzoisoxazole base, the benzopyrazoles base, quinazolyl, different quinazolyl, dibenzofuran group, the dibenzothiophene base, the bisbenzimidazole base, the dibenzo pyrimidyl, the dibenzopyridine base, carbazyl, and above-mentioned cyclic group can independently be selected from following substituent group by one or more and replace: (1) halogen atom, (2) itrile group, (3) nitro, (4) C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl group, wherein each group all can be replaced by at least one or a plurality of halogen atom substituting group, (5) C1-6 alkoxyl group, C2-6 alkenyloxy or C2-6 chain oxy-acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom substituting group.
4, compound according to claim 3, wherein R
2Be 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 3,4-dichlorophenyl, 2,5-Dimethoxyphenyl, 3,4-difluorophenyl, 2,3-Dimethoxyphenyl, 4-chloro-3-nitrophenyl, 3,5-dichlorophenyl, 2,4-Dimethoxyphenyl, 2,6-dichlorophenyl, 3,4, the 5-trimethoxyphenyl.
5, according to any described compound in the claim 1, R in the general formula
3Be ethanoyl, propionyl, different propionyl, ethanethioyl, sulfo-propionyl, the different propionyl of sulfo-.
6,, it is characterized in that the compound of partial synthesis is as follows according to the described compound of one of claim 1-5:
A.3-ethanoyl-2-(2-fluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole
B.3-ethanoyl-2-(3-fluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole
C.3-ethanoyl-2-(4-fluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole
D.3-ethanoyl-2-(2-trifluoromethyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole
E.3-ethanoyl-2-(3-trifluoromethyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole
F.3-ethanoyl-2-(4-trifluoromethyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole
G.3-ethanoyl-2-(3, the 4-dichlorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole
H.3-ethanoyl-2-(2, the 5-Dimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole
I.3-ethanoyl-2-(3, the 4-difluorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole
J.3-ethanoyl-2-(2, the 3-Dimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole
K.3-ethanoyl-2-(4-chloro-3-nitrophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole
L.3-ethanoyl-2-(3, the 5-dichlorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole
M.3-ethanoyl-2-(2, the 4-Dimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole
N.3-ethanoyl-2-(2, the 6-dichlorophenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole
O.3-ethanoyl-2-(3,4, the 5-trimethoxyphenyl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole
7, according to the medicine of any described compound among the claim 1-6 as antitumor action.
8, the preparation method with compound of anti-tumor activity according to claim 1, it is characterized in that with 3,4,5-tri-alkoxy benzoyl hydrazine, aromatic aldehyde, acid anhydrides are raw material, with methyl alcohol, ethanol, Virahol, dehydrated alcohol, benzene,toluene,xylene, N, dinethylformamide, dioxane, methyl-sulphoxide, hexanaphthene, normal hexane or its mixture are solvent, and be synthetic through two steps:
The first step: replace aromatic aldehyde-3,4,5-tri-alkoxy benzoyl hydrazone synthetic
At the bottom of having three mouthfuls of gardens of reflux, drop into 3,4 in the flask, 5-tri-alkoxy benzoyl hydrazine, aromatic aldehyde, solvent, reflux, the 0.5-5h reaction finishes, and is replacement aromatic aldehyde-3,4,5-tri-alkoxy benzoyl hydrazone.
Second step: the 3-replacements-2-aryl replacement-5-(3,4, the 5-tri-alkoxy phenyl)-1,3, the synthesizing of 4-oxadiazole
The product of the first step is dissolved in the acid anhydrides, reacts 0.5-5h under the stirring and refluxing condition, pour in the trash ice, spend the night suction filtration, washing, drying, thick product acetone-water recrystallization gets white solid, is 3-replacement-2-aryl replacement-5-(3,4, the 5-tri-alkoxy phenyl)-1,3, the 4-oxadiazole.
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| CN102731488A (en) * | 2011-04-02 | 2012-10-17 | 中国医学科学院药物研究所 | Benzimidazole derivatives, preparation method thereof, pharmaceutical composition thereof and application thereof |
| CN103087053A (en) * | 2011-11-03 | 2013-05-08 | 南京大学 | Preparation of oxadiazole compound and application thereof to anti-inflammatory treatment |
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| JP2015504432A (en) * | 2011-11-25 | 2015-02-12 | ウニベルシダージ フェデラル デ サンタ カタリーナ | Acyl-hydrazones and oxadiazole compounds, pharmaceutical compositions containing them and uses thereof |
| CN105949181A (en) * | 2016-06-03 | 2016-09-21 | 贵州大学 | 4-hydroxyl pyrroline-2-ketone derivative containing 1,3,4-oxadiazole and preparation method and application of 4-hydroxyl pyrroline-2-ketone derivative |
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| CN102731488A (en) * | 2011-04-02 | 2012-10-17 | 中国医学科学院药物研究所 | Benzimidazole derivatives, preparation method thereof, pharmaceutical composition thereof and application thereof |
| CN103087053A (en) * | 2011-11-03 | 2013-05-08 | 南京大学 | Preparation of oxadiazole compound and application thereof to anti-inflammatory treatment |
| JP2015504432A (en) * | 2011-11-25 | 2015-02-12 | ウニベルシダージ フェデラル デ サンタ カタリーナ | Acyl-hydrazones and oxadiazole compounds, pharmaceutical compositions containing them and uses thereof |
| EP2784061A4 (en) * | 2011-11-25 | 2015-05-27 | Univ Fed De Santa Catarina Ufsc | Acyl-hydrazone and oxadiazole compounds, pharmaceutical compositions containing the same and uses thereof |
| RU2664327C2 (en) * | 2011-11-25 | 2018-08-16 | Универсидаде Федераль Де Санта Катарина | Acyl-hydrazone and oxadiazole compounds, pharmaceutical compositions containing same and uses thereof |
| CN103664932A (en) * | 2013-11-04 | 2014-03-26 | 南京大学 | Indole grafted thiazole hydrazone derivatives, preparation method thereof and inhibiting effect of indole grafted thiazole hydrazone derivatives for polymerization of cancer cell microtubulin |
| CN103664932B (en) * | 2013-11-04 | 2016-08-17 | 南京大学 | One class indoles grafting thiazole hydrazone analog derivative and preparation method thereof and the inhibitory action to cancer cell tubulin polymerization |
| CN105949181A (en) * | 2016-06-03 | 2016-09-21 | 贵州大学 | 4-hydroxyl pyrroline-2-ketone derivative containing 1,3,4-oxadiazole and preparation method and application of 4-hydroxyl pyrroline-2-ketone derivative |
| CN105949181B (en) * | 2016-06-03 | 2019-08-02 | 贵州大学 | 4- hydroxypyrrole quinoline -2- ketone derivatives, preparation method and the application of the oxadiazoles containing 1,3,4- |
| CN116082269A (en) * | 2023-01-03 | 2023-05-09 | 盐城工学院 | 1,3, 4-oxazoline compound containing trifluoromethyl quaternary carbon center and preparation method thereof |
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