CN105646386B - Substituted azole five-ring heterocycles derivative and its solvent heat one-pot synthesis and application - Google Patents

Substituted azole five-ring heterocycles derivative and its solvent heat one-pot synthesis and application Download PDF

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CN105646386B
CN105646386B CN201610058287.2A CN201610058287A CN105646386B CN 105646386 B CN105646386 B CN 105646386B CN 201610058287 A CN201610058287 A CN 201610058287A CN 105646386 B CN105646386 B CN 105646386B
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CN105646386A (en
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陈连清
万子露
牛雄雷
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South Central Minzu University
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Abstract

The invention belongs to technical field of organic synthesis, specifically discloses a series of substituted azole five-ring heterocycles derivative and its solvent heat One-step Synthesis methods.The present invention prepares object using solvent heat one-pot synthesis, reaction time is short, solvent is not volatile in enclosed system, recoverable, effectively reduces production cost, the advantages of with energy-conserving and environment-protective, and simple to operate, yield is higher, the substituted azole five-ring heterocycles derivative being prepared has good antibiotic bioactive, and with excellent electronic conductivity, fluorescence and the Photophysics such as ultraviolet, therefore there are very big development and application values.

Description

Substituted azole five-ring heterocycles derivative and its solvent heat one-pot synthesis and application
Technical field
The present invention relates to technical field of organic synthesis, more particularly to a kind of substituted azole five-ring heterocycles derivative and its solvent Hot One-step Synthesis method, further relates to the application of such compound.
Background technology
Azole compounds are a kind of important nitrogenous five-membered heterocycles, because it easily forms hydrogen bond, coordinate bond etc., A variety of non-covalent interactions can be played, there is the extensive uses such as antibacterial, antiviral, anti-inflammatory in terms of bioactivity, new Often by as pharmacophoric group in medicine design, and it is widely used in the fields such as medicine, agricultural chemicals；In terms of photoelectric properties, some azoles Class compound can be used as photosensitive macromolecular material application because it has excellent electronic transmission performance in electroluminescent device In electroluminescent instrument, some azole derivatives have photo-sensitive characteristic, available for production fluorescer, scintillator etc..Due to azole Five-ring heterocycles derivative is widely used and the diversity of its structure, causes the great interest of people, has boundless Research and development prospect.
The traditional synthetic method of substituted azole five-ring heterocycles derivative is being carried out under oil bath heating counterflow condition, is deposited Energy consumption is big, the time is long, low yield, post processing trouble, solvent volatilization the shortcomings of, limit to a certain extent to substituted azole Improvement is optimized for these shortcomings in the application of five-ring heterocycles derivative, the present invention.
Solvent-thermal method refer to it is inner in special closed reaction vessel (autoclave), using different solvents as reaction medium, By being heated to reaction vessel, create a high temperature, reaction under high pressure environment so that usual indissoluble or the dissolving of insoluble material and Recrystallization.One-pot synthesis have the characteristics that efficiently, it is high selectivity, mild condition, easy to operate, it can also relatively easily be synthesized Some conventional methods are difficult to the object synthesized.Solvent-thermal method has a very wide application in inorganic material synthesis at present, but Application in organic synthesis is rarely reported, it is demonstrated experimentally that solvent heat one-pot synthesis has yield high, the time is short, simple to operate, The advantages that energy-conserving and environment-protective, it is expected to turn into the new method for efficiently preparing substituted azole five-ring heterocycles derivative, application prospect will very It is wide.
The content of the invention
For the deficiencies in the prior art, the present invention is devised by N- (2- oxos) amide derivatives (I a) or 1, 4 '-bishydrazide derivative (I b) is inner in closed reaction vessel (autoclave), using different solvents as reaction medium, by right Reaction vessel heats, and creates a high temperature, reaction under high pressure environment, a series of substituted azole five-ring heterocycles derivatives of One-step Synthesis (II), (III) and (IV) type compound.
Based on considerations above, of the invention four goals of the invention are：
First purpose：A kind of substituted azole five-ring heterocycles derivative is provided, shown in its structural formula such as formula (A)：
Wherein, M is-O- ,-S- or-NH-；
When M is-O-, the formula (A) is shown in following structural formula (II)：
When M is-S-, the formula (A) is shown in following structural formula (III)：
When M is-NH-, the formula (A) is shown in following structural formula (IV)：
In the structural formula (A), (II), (III), (IV), X is-CR3Or-N=；
When X is-CR3When, the structural formula (II), (III) and (IV) be respectively 2,4,5 three substitution -1,3- oxazoles (II a), 2,4,5 three substitutions -1,3-thiazoles (III a) and 2,4,5 three substitution -1,3- imidazoles (IV a) type compounds, its structural formula are as follows：
When X is-N=, the structure formula (III), (IV) and (V) are respectively 2,5 two -1,3,4- oxadiazoles (II of substitution B), 2,5 two -1,3,4- thiadiazoles of substitution (III b) and 2,5 two substitution -1,3,4- triazoles (IV b) type compounds, its structural formula is such as Under：
In above-mentioned each structural formula, R1、R2It is each independently selected from any one in following group：
CH3-、CH3CH2-、CH3CH2CH2-、CH3(CH2)2CH2-、CH3(CH2)3CH2-、CH3(CH2)4CH2-、CH3(CH2)5CH2-、CH(CH3)2CH2CH2-、ClCH2-、ClCH2CH2-、Cl2CHCH2CH2-、Cl3CCH2CH2-、 And
Preferably, the R1、R2It is each independently selected from any one in following group：
And
Optimal, the R1、R2Any one in following group is independently chosen from respectively：
And
R3Any one in following group：-H、Substituted or unsubstituted benzene Base；
The 2,4,5 3 substitution -1,3- oxazoles (II a), 2,4,5 3 substitution -1,3- thiazoles (III a) and 2,4,5 3 substitutions - In 1,3- imidazoles (IV a) compound, work as R1For substituted or unsubstituted phenyl when, R2With R3It is connected to form six-membered ring structure；
Second purpose：There is provided and a kind of be easy to the relatively low substituted azole five of efficient preparation, energy-conserving and environment-protective, production cost The synthetic method of membered heterocycle derivatives (A).
A kind of synthetic method of structural formula compound as shown in formula (A)：
By compound N-(2- oxos) amide derivatives (I a) or Isosorbide-5-Nitrae '-bishydrazide derivative (I b) and cyclizing agent be molten Condition existing for agent is inner in closed reaction vessel (autoclave), and 2-14h, one pot of system are reacted at 70~180 DEG C by solvent-thermal method It is standby to obtain compound shown in formula (A)；
N- (2- oxos) amide derivatives (I a) and Isosorbide-5-Nitrae '-bishydrazide derivative (I b) structural formula it is as follows：
Synthetic route is as follows：
Any one of the solvent in cyclic ethers class, arene, chain ethers, amine and other solvents；
Further, the cyclic ether solvents include tetrahydrofuran and dioxane；
The aromatic hydrocarbon solvent includes toluene, dimethylbenzene, mesitylene, chlorobenzene, bromobenzene and pyridine；
The chain ethers solvent includes ethylene glycol diethyl ether, butyl glycol ether, diethylene glycol monomethyl ether, diethylene glycol two Methyl ether, propylene glycol monomethyl ether and dihydroxypropane single-ether；
The amine solvent includes N,N-dimethylformamide and DMAC N,N' dimethyl acetamide；
Other described class solvents include dimethyl sulfoxide and CHP；
Preferably, the solvent is tetrahydrofuran, dioxane, toluene, pyridine, chlorobenzene, dimethylbenzene, ethylene glycol diethyl Any one in ether, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide and CHP.
Optimal, the organic solvent is tetrahydrofuran, toluene, pyridine, chlorobenzene, ethylene glycol diethyl ether and N, N- dimethyl Any one in formamide；
The cyclizing agent is selected from one of following three types cyclizing agent, and first kind cyclizing agent spreads out for synthesis substituted azole five-ring heterocycles Cyclizing agent used in biological (II), the second class cyclizing agent are cyclizing agent used in synthesis substituted azole five-ring heterocycles derivative (III), the Three class cyclizing agents are cyclizing agent used in synthesis substituted azole five-ring heterocycles derivative (IV)；
The first kind cyclizing agent is selected from phosphorus pentoxide, polyphosphoric acids, POCl3, phosphorus trichloride, phosphorus pentachloride, chlorine Any one in sulfonic acid and trim,ethylchlorosilane, preferably is selected from phosphorus pentoxide, POCl3, phosphorus trichloride, phosphorus pentachloride, chlorine Any one in sulfonic acid and trim,ethylchlorosilane；
Any one of the second class cyclizing agent in phosphorus pentasulfide, thiocarbamide and 2- TGAs, preferably five Vulcanize two phosphorus or thiocarbamide；
The 3rd class cyclizing agent is selected from the aminated compounds for having hydrogen on ammonium salt or nitrogen, such as ammonia, ammonium carbonate, bicarbonate Any one in ammonium, ammonium nitrate, ammonium sulfate and ammonium hydrogen sulfate, it is preferably any in ammonium hydrogen carbonate, ammonium nitrate and ammonium sulfate It is a kind of；
Preferably, the solvent thermal reaction temperature is 100~170 DEG C, and the reaction time is 3~10h.
Optimal, the solvent thermal reaction temperature is 140~160 DEG C, and the reaction time is 4~8h.
The compound N-(2- oxos) amide derivatives (I a) or Isosorbide-5-Nitrae '-bishydrazide derivative (I b) and cyclizing agent Mol ratio is 1：1.2.
3rd purpose：A kind of application of above-mentioned substituted azole five-ring heterocycles derivative in antibacterials is provided.
To realize third object of the present invention, the present invention distinguishes the substituted azole five-ring heterocycles derivative being prepared Tested for anti-Staphylococcus aureus, ETEC and proteus vulgaris, achieve good antibacterial effect.
4th purpose：A kind of application of above-mentioned substituted azole five-ring heterocycles derivative in terms of luminescent material is provided.
To realize fourth object of the present invention, by the present invention by the substituted azole five-ring heterocycles derivative being prepared from Fluorescence emission spectrum and the aspect of uv-visible absorption spectra two have investigated the photophysical property of product, and it is preferable to determine that it has Photophysics.
Compared with prior art, the advantages of the present invention are as follows：
The substituted azole five-ring heterocycles derivative (A) that the present invention is prepared using solvent heat one-pot synthesis, the reaction time is short, Solvent is not volatile in enclosed system, recoverable, significantly reduces production cost, has the advantages of energy-conserving and environment-protective, And simple to operate, yield is higher.
The substituted azole five-ring heterocycles derivative (A) being prepared has good bioactivity, particularly in antibacterial side Face shows high activity, and has excellent Photophysics, therefore has very big development and application values.
Brief description of the drawings
Fig. 1 is the fluorescence emission spectrogram of compound that substituted azole five-ring heterocycles derivative is dissolved in dichloromethane solution.
Fig. 2 is the UV-visible absorption spectrum that substituted azole five-ring heterocycles derivative is dissolved in dichloromethane solution.
Embodiment
With reference to specific embodiment, the present invention is described in further detail, but these specific embodiments are not with any Mode limits the scope of the invention.
Raw material used is known compound in following embodiment, is commercially available, or can be with this area The method synthesis known.
The synthesis of embodiment 1,2,5 diphenyl-oxazoles ((II) 1)
25mL pyridines, 2.39g N- (2- oxygen -2- phenyl) ethyl benzamides and 1.7g five are added in 100mL reactors Two phosphorus are aoxidized, is well mixed, is tightened closure, be put into electric drying oven with forced convection, reaction temperature 120 is heated to from room temperature DEG C, after isothermal reaction 6h, stop heating, naturally cool to room temperature, mixture with distillation water washing, is dried, ethanol is tied again Crystalline substance, weigh, obtain faint yellow solid 1.82g (II) 1, yield 82.3%.mp:180.1~183.6 DEG C of .IR ν (cm-1):3045, 1584,1483,1443,1126,1062,1020,944,908,820,760,683；1H-NMR(CDCl3,400MHz):8.12 (dd, J=7.7,1.5Hz, 2H), 7.74 (dd, J=8.2,1.3Hz, 2H), 7.51-7.44 (m, 6H), 7.35 (t, J= 7.5Hz,1H)；13C-NMR(125MHz,CDCl3):161.5,151.7,130.8,129.4,129.3,128.9,128.4, 127.9,126.7,124.6,123.9；HRMS(MALDI-FTMS)calcd for C15H12NO+[M+H]+222.0913,found 222.0914.
The synthesis of embodiment 2,2- indyl -5- Ben Ji oxazoles ((II) 2)
25mL toluene, 2.78g N- (2- oxygen -2- phenyl) ethyl -1H- indoles -3- formyls are added in 100mL reactors Amine and 1.7g phosphorus pentoxides, it is well mixed, tightens closure, be put into electric drying oven with forced convection, heated to from room temperature 150 DEG C of reaction temperature, after isothermal reaction 6h, stop heating, naturally cool to room temperature, mixture with distillation water washing, is done It is dry, ethyl alcohol recrystallization, weigh, obtain pale white solid 2.31g (II) 2, yield is 88.7%.IR ν (cm-1):3413,3154, 2919,1625,1602,1443,1361,1249,1120,914,767,726；1H-NMR(400MHz,DMSO-d6):8.10– 8.07(m,2H),7.98–7.95(m,2H),7.60–7.48(m,5H),7.25–7.17(m,2H)；13C-NMR(125MHz, DMSO-d6):158.0,148.3,136.4,130.1,129.2,127.2,125.5,123.9,123.5,122.3,120.8, 120.3,119.6,112.2,103.6；HRMS(MALDI-FTMS)calcd for C17H13N2O+[M+H]+261.1022, found 261.1021.
The synthesis of embodiment 3, the Bi Ding Ji oxazoles ((II) 3) of 2- indyls -5
25mL dimethylbenzene, 2.78g N- (2- oxygen -2- pyridine radicals) ethyl -1H- indoles -3- are added in 100mL reactors Formamide and 1.7g phosphorus pentoxides, it is well mixed, tightens closure, be put into electric drying oven with forced convection, heats and rise from room temperature Temperature arrive 150 DEG C of reaction temperature, after isothermal reaction 6h, stops heating, naturally cools to room temperature, by mixture, with distilling water washing, Dry, ethyl alcohol recrystallization, weigh, obtain yellow solid 2.35g (II) 3, yield is 90%.IR ν (cm-1):3173,2919,1755, 1628,1431,1331,1255,1120,1008,920,803,750,703,614；1H-NMR(400MHz,DMSO-d6):9.27 (s, 1H), 8.69 (d, J=5.0Hz, 1H), 8.41 (d, J=6.7Hz, 1H), 8.01 (d, J=2.4Hz, 1H), 7.97 (d, J= 7.9Hz, 1H), 7.67 (s, 1H), 7.59 (dd, J=7.9,5.0Hz, 1H), 7.49 (d, J=7.9Hz, 1H), 7.25-7.17 (m,2H)；13C-NMR(100MHz,DMSO-d6):155.9,150.6,149.0,136.4,132.8,124.2,124.1, 123.5,123.4,122.3,120.9,120.4,119.6,112.2,103.4；HRMS(MALDI-FTMS)calcd for C16H12N3O+[M+H]+262.0975,found 262.0972.
The synthesis of embodiment 4, the Sai fen Ji oxazoles ((II) 4) of 2- (4- fluorophenyls) -5
25mL N,N-dimethylformamides, the fluoro- N- of 2.63g 4- (2- oxygen -2- thiophene -3- are added in 100mL reactors Base) ethyl benzamide and 1.7g phosphorus pentoxides, it is well mixed, tightens closure, be put into electric drying oven with forced convection, from room Temperature heats to 150 DEG C of reaction temperature, after isothermal reaction 6h, stops heating, naturally cools to room temperature, by mixture, with steaming Distilled water is washed, and is dried, ethyl alcohol recrystallization, is weighed, obtain yellow solid 1.64g (II) 4, yield is 67%.M.p.65~67.IR ν (cm-1):3100,1610,1600.1H-NMR(DMSO-d6,400MHz):7.2~8.3 (8H, m, CH, arom-H, thiophene-H).HRM S(MALDI-FTMS)calcd for C13H8FNOS+[M+H]+222.0913,C,63.66；H, 3.29；N,5.71；S,13.07.Found:222.0914,C,63.57；H,3.41；N,5.82；S,12.93.
The embodiment 5, [synthesis of d] oxazoles ((II) 5) of 2- phenyl -4,5,6,7- tetrahydro benzos
25mL pyridines, 2.17g N- (2- oxygen-cyclohexyl) benzamides and 5mL trichlorine oxygen are added in 100mL reactors Phosphorus, it is well mixed, tightens closure, be put into electric drying oven with forced convection, 80 DEG C of reaction temperature, constant temperature are heated to from room temperature After reacting 12h, stop heating, naturally cool to room temperature, by mixture, with distillation water washing, dry, ethyl alcohol recrystallization, weigh, White solid 1.3g (II) 5 is obtained, yield is 65%.IR ν (cm-1):2931,2837,1637,1542,1478,1443,1284, 1055,920,767,709.1H-NMR(CDCl3,400MHz):8.07 (dd, J=8.1,1.2Hz, 2H), 7.52-7.45 (m, 3H),2.78–2.67(m,4H),2.00–1.89(m,4H).13C-NMR(100MHz,CDCl3):159.7,146.9,135.0, 129.6,128.6,128.0,125.8,23.1,23.0,22.9,21.9；HRMS(MALDI-FTMS)calcd for C13H14NO+ [M+H]+200.1070,found 200.1068.
The synthesis of embodiment 6,1- benzyl groups -5- (5- methyl isophthalic acids, 3,4 oxadiazole -2- bases) nafoxidine -2- ketone ((II) 6)
25mL toluene, 2.75g N- acetyl group -1- benzyl -2- carbohydrazides -5- oxygen-tetrahydrochysene are added in 100mL reactors Pyrroles and 5mL POCl3s, it is well mixed, tightens closure, be put into electric drying oven with forced convection, heated to instead from room temperature Answer 150 DEG C of temperature, after isothermal reaction 6h, stop heating, naturally cool to room temperature, mixture with distillation water washing, is dried, Ethyl alcohol recrystallization, weigh, obtain white solid 2.18g (II) 6, yield 85%.Mp:86℃.IRν(cm-1):1680 (C=O), 1585-1565-1495 (C=C, C=N)1H-NMR(CDCl3,400MHz):2-2.9(m,4H),2.36(s,3H),4.24(d, LH, J=14.4Hz), 4.65 (d, lH, J=14.4Hz), 4.7-5 (m, IH), 7.25 (s, 5H) .Anal.Calcd.for C14H15N3O2:C,65.35；H,5.88；N,16.33.Found:C,65.24；H,5.98；N,16.27.
The synthesis of embodiment 7,2- (3,4,5- trimethoxyphenyls) -4- carboxymethyl -5- Jia Ji oxazoles ((II) 7)
25mL pyridines, 3.25g 2- (3,4,5- trimethoxybenzoys) 3- oxy butyrates are added in 100mL reactors Methyl esters and 5mL POCl3s, it is well mixed, tightens closure, be put into electric drying oven with forced convection, heated to instead from room temperature Answer 150 DEG C of temperature, after isothermal reaction 6h, stop heating, naturally cool to room temperature, mixture with distillation water washing, is dried, Ethyl alcohol recrystallization, weigh, obtain white solid 2.2g (II) 7, yield 68%.mp:152-154℃.1H-NMR(400MHz, CDCl3):7.24(s,2H),3.90(s,3H),3.89(s,6H),3.85(s,3H),2.66(s,3H)；13C-NMR(125MHz, CDCl3):162.7(C),159.4(C),156.1(C),153.3(C),140.3(C),128.4(C),121.7(C),103.7 (CH),60.8(CH3),56.2(CH3),51.9(CH3),12.0(CH3)；HRMS(EI)m/z:calcd for C15H17NO6: 307.1056,found:307.1051.
The synthesis of embodiment 8,2,5 diphenylthiazols ((III) 1)
25mL ethylene glycol diethyl ethers, 2.39g N- (2- oxygen -2- phenyl) ethyl benzamide are added in 100mL reactors With 2.66g phosphorus pentasulfides, it is well mixed, tightens closure, be put into electric drying oven with forced convection, heated to instead from room temperature Answer 150 DEG C of temperature, after isothermal reaction 6h, stop heating, naturally cool to room temperature, mixture with distillation water washing, is dried, Ethyl alcohol recrystallization, weigh, obtain yellow solid 2.05g (III) 1, yield 86.7%.mp:180.1~183.6 DEG C of .IR ν (cm-1): 3056,3021,2915,2833,1602,1488,1441,1306,1236,1171,1077,1000,942,760,689,601；1H-NMR(CDCl3,400MHz):7.88 (dd, J=8.3,1.3Hz, 2H), 7.51-7.26 (m, 8H), 5.08 (dd, J=8.8, 5.5Hz, 1H), 4.79 (dd, J=16.1,8.8Hz, 1H), 4.63 (dd, J=16.1,5.5Hz, 1H)；13C-NMR(125MHz, CDCl3):167.7,142.1,133.1,131.3,128.8,128.5,128.4,127.8,127.0,73.2,54.5；HRMS (MALDI-FTMS)calcd for C15H12NS+[M+H]+240.0841,found 240.0837.
The synthesis of embodiment 9,2- indyl -5- phenyl thiazoles ((III) 2)
25mL toluene, 2.78g N- (2- oxygen -2- phenyl) ethyl benzamides and 2.66g are added in 100mL reactors Phosphorus pentasulfide, it is well mixed, tightens closure, be put into electric drying oven with forced convection, reaction temperature is heated to from room temperature 150 DEG C, after isothermal reaction 6h, stop heating, naturally cool to room temperature, mixture with distillation water washing, is dried, ethanol weight Crystallization, weighs, obtains yellow solid 2.31g (III) 2, yield 83.6%.mp:180.1~183.6 DEG C of .IR (film) ν max 3399,3170,2912,1562,1487,1452,1421,1337,1245,1120,978,911,740,689,630cm–1；1H NMR (500MHz, CDCl3) δ 7.85 (m, 2H), 7.47-7.38 (m, 3H), 4.26 (dt, J=11.0,5.5Hz, 1H), 3.82 (dt, J=8.8,5.8Hz, 1H), 2.28 (m, 1H), 1.89-1.80 (m, 2H), 1.70-1.51 (m, 4H), 1.37-1.29 (m, 1H)；13C NMR(100MHz,CDCl3)δ165.1,138.4,136.4,133.8,132.7,129.7,129.0,126.3, 125.4,123.1,122.8,121.0,119.7,111.6,108.3；HRMS(MALDI-FTMS)calcd for C17H13N2S+ [M+H]+277.0794,found 277.0788.
The synthesis of embodiment 10,2- (4- chlorphenyls) -5- thienyls thiazoles ((III) 3)
Added in 100mL reactors 25mL toluene, 2.3g 4- chlorine N- (2- oxygen -2- thienyls) ethyl benzamides and 2.66g phosphorus pentasulfides, it is well mixed, tightens closure, be put into electric drying oven with forced convection, reaction is heated to from room temperature 150 DEG C of temperature, after isothermal reaction 6h, stop heating, naturally cool to room temperature, mixture with distillation water washing, is dried, second Alcohol recrystallizes, and weighs, obtains white solid 1.68g (III) 3, yield is 64%.M.p.143~144 DEG C .IR ν (cm-1):3100, 1595.1H-NMR(DMSO-d6,400MHz):7.9~7.41 (4H, m, arom-H), 7.78 (1H, s, thiophene-H) 7.2~ 7.5(3H,m,thiophene-H).Anal calcd for C13H8ClNOS2:C,56.21；H,2.90；N,5.04；Cl, 12.76；S,23.08.Found:C,56.11；H,2.84；N,5.08；Cl,12.99；S,22.75.
The synthesis of embodiment 11,2- phenyl -4,5,6,7- tetrahydro benzos [d] thiazole ((III) 4)
25mL toluene, 2.17g N- (2- oxygen-cyclohexyl) benzamides and the sulphur of 2.66g five are added in 100mL reactors Change two phosphorus, be well mixed, tighten closure, be put into electric drying oven with forced convection, reaction temperature 150 is heated to from room temperature DEG C, after isothermal reaction 6h, stop heating, naturally cool to room temperature, mixture with distillation water washing, is dried, ethanol is tied again Crystalline substance, weigh, obtain white solid 1.5g (III) 4, yield is 68%.IR ν (cm-1):3060,2919,2849,1572,1484, 1443,1302,1243,1078,997,950,761,686,609.1H-NMR(CDCl3,400MHz):7.85(m,2H),7.47– 7.38 (m, 3H), 4.26 (dt, J=11.0,5.5Hz, 1H), 3.82 (dt, J=8.8,5.8Hz, 1H), 2.28 (m, 1H), 1.89–1.80(m,2H),1.70–1.51(m,4H),1.37–1.29(m,1H).13C-NMR(100MHz,CDCl3):134.4, 131.5,128.8,128.6,75.2,51.6,30.2,29.0,23.5,22.1；HRMS(MALDI-FTMS)calcd for C13H14NO+[M+H]+218.0998,found 218.0997.
The synthesis of embodiment 12,2,5- bis- (4- aminomethyl phenyls) -1,3,4- thiadiazoles ((III) 5)
25mL tetrahydrofurans, 2.67g 4- methyl-N- (2- oxygen -2- (4- aminomethyl phenyls)) are added in 100mL reactors Ethyl benzamide and 2.66g phosphorus pentasulfides, it is well mixed, tightens closure, be put into electric drying oven with forced convection, from room temperature Heat to 150 DEG C of reaction temperature, after isothermal reaction 6h, stop heating, naturally cool to room temperature, by mixture, with distillation Water washing, dry, ethyl alcohol recrystallization, weigh, obtain white solid 2.3g (III) 5, yield 87%.1H-NMR(CDCl3, 400MHz):7.91 (d, J=8.2Hz, 4H, C6H5), 7.31 (d, J=8.1Hz, 4H, C6H5),2.44(s,6H,CH3)；13C- NMR(125MHz,CDCl3):168.0,141.6,129.9,127.9,127.6,21.6.
The synthesis of embodiment 13,2- (4- nitrobenzophenones) -4- carboxymethyl -5- methylthiazols ((III) 6)
25mL tetrahydrofurans, 2.8g 2- (4- nitro benzoyls) 3- oxygen-methyl butyrate are added in 100mL reactors With 2.66g phosphorus pentasulfides, it is well mixed, tightens closure, be put into electric drying oven with forced convection, heated to instead from room temperature Answer 150 DEG C of temperature, after isothermal reaction 6h, stop heating, naturally cool to room temperature, mixture with distillation water washing, is dried, Ethyl alcohol recrystallization, weigh, obtain white solid 2.3g (III) 6, yield is 83%.m.p.191~193 DEG C1H-NMR(CDCl3, 400MHz):8.27 (d, J=9.0Hz, 2H), 8.07 (d, J=9.0Hz, 2H), 3.97 (s, 3H), 2.84 (s, 3H)；13C-NMR (125MHz,CDCl3):162.6(C),160.7(C),148.6(C),146.8(C),142.8(C),138.2(C),127.3 (CH),124.2(CH),52.3(CH3),13.4(CH3)；HRMS(EI)m/z:calcd for C12H10N2O4S:278.0361, found:278.0358.
The synthesis of embodiment 14,2,5 2 (4- hydroxy phenyls) imidazoles ((IV) 1)
25mL pyridines, 2.71g N- (2- oxygen -2- (4- hydroxy phenyls)) ethyl benzamide are added in 100mL reactors With 1.15g ammonium carbonates, it is well mixed, tightens closure, be put into electric drying oven with forced convection, reaction temperature is heated to from room temperature 150 DEG C of degree, after isothermal reaction 6h, stop heating, naturally cool to room temperature, mixture with distillation water washing, is dried, ethanol Recrystallization, weighs, obtains yellow solid 1.45g (IV) 1, yield 57%.IRν(cm-1):2590,1645,1488,1114,841；1H-NMR(CD3OD,400MHz):7.83 (d, J=8.70Hz, 2H), 7.62 (d, J=8.70Hz, 2H), 7.60 (s, 1H), 7.03 (d, J=8.70Hz, 2H), 6.92 (d, J=8.70Hz, 2H)；13C-NMR(125MHz,CD3OD):131.30,129.15, 120.15(2C),119.80(2C),115.55(2C),114.75(2C),114.30；MS(ESI):253(M+H)+； Anal.Calcd C15H12N2O2:C,71.42；H,4.79；N,11.10.Found:C,71.30；H,4.52；N,11.00.
The synthesis of embodiment 15,2- (4- methoxyphenyls) -5- (3- methoxyphenyls) imidazoles ((IV) 2)
25mL tetrahydrofurans, 2.99g N- (2- oxygen -2- (4- methoxyphenyls)) ethylo benzene are added in 100mL reactors Formamide and 1.15g ammonium carbonates, it is well mixed, tightens closure, be put into electric drying oven with forced convection, heated to from room temperature 100 DEG C of reaction temperature, after isothermal reaction 6h, stop heating, naturally cool to room temperature, mixture with distillation water washing, is done It is dry, ethyl alcohol recrystallization, weigh, obtain white solid 1.26g (IV) 2, yield 45%.mp:198℃；IRν(cm-1):3070,2950, 1578,1242,742；1H-NMR(CD3OD,400MHz):8.07 (d, J=2.50Hz, 1H), 7.98 (d, J=8.50Hz, 2H), 7.78 (d, J=8.50Hz, 1H), 7.57 (s, 1H), 7.37 (s, 1H), 7.12-7.08 (m, 2H), 6.75 (s, 1H), 3.83 (s, 3H,OMe),3.82(s,3H,OMe)；13C-NMR(125MHz,CD3OD):162.10,160.85,151.40,137.50, 128.65(2C),127.25,125.40,123.35,20.75,115.75(2C),113.70,56.80,56.50；MS(ESI): 281(M+H)+.Anal.Calcd C21H12N2O2:C,76.42；H,3.79；N,7.10.Found:C,76.30；H,3.52；N, 7.00.
The synthesis of embodiment 16, the diphenyl 1-H- imidazoles ((IV) 3) of 5- methyl -2,4
Added in 100mL reactors 25mL toluene, 2.99g N- (1- phenyl -2- oxygen-propyl group) ethyl benzamides and 1.15g ammonium carbonates, it is well mixed, tightens closure, be put into electric drying oven with forced convection, reaction temperature is heated to from room temperature 150 DEG C, after isothermal reaction 6h, stop heating, naturally cool to room temperature, mixture with distillation water washing, is dried, ethanol weight Crystallization, weighs, obtains white solid 1.26g (IV) 2, yield 45%.IRν(cm-1):3020,2930,1568,1252,772；1H- NMR(CD3OD,400MHz):8.07-7.21(m,10H,Ar-H),3.82(s,3H,CH3)；13C-NMR(125MHz,CD3OD): 161.10,158.85,151.40,133.50,124.65(2C),127.25,125.40,123.35,20.75,115.75(2C), 113.70,55.80,53.50；
The synthesis of embodiment 17,2- (4- methoxyphenyls) -5- phenyl -1H-1,2,4- triazoles ((IV) 4)
25mL chlorobenzenes, 2.7g N`- benzoyls -4- methoxybenzoyls hydrazines and 1.15g are added in 100mL reactors Ammonium carbonate, it is well mixed, tightens closure, be put into electric drying oven with forced convection, reaction temperature 150 is heated to from room temperature DEG C, after isothermal reaction 6h, stop heating, naturally cool to room temperature, mixture with distillation water washing, is dried, ethanol is tied again Crystalline substance, weigh, obtain white solid 1.95g (IV) 3, yield 78%.mp:169.5-72.0℃；IRν(cm-1):3500-2500 (broad),1614,1508,1471,1441,1408,1394,1310,1304,1290,1278,1260,1180,1142, 1034,982,836,749,722；1H-NMR(400MHz,DMSO-d6):3.84 (s, 3H), 7.10 (d, 2H, J=8.8Hz), 7.49-7.53(m,3H),8.00-8.20(m,4H)ppm；13C-NMR(125MHz,DMSO-d6):55.2,114.2,121.4, 125.9,127.5,128.7,129.3,129.7,157.5,160.3ppm；Analysis:Calc.for C15H13N3O:C, 71.70；H,5.21；N,16.72；O,6.37.Found:C,71.88；H,5.41；N,16.67.
The synthesis of comparative example, 2,5 diphenyl-oxazoles ((II) 1)
Separately or concurrently change temperature, reaction time and the mode of heating of embodiment 1, other are same as Example 1, prepare 2,5 diphenyl-oxazoles ((II) 1), the result for preparing result and embodiment 1 are listed in the table below in 1 simultaneously：
(II) 1 synthesis and its yield under the different condition of table 1.
As can be seen that reaction temperature influences yield with the reaction time from comparative example 1~3, solvent-thermal method and oil are used Bath backflow is obviously improved compared to yield.
The preparation of embodiment 18, substituted azole five-ring heterocycles derivative (II), (III), (IV) solution
Antibacterial formulation prepared by the present embodiment is solution, and test compound is dissolved in DMSO, is made into 0.1% in advance (m/v) concentration, 10,1,0.1mg/L 3 kind of concentration then is diluted to as supplying sample with 1% (m/v) acetic acid distilled water solution Product, positive control drug Norfloxacin (NF), 10,1,0.1mg/L 3 kind of concentration directly is configured to 1% (m/v) acetic acid distilled water, Blank control group is 1% (m/v) acetum.
Prepared dilute solution agent is ready for use on following embodiment.
Embodiment 19, the antibacterial activity to staphylococcus aureus are evaluated
Antibacterial activity evaluation to staphylococcus aureus uses plate test method determination, is prepared using embodiment 18 each The dilute solution agent of compound, using beef extract-peptone as culture medium, be inoculated with after 37 DEG C cultivate 24h, observe, record it is antibacterial Size is enclosed, and compared with positive control drug Norfloxacin (NF), evaluates the bacteriostatic activity height of test compound according to this, ++ represent High activity ,+medium activity is represented ,-represent that activity is weaker.Preliminary pharmacological tests are shown in Table 2.
The anti-Staphylococcus aureus activity of the compound (III) 1~(V) 4 of table 2.
Embodiment 20, the antibacterial activity to ETEC are evaluated
Antibacterial activity evaluation to ETEC uses plate test method determination, eachization prepared using embodiment 18 The dilute solution agent of compound, using beef extract-peptone as culture medium, it is inoculated with and 24h is cultivated after 37 DEG C, observation, record inhibition zone Size, and compared with positive control drug Norfloxacin (NF), the bacteriostatic activity height of test compound is evaluated according to this, ++ represent high Activity ,+medium activity is represented ,-represent that activity is weaker.Preliminary pharmacological tests are shown in Table 3.
The anti-ETEC activity of the compound (III) 1~(V) 4 of table 3.
Embodiment 21, the antibacterial activity to proteus vulgaris are evaluated
Antibacterial activity evaluation to proteus vulgaris uses plate test method determination, eachization prepared using embodiment 18 The dilute solution agent of compound, using beef extract-peptone as culture medium, it is inoculated with and 24h is cultivated after 37 DEG C, observation, record inhibition zone Size, and compared with positive control drug Norfloxacin (NF), the bacteriostatic activity height of test compound is evaluated according to this, ++ represent high Activity ,+medium activity is represented ,-represent that activity is weaker.Preliminary pharmacological tests are shown in Table 4.
The anti-proteus vulgaris activity of the compound (III) 1~(V) 4 of table 4.
The Photophysics evaluation of embodiment 22, substituted azole five-ring heterocycles derivative
Substituted azole five-ring heterocycles derivative has been investigated in terms of fluorescence emission spectrum and uv-visible absorption spectra two Photophysical property, substituted azole five-ring heterocycles derivative be dissolved in fluorescence emission spectrogram of compound in dichloromethane solution and ultraviolet- Visible absorption spectra figure is shown in Fig. 1, Fig. 2 respectively.
As shown in Figure 1, (II) 1 in nine compounds tested, (II) 5, (II) 6, (III) 2, (III) 3, (III) 5, (IV) 3 and (IV's) 4 is luminous all in ultraviolet region, lighting in visibility region for the compound (III) 6 of nitro substitution, all belongs to The pi-electron transition of conjugated system.Simultaneously it can also be seen that the influence of substituent different on phenyl ring to launch wavelength is different, first Epoxide and methyl influence less on launch wavelength, and inhale electrical group by force, disperse the electronics of excitation state, excited energy becomes It is low, it is red to have been moved at visibility region 422nm so as to cause fluorescence emission wavelengths elongated.
As shown in Figure 2, nine compounds (II) 1 being tested, (II) 5, (II) 6, (III) 2, (III) (III) 3, (III) 5, (III) 6, (IV) 3 and (IV) 4 have absworption peak in ultra-violet (UV) band, have eight compounds to have absworption peak in 280nm or so, And the compound (III) 6 of nitro substitution has absworption peak at 317nm, the pi-electron transition of conjugated system is all belonged to.Also may be used simultaneously To find out, influence of the different substituents to absorbing wavelength is different on phenyl ring, and methoxyl group and methyl influence less on absorbing wavelength, And electrical nitro is inhaled by force, the electronics of excitation state is more disperseed, excited energy is lower, so as to cause ultraviolet-ray visible absorbing Wavelength is elongated.

Claims (7)

1. a kind of synthetic method of substituted azole five-ring heterocycles derivative, the structural formula of the substituted azole five-ring heterocycles derivative As shown in formula (A)：
Wherein, M is-O- ,-S- or-NH-；
When M is-O-, the formula (A) is shown in following structural formula (II)：
When M is-S-, the formula (A) is shown in following structural formula (III)：
When M is-NH-, the formula (A) is shown in following structural formula (IV)：
In the structural formula (A), (II), (III), (IV), X is-CR3Or-N=；
In the structural formula (A), (II), (III), (IV), R1、R2It is each independently selected from any one in following group：
CH3-、CH3CH2-、CH3CH2CH2-、CH3(CH2)2CH2-、CH3(CH2)3CH2-、CH3(CH2)4CH2-、CH3(CH2)5CH2-、 CH(CH3)2CH2CH2-、ClCH2-、ClCH2CH2-、Cl2CHCH2CH2-、Cl3CCH2CH2-、
R3Any one in following group：-H、Substituted or unsubstituted phenyl；
Or R1、R2、R3Combination is as follows：
When X is-CR3When, and work as R1For substituted or unsubstituted phenyl when, R2With R3It is connected to form six-membered ring structure；
Characterized in that, the synthetic method comprises the following steps：
By compound N-(2- oxos) amide derivatives (Ia) or Isosorbide-5-Nitrae '-bishydrazide derivative (Ib) and cyclizing agent exist in solvent Condition in closed reaction vessel, by solvent-thermal method 70~180 DEG C react 2-14h, one pot is prepared；
N- (2- oxos) amide derivatives (Ia) and Isosorbide-5-Nitrae '-bishydrazide derivative (Ib) structural formula it is as follows：
The cyclizing agent is selected from one of following three types cyclizing agent, and first kind cyclizing agent is compound institute shown in composite structure formula (II) With cyclizing agent, the second class cyclizing agent is cyclizing agent used in compound shown in composite structure formula (III), and the 3rd class cyclizing agent is synthesis Cyclizing agent used in compound shown in structural formula (IV)；
The first kind cyclizing agent is selected from phosphorus pentoxide, polyphosphoric acids, POCl3, phosphorus trichloride, phosphorus pentachloride, chlorosulfonic acid With any one in trim,ethylchlorosilane；
Any one of the second class cyclizing agent in phosphorus pentasulfide, thiocarbamide and 2- TGAs；
The 3rd class cyclizing agent is selected from aminated compounds ammonia, ammonium carbonate, ammonium hydrogen carbonate, the nitric acid for having hydrogen on ammonium salt or nitrogen Any one in ammonium, ammonium sulfate and ammonium hydrogen sulfate；
Any one of the solvent in cyclic ethers class, arene, chain ethers, amine and other solvents；
The cyclic ether solvents include tetrahydrofuran and dioxane；
The aromatic hydrocarbon solvent includes toluene, dimethylbenzene, mesitylene, chlorobenzene, bromobenzene and pyridine；
The chain ethers solvent includes ethylene glycol diethyl ether, butyl glycol ether, diethylene glycol monomethyl ether, diethylene glycol diformazan Ether, propylene glycol monomethyl ether and dihydroxypropane single-ether；
The amine solvent includes N,N-dimethylformamide and DMAC N,N' dimethyl acetamide；
Other described class solvents include dimethyl sulfoxide and CHP.
2. synthetic method according to claim 1, it is characterised in that：The R1、R2It is each independently selected from following group Any one：
CH3-、
3. synthetic method according to claim 1, it is characterised in that：The R1、R2It is each independently selected from following group Any one：
CH3-、
4. synthetic method according to claim 1, it is characterised in that：The first kind cyclizing agent is selected from selected from five oxidations two Any one in phosphorus, POCl3, phosphorus trichloride, phosphorus pentachloride, chlorosulfonic acid and trim,ethylchlorosilane；The second class cyclization Agent is selected from phosphorus pentasulfide or thiocarbamide；The 3rd class cyclizing agent is any one in ammonium hydrogen carbonate, ammonium nitrate and ammonium sulfate Kind.
5. the synthetic method according to claim 1 or 4, it is characterised in that：The solvent be tetrahydrofuran, dioxane, Toluene, pyridine, chlorobenzene, dimethylbenzene, ethylene glycol diethyl ether, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide and N- hexamethylenes Any one in base -2-Pyrrolidone.
6. the synthetic method according to claim 1 or 4, it is characterised in that：The solvent be tetrahydrofuran, toluene, pyridine, Any one in chlorobenzene, ethylene glycol diethyl ether and N,N-dimethylformamide.
7. the synthetic method according to claim 1 or 4, it is characterised in that：The solvent thermal reaction temperature is 100~170 DEG C, the reaction time is 3~10h.
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