CN104059011B - A kind of substituted azole derivatives and its preparation method and application - Google Patents
A kind of substituted azole derivatives and its preparation method and application Download PDFInfo
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- CN104059011B CN104059011B CN201410284371.7A CN201410284371A CN104059011B CN 104059011 B CN104059011 B CN 104059011B CN 201410284371 A CN201410284371 A CN 201410284371A CN 104059011 B CN104059011 B CN 104059011B
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- 0 *c1ccc(C(Cc2ccc[n]2*)c(c(*)c2*)c(*)c(*)c2C#N)c(*)c1 Chemical compound *c1ccc(C(Cc2ccc[n]2*)c(c(*)c2*)c(*)c(*)c2C#N)c(*)c1 0.000 description 1
- CQFWGGBRVRNSLD-UHFFFAOYSA-N CC(C)(C)c1ccc(C(Cc2ccc[n]2C(OC(C)(C)C)=O)c(c(C#N)c2)cc(C#N)c2C#N)cc1 Chemical compound CC(C)(C)c1ccc(C(Cc2ccc[n]2C(OC(C)(C)C)=O)c(c(C#N)c2)cc(C#N)c2C#N)cc1 CQFWGGBRVRNSLD-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The invention provides a kind of substituted azole derivatives and pharmaceutically acceptable salt thereof, additionally provide the preparation method of aforesaid compound and the application in preparation antibacterials thereof.The present invention does not use noble metal catalyst, thus avoiding the problem of trace metal residual in pharmaceutical synthesis；Photoreaction can carry out when room temperature, reduces the temperature of reaction, obtains the new azole derivatives with antibacterial activity by introducing other active groups at pyrrole ring.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to a kind of substituted azole derivatives, particularly to a kind of photoinduction three component reaction synthesis substituted azole derivatives preparation method.
Background technology
Many natural products all contain the construction unit of substituted azole ring, and this row compound generally all has the physiologically actives such as strong antibacterial, antitumor and anti AIDS virus.Such as patent CN1882568A discloses a series of azole derivatives with antibacterial activity.
Due to the height electron rich of pyrroles with to acid and the sensitivity of oxygen, the nitrogenous heterocyclic alkylation reaction of electron rich such as pyrroles is still the problem of comparatively difficulty.Conventional Friedel-Crafts alkylation reaction is not suitable for pyrroles, because useOr Lewis strong acidic condition can cause the many alkylation reactions without regioselectivity and the side reaction such as open loop, polymerization of pyrroles.The alkylation reaction of current pyrroles generally requires heavy metal catalyst, can cause heavy-metal residual in Subsequent pharmacological；Reaction temperature is high, it is desirable to high.
Summary of the invention
It is an object of the invention to provide a kind of new approach-photoinduction three component reaction synthesis substituted azole derivatives, to overcome the deficiencies in the prior art.
For achieving the above object, the present invention takes following technical proposals to realize:
There is the compound of Formulas I structure and pharmaceutically acceptable salt thereof:
Formulas I
Wherein R1For CN, F, H；R2For F, H；R3For H, Me, Et, Pr, F, Cl；R4For, H, Me, F, Cl, t-Bu；R5For H, Me, Boc, Ph.
The present invention also provides for a kind of method of compound described in photoinduction synthesis type I, to dicyano aryl compound, substituted olefine and azole derivatives be dissolved in reaction dissolvent, irradiate (reaction equation is such as shown in Formula II) when logical argon with the light of λ > 300nm；Then with silica gel column chromatography separation product after being concentrated by reactant mixture, petroleum ether-ethyl acetate is that eluent does gradient elution, obtains product.
Wherein R1For CN, F, H；R2For F, H；R3For H, Me, Et, Pr, F, Cl；R4, H, Me, F, Cl, t-Bu；R5For H, Me, Boc, Ph.
Compound described in optional Formulas I gets final product acceptable salt on synthetic drug according to a conventional method.
Further, the solvent of reaction is the one in benzene, dichloromethane, acetonitrile, normal hexane, acetone.
Preferably, the solvent of reaction is acetonitrile.
Further, to dicyano aryl compound, the mol ratio of substituted olefine and three kinds of reactive components of azole derivatives is 1: 2: 4～1: 6: 12.
Further, it is 0.01～0.1mol/L to the molar concentration of dicyano aryl compound.
Further, the time of photoreaction is 8-48 hour.
Preferably, the time of photoreaction is 16 hours.
The present invention also provides for the application in preparation antibacterials of a kind of compound with Formulas I structure and pharmaceutically acceptable salt thereof.
Compared with prior art, the invention have the advantages that
The present invention is synthesized a series of polysubstituted azole derivatives by a kind of photoinduced three components of new reaction path one, owing to not using noble metal catalyst, thus avoiding the problem of trace metal residual in pharmaceutical synthesis.Photoreaction can carry out when room temperature, reduces the temperature of reaction, obtains the new azole derivatives with antibacterial activity by introducing other active groups at pyrrole ring.
Accompanying drawing explanation
Fig. 1 is the nuclear magnetic resonance map of the compound 1 that embodiment 1 prepares in the present invention.
Fig. 2 is the nuclear magnetic resonance map of the compound 2 that embodiment 2 prepares in the present invention.
Fig. 3 is the nuclear magnetic resonance map of the compound 3 that embodiment 3 prepares in the present invention.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention will be described in detail.
Embodiment 1
The three component photochemical reactions of four cyano benzene (TCNB), 4-t-butyl styrene and 1-tertbutyloxycarbonyl-pyrroles
By four cyano benzene 0.530g (3mmol), 4-t-butyl styrene 1.923g (12mmol), 1-Boc-pyrroles 4.013g (24mmol) adds in teat glass, then adds 60ml acetonitrile in test tube, utilizes ultrasonic dissolving.Oxygen in logical 15 minutes removing systems of argon.Then illumination 15h under 500W high voltage mercury lamp.After having reacted, with silica gel column chromatography separation product after being concentrated by reactant mixture, petroleum ether (b.p.60-90 DEG C)-ethyl acetate is that eluent does gradient elution.Obtaining compound 1 as shown in Equation 3, productivity is 45%.
The testing result of compound:
Fusing point: mp200 DEG C；1HNMR(CDCl3) δ 1HNMR (CDCl3,400MHz) δ 1.31 (s, 9H), 1.56 (s, 9H), 3.43 (dd, 1H, J=15.2,9.2Hz), 3.72 (dd, 1H, J=14.8,6.0Hz), 4.79 (dd, 1H, J=9.2,6.0Hz), 5.49 (d, 1H, J=1.6Hz), 5.89 (t, 1H, J=3.2Hz), 7.13-7.16 (m, 3H), 7.26 (s, 1H), 7.32 (d, 2H, J=8.0Hz), 7.52 (s, 1H).Fig. 1 be compound 1 (1HNMR, 400M, solvent C DCl3) nuclear magnetic resonance map.
Embodiment 2: three component photochemical reactions of four cyano benzene (TCNB), 4-fluorobenzene ethylene and N-methylpyrrole
By four cyano benzene 0.530g (3mmol), 4-fluorobenzene ethylene 1.446g (12mmol) N-methylpyrrole 1.497g (24mmol) adds in teat glass, then adds 60ml acetonitrile in test tube, utilizes ultrasonic dissolving.Oxygen in logical 15 minutes removing systems of argon.Then illumination 15h under 500W high voltage mercury lamp.After having reacted, with silica gel column chromatography separation product after being concentrated by reactant mixture, petroleum ether (b.p.60-90 DEG C)-ethyl acetate is that eluent does gradient elution.Obtaining the compound 2 as shown in Formulas I V, productivity is 51%.
The testing result of compound:
Fusing point: mp182 DEG C；1HNMR(CDCl3, 400MHz) and δ 3.28 (dd, 1H, J=16.4,10.0Hz), 3.40 (dd, 1H, J=15.2,5.6Hz), 3.56 (s, 3H), 4.76 (dd, 1H, J=9.2,6.4Hz), 5.42 (s, 1H), 5.91 (d, 1H, J=2.0Hz), 6.56 (s, 1H), 7.08 (t, 2H, J=7.8Hz), 7.24-7.27 (m, 2H), 7.80 (s, 1H), 7.92 (s, 1H).Fig. 2 be compound 2 (1HNMR, 400M, solvent C DCl3) nuclear magnetic resonance map.
Embodiment 3: three component photochemical reactions of four cyano benzene (TCNB), 2,5-dimethyl styrenes and N-phenylpyrrole
By four cyano benzene 0.530g (3mmol), 2,5-dimethyl styrene 1.586g (12mmol) N-phenylpyrrole 1.718g (24mmol) add in teat glass, then add 60ml acetonitrile in test tube, utilize ultrasonic dissolving.Oxygen in logical 15 minutes removing systems of argon.Then illumination 15h under 500W high voltage mercury lamp.After having reacted, with silica gel column chromatography separation product after being concentrated by reactant mixture, petroleum ether (b.p.60-90 DEG C)-ethyl acetate is that eluent does gradient elution.Obtaining compound 3 shown as a formula V, productivity is 80%.
The testing result of compound 3:
Fusing point: mp176-177 DEG C；1HNMR(CDCl3, 400MHz) and δ 2.00 (s, 3H), 2.31 (s, 3H), 3.22 (dd, 1H, J=15.2,10.8Hz), 3.42 (dd, 1H, J=15.2,4.8Hz), 4.61 (dd, 1H, J=10.8,4.8Hz), 5.75 (t, 1H, J=1.6Hz), 6.15 (t, 1H, J=3.2Hz), 6.74 (t, 1H, J=1.6Hz), 6.84 (s, 1H), 7.00 (s, 2H), 7.24 (d, 2H, J=7.2Hz), 7.39-7.47 (m, 3H), 7.51 (s, 1H), 7.89 (s, 1H).Fig. 3 be compound 3 (1HNMR, 400M, solvent C DCl3) nuclear magnetic resonance map.
Embodiment 4: the mensuration of antibacterial activity
(1) preparation of culture fluid
RPMI1640 culture fluid: RPMI164010g, NaHCO32.0g, MOPS34.5g (0.165M), add tri-distilled water 900mL and dissolve, and 1NNaOH adjusts pH to 7.0 (25 DEG C), is settled to 1000mL, filters sterilization, 4 DEG C of preservations.
Husky fort glucose agar medium (SDA): peptone 10g, glucose 40g, agar 18g, adds tri-distilled water 900mL and dissolves, add 2mg/mL chloramphenicol solution 50mL, adjust pH to 7.0, be settled to 1000mL, 4 DEG C of preservations after autoclaving.
YEPD culture fluid: yeast extract 10g, peptone 20g, glucose 20g, add tri-distilled water 900mL and dissolve, add 2mg/mL chloramphenicol solution 50mL, be settled to 1000mL, 4 DEG C of preservations after autoclaving.
(2) bacterium solution preparation
Before experiment, with inoculation circle from picking bacillus subtilis, colon bacillus, pseudomonas fluorescens and staphylococcus aureus 4 DEG C of SDA culture medium preserved, it is seeded to 1mLYEPD culture fluid, in 35 DEG C, 250rpm shaken cultivation, activates 16h, makes fungus be in later stage exponential phase of growth.Take this bacterium solution to 1mLYEPD culture fluid, again activate in aforementioned manners, after 16h, count with blood cell counting plate, adjust bacterial concentration to 1 × 10 with RPMI1640 culture fluid3～5 × 103cfu/mL。
(3) drug solution preparing
The compound that embodiment 1-3 prepares is made into 1mg/mL solution with DMSO respectively ,-20 DEG C of preservations, before experiment, medicinal liquid taking-up is put 35 DEG C of incubators and melts standby.It is made into Concentraton gradient by four times of dilution methods during test.Being made into final test concentration is 50,12.5,3.125,0.781,0.195,0.049 μ g/mL.
(4) preparation of drug sensitive plate
Bacterial suspension is in RPMI1640 culture medium, and dispersion concentration is approximately 1 × 103～5 × 103Cfu/mL, joins the first row of 96 orifice plates by culture medium, and every hole 100 μ L, as blank (negative control).Second row adds bacterium solution, every hole 100 μ L, is not added with tested sample, as reagent blank.The gradient solution prepared by sample, joins the 3rd～12 row of 96 orifice plates with the amount of every hole 11 μ L, and making ultimate density is 50,12.5,3.125,0.781,0.195,0.049 μ g/mL.Each Concentraton gradient does three parallel laboratory tests.96 orifice plates are put in the incubator of 37 DEG C and cultivate 24 hours, it is subsequently adding in every hole 25 μ L D-hanks solution containing 4mgMTT/mL, cultivate 4 hours under similarity condition again, add every hole 100 μ LSDS lysate (90mL tri-distilled water+10gSDS+5mL isopropanol+2mL concentrated hydrochloric acid) and cultivate 12h afterwards.
(5) MIC value judges
Under 570nm, measure OD value by microplate reader, be calculated as follows suppression ratio:
Suppression ratio=[1-(test sample OD value-blank OD value)/(negative control OD value-blank OD value)] × 100
It is not less than the least concentration of 50% MIC as sample using suppression ratio50(minimum inhibitory concentration).When the MIC value of medicine exceedes mensuration concentration range, add up by the following method: when MIC value is higher than maximum concentration 50 μ g/mL, be calculated as " > 50 μ g/mL "；MIC value is least concentration or below least concentration time, does not make difference, is all calculated as "≤0.0049 μ g/mL ".The equal operation repetitive of above-mentioned experiment 3 times, average the final MIC as this compound.
This work adopt adopt MIC method to target compound to bacillus subtilis (B.subtilis), staphylococcus aureus (S.aureus), colon bacillus (E.coli), pseudomonas fluorescens (P.fluorescens) antibacterial activity in vitro.
Antibacterial activity research (MIC, mg/mL) of table one compound.
As can be seen from the above table, bacillus subtilis (B.subtilis), staphylococcus aureus (S.aureus), colon bacillus (E.coli), pseudomonas fluorescens (P.fluorescens) are respectively provided with antibacterial activity in vitro by compound 1-3, and wherein bacillus subtilis (B.subtilis) is had good fungistatic effect by compound 1；Staphylococcus aureus (S.aureus), colon bacillus (E.coli) are had good fungistatic effect by compound 2, especially that staphylococcus aureus (S.aureus) fungistatic effect is good；Compound 3 bacillus subtilis (B.subtilis) has better fungistatic effect.
Although the present invention is with preferred embodiment openly as above; but it is not for limiting the present invention; any those skilled in the art are without departing from the spirit and scope of the present invention; may be by the method for the disclosure above and technology contents and technical solution of the present invention is made possible variation and amendment; therefore; every content without departing from technical solution of the present invention; the technical spirit of the foundation present invention, to any simple modification made for any of the above embodiments, equivalent variations and modification, belongs to the protection domain of technical solution of the present invention.
Claims (9)
1. there is the compound of structure shown in formula I and pharmaceutically acceptable salt thereof:
Wherein R1For CN, F, H；R2For F, H；R3For H, Me, Et, Pr, F, Cl；R4For H, Me, F, Cl, t-Bu；R5For H, Me, Boc, Ph.
2. the method that a photocatalytic synthesis becomes compound described in formula I, it is characterised in that described synthetic reaction equation is Formula II, is dissolved in reaction dissolvent to dicyano aryl compound, substituted olefine and azole derivatives, the light of the λ when logical argon > 300nm irradiates；Then with silica gel column chromatography separation product after being concentrated by reactant mixture, petroleum ether-ethyl acetate is that eluent does gradient elution, obtains product；
Wherein R1For CN, F, H；R2For F, H；R3For H, Me, Et, Pr, F, Cl；R4For H, Me, F, Cl, t-Bu；R5For H, Me, Boc, Ph.
3. method according to claim 2, it is characterised in that the solvent of reaction is the one in benzene, dichloromethane, acetonitrile, normal hexane, acetone.
4. method according to claim 3, it is characterised in that the solvent of reaction is acetonitrile.
5. method according to claim 2, it is characterised in that to dicyano aryl compound, the mol ratio of substituted olefine and three kinds of reactive components of azole derivatives is 1:2:4～1:6:12.
6. method according to claim 2, it is characterised in that the molar concentration to dicyano aryl compound is 0.01～0.1mol/L.
7. method according to claim 2, it is characterised in that the time of photoreaction is 8-48 hour.
8. method according to claim 7, it is characterised in that the time of photoreaction is 16 hours.
9. compound as claimed in claim 1 and the application in preparation antibacterials of the pharmaceutically acceptable salt thereof.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1092064A (en) * | 1992-12-23 | 1994-09-14 | 塞尔特奇公司 | Trisubstd phenyl derivs and preparation method thereof |
| CN1882568A (en) * | 2003-09-13 | 2006-12-20 | 阿斯利康(瑞典)有限公司 | Pyrrol derivatives with antibacterial activity |
| WO2007081966A2 (en) * | 2006-01-09 | 2007-07-19 | University Of Southern California | Small molecules for treating cancer and abnormal cell proliferation disorders |
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- 2014-06-23 CN CN201410284371.7A patent/CN104059011B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1092064A (en) * | 1992-12-23 | 1994-09-14 | 塞尔特奇公司 | Trisubstd phenyl derivs and preparation method thereof |
| CN1882568A (en) * | 2003-09-13 | 2006-12-20 | 阿斯利康(瑞典)有限公司 | Pyrrol derivatives with antibacterial activity |
| WO2007081966A2 (en) * | 2006-01-09 | 2007-07-19 | University Of Southern California | Small molecules for treating cancer and abnormal cell proliferation disorders |
Non-Patent Citations (1)
| Title |
|---|
| Alkene Isomerization–Hydroarylation Tandem Catalysis: Indole C2-Alkylation with Aryl-Substituted Alkenes Leading to 1,1-Diarylalkanes;Takeshi Yamakawa，等;《Chem. Asian J.》;20140311;第9卷;第1242-1246页 * |
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