CN105777731A - Oxadiazole-containing piperazine derivative as well as preparation method and use thereof - Google Patents
Oxadiazole-containing piperazine derivative as well as preparation method and use thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to an oxadiazole-containing piperazine derivative as well as a preparation method and use thereof. The oxadiazole-containing piperazine derivative provided by the invention has the following structural formula (shown in the description), wherein R is one of o-chlorophenyl, phenmethyl, o-methoxyphenyl, p-methoxyphenyl, p-fluorophenyl, pyridyl, o-fluorophenyl, p-nitrophenyl, p-chlorophenyl, 2, 3-dichlorophenyl, 3, 4-dichlorophenyl, m-methoxyphenyl, diphenylmethyl or m-trifluoromethylphenyl. Oxadiazole having excellent anti-cancer activity is introduced into a phenyl piperazine ring, to prepare the oxadiazole-containing piperazine derivative provided by the invention; the oxadiazole-containing piperazine derivative has an obvious inhibitory effect on the growth of cancer cells; the oxadiazole-containing piperazine derivative is cheap in used raw material, simple and easy to get, has few reaction steps and high yield, is suitable for industrial production and is used for preparing anti-cancer drugs.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to a kind of bridged piperazine derivatives containing diazole and its production and use.
Background technology
In recent years, piperazine compounds application in organic synthesis and medicine has caused the extensive concern of organise educational circles and pharmacy circle.Piperazine ring is the hexa-member heterocycle in molecule containing two nitrogen-atoms, is the ideal building blocks of azotic heterocyclic compound, has the features such as enthalpy of formation height, Heat stability is good.Compound containing phenylpiperazine ring has efficient pharmacologically active mostly, and some has been developed into clinical medicine.
From the point of view of currently available technology, diazole and derivant have potential active anticancer, all cancerous cell are had active anticancer the non-selective wide spectrum of these compounds.Owing to growth of cancer cells is had obvious inhibitory action, the prospect as very promising cancer therapy drug extremely to merit attention by its derivant of diazole.Along with deepening continuously of piperazines and diazoles drug research, effective structure of modification and modification and MOLECULE DESIGN is carried out on the basis of its pharmacologically active and mechanism of anticancer action are constantly understood, by have increasing efficiently, the piperazines medicine containing diazole of low toxicity be used for clinic, promote the well-being of mankind.
Summary of the invention
It is an object of the invention to provide a kind of bridged piperazine derivatives containing diazole that cancerous cell is had obvious inhibiting effect；Present invention simultaneously provides its scientific and reasonable, simple preparation method and purposes.
Bridged piperazine derivatives containing diazole of the present invention, structural formula is as follows:
Wherein, R be Chloro-O-Phenyl, benzyl, o-methoxyphenyl, p-methoxyphenyl, to fluorophenyl, pyridine radicals, adjacent fluorophenyl, p-nitrophenyl, rubigan, 2,3-Dichlorobenzene base, 3, the one of 4-Dichlorobenzene base, m-methoxyphenyl, diphenyl methyl or m-trifluoromethylphenyl；
Structural formula is as follows:
The preparation method of the described bridged piperazine derivatives containing diazole, comprises the following steps:
(1) PCA, concentrated sulphuric acid, methanol being carried out back flow reaction, TLC detection, until raw material disappears, obtains solid product；
(2) solid product that step (1) obtained, acetone, Bromofume, potassium carbonate carry out back flow reaction, obtain solid product；
(3) solid product that step (2) obtained, ethanol, hydrazine hydrate carry out back flow reaction, obtain solid product；
(4) solid product that step (3) obtained, ethanol, Carbon bisulfide, potassium hydroxide carry out back flow reaction, are then evaporated, and add distilled water and dissolve, filter, and the filtrate obtained adjusts its pH value to 4～5 with dilute hydrochloric acid, filters, separates out to obtain solid product；
(5) solid product that step (4) obtained, the phenylpiperazine of substituent group, ethanol, formaldehyde, through stirring at normal temperature, filtration, obtain the bridged piperazine derivatives containing diazole.
Wherein:
In step (1), PCA, concentrated sulphuric acid, the usage ratio of methanol are 1:0.1:5, and wherein, PCA is in terms of mmol, and concentrated sulphuric acid, methanol are all in terms of mL.
In step (2), solid product that step (1) obtains, acetone, Bromofume, the usage ratio of potassium carbonate are 1:20:1:1.5, wherein, solid product that step (1) obtains, Bromofume, potassium carbonate are all in terms of mmol, acetone is in terms of mL, and reflux time is 15h.
In step (3), solid product that step (2) obtains, ethanol, the usage ratio of hydrazine hydrate are 0.1:2:0.5, and wherein, the solid product that step (2) obtains is in terms of mmol, ethanol, hydrazine hydrate are all in terms of mL, and reflux time is 15h.
In step (4), solid product that step (3) obtains, ethanol, Carbon bisulfide, the usage ratio of potassium hydroxide are 1:20:1:1, wherein, solid product that step (3) obtains, Carbon bisulfide, potassium hydroxide are all in terms of mmol, ethanol is in terms of mL, and reflux time is 24h.
In step (5), solid product that step (4) obtains, the phenylpiperazine of substituent group, ethanol, the usage ratio of formaldehyde are 1:1:20:1.5, wherein, the phenylpiperazine of solid product, phenylpiperazine or substituent group that step (4) obtains, formaldehyde are all in terms of mmol, ethanol in terms of mL, stirring at normal temperature 12h.
In step (5), substituted phenylpiperazine be Chloro-O-Phenyl piperazine, benzyl piperazine, o-methoxyphenyl piperazine, p-methoxyphenyl piperazine, to fluorophenyl piperazine, Pyridylpiperazine, adjacent fluorophenyl piperazine, p-nitrophenyl piperazine, rubigan piperazine, 2,3-dichlorophenylpiperazine, 3, the one in 4-dichlorophenylpiperazine, m-methoxyphenyl piperazine, diphenylmethyl piperazine or m-trifluoromethyl phenylpiperazine.
Bridged piperazine derivatives containing diazole of the present invention can be used in preparing cancer therapy drug.
Beneficial effects of the present invention is as follows:
The diazole with high anti-cancer activity is introduced phenylpiperazine ring, the preparation bridged piperazine derivatives containing diazole by the present invention.Bridged piperazine derivatives containing diazole has an obvious inhibitory action to growth of cancer cells, and raw materials used cheaply simple and easy to get, reactions steps is few, and productivity is high, is suitable for industrialized production, is used for preparing cancer therapy drug.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described further.
Embodiment 1
The preparation of 5-(2,3-dihydrobenzo [b] [1,4] dioxine-6-base)-3-((4-(4-methoxyphenyl) piperazine-1-base) methyl)-1,3,4-diazole-2 (3H)-thioketone.
Above-claimed cpd preparation method is as follows:
(1) PCA, concentrated sulphuric acid, methanol being carried out back flow reaction, TLC detection, until raw material disappears, obtains solid product；
PCA, concentrated sulphuric acid are 1:0.1:5 with the usage ratio of methanol, and wherein, PCA is in terms of mmol, and concentrated sulphuric acid, methanol are all in terms of mL.
(2) solid product that step (1) obtained, acetone, Bromofume, potassium carbonate carry out back flow reaction, obtain solid product；
Solid product that step (1) obtains, acetone, Bromofume, the usage ratio of potassium carbonate are 1:20:1:1.5, wherein, solid product that step (1) obtains, Bromofume, potassium carbonate are all in terms of mmol, and acetone is in terms of mL, and reflux time is 15h.
(3) solid product that step (2) obtained, ethanol, hydrazine hydrate carry out back flow reaction, obtain solid product；
Solid product that step (2) obtains, ethanol, the usage ratio of hydrazine hydrate are 0.1:2:0.5, and wherein, the solid product that step (2) obtains is in terms of mmol, and ethanol, hydrazine hydrate are all in terms of mL, and reflux time is 15h.
(4) solid product that step (3) obtained, ethanol, Carbon bisulfide, potassium hydroxide carry out back flow reaction, are then evaporated, and add distilled water and dissolve, filter, and the filtrate obtained adjusts its pH value to 4～5 with dilute hydrochloric acid, filters, separates out to obtain solid product；
Solid product that step (3) obtains, ethanol, Carbon bisulfide, the usage ratio of potassium hydroxide are 1:20:1:1, wherein, solid product that step (3) obtains, Carbon bisulfide, potassium hydroxide are in terms of mmol, and ethanol is in terms of mL, and reflux time is 24h.
(5) solid product that step (4) obtained, p-methoxyphenyl piperazine, ethanol, formaldehyde, through stirring at normal temperature 12h, filtration, obtain the bridged piperazine derivatives containing diazole；
Solid product that step (4) obtains, p-methoxyphenyl piperazine, ethanol, the usage ratio of formaldehyde are 1:1:20:1.5, wherein, solid product that step (4) obtains, p-methoxyphenyl piperazine, formaldehyde are in terms of mmol, and ethanol is in terms of mL.
White powder, productivity is 80%, Mp:147.2-148.1 DEG C of .1H NMR (400MHz, CDCl3): 3.077-3.134 (m, 8H), 3.808-3.825 (m, 3H), (4.345-4.385 m, 4H), 5.166 (s, 2H), 6.863-6.886 (d, J=9.2Hz, 2H), 6.920-6.943 (d, J=9.2Hz, 2H), 6.992-7.013 (d, J=8.4Hz, 1H), 7.471-7.498 (m, 2H).
Embodiment 2
The preparation of 5-(2,3-dihydrobenzo [b] [1,4] dioxine-6-base)-3-((4-(4-nitrobenzophenone) piperazine-1-base) methyl)-1,3,4-diazole-2 (3H)-thioketone.
Preparation method is with embodiment 1.Replace p-methoxyphenyl piperazine with p-nitrophenyl piperazine, obtain target compound.
Yellow powder, productivity is 85%, Mp:202.6-202.7 DEG C of .1H NMR (400MHz, CDCl3): 3.035-3.061 (m, 4H), 3.487-3.513 (m, 4H), (4.352-4.380 m, 4H), 5.165 (s, 2H), 6.832-6.856 (d, J=9.6Hz, 2H), 6.988-7.008 (d, J=8.0Hz, 1H), 7.454-7.480 (m, 2H), (8.139-8.162 d, J=9.2Hz, 2H).
Embodiment 3
The preparation of 5-(2,3-dihydrobenzo [b] [1,4] dioxine-6-base)-3-((4-(2-methoxyphenyl) piperazine-1-base) methyl)-1,3,4-diazole-2 (3H)-thioketone.
Preparation method is with embodiment 1.Replace p-methoxyphenyl piperazine with o-methoxyphenyl piperazine, obtain target compound.
White powder, productivity is 80%, Mp:181.0-181.7 DEG C of .1H NMR (400MHz, CDCl3): 3.120 (s, 8H), 3.877 (s, 3H), 4.348-4.388 (m, 4H), 5.181 (s, 2H), 6.879-6.899 (d, J=8.0Hz, 1H), 6.942-7.071 (m, 4H), (7.468-7.494 m, 2H).
Embodiment 4
3-(4-(2-chlorphenyl) piperazine-1-base) methyl) preparation of-5-(2,3-dihydrobenzo [b] [1,4] dioxine-6-base)-1,3,4-diazole-2 (3H)-thioketone.
Preparation method is with embodiment 1.Replace p-methoxyphenyl piperazine with Chloro-O-Phenyl piperazine, obtain target compound.
White powder, productivity is 75%, Mp:179.1-179.6 DEG C of .1H NMR (400MHz, CDCl3): 3.105-3.117 (d, J=4.4Hz, 8H), (4.347-4.387 m, 4H), 5.168 (s, 2H), 6.998-7.036 (m, 2H), (7.076-7.099 m, 1H), 7.243-7.385 (m, 1H), 7.372-7.395 (m, 1H), (7.487-7.518 m, 2H).
Embodiment 5
The preparation of 5-(2,3-dihydrobenzo [b] [1,4] dioxine-6-base)-3-((4-(pyridine-2-base) piperazine-1-base) methyl)-1,3,4-diazole-2 (3H)-thioketone.
Preparation method is with embodiment 1.Replace p-methoxyphenyl piperazine with Pyridylpiperazine, obtain target compound.
White powder, productivity is 86%, Mp:171.6-172.4 DEG C of .1H NMR (400MHz, CDCl3): 3.003-3.028 (m, 4H), 3.635 (s, 4H), 4.335-4.376 (m, 4H), (5.167 s, 2H), 6.646-6.695 (m, 2H), 6.981-7.002 (d, J=8.4Hz, 1H), 7.454-7.534 (m, 3H), (8.203-8.218 m, 1H).
Embodiment 6
The preparation of 5-(2,3-dihydrobenzo [b] [1,4] dioxine-6-base)-3-((4-(4-fluorophenyl) piperazine-1-base) methyl)-1,3,4-diazole-2 (3H)-thioketone.
Preparation method is with embodiment 1.So that fluorophenyl piperazine is replaced p-methoxyphenyl piperazine, obtain target compound.
White powder, productivity is 85%, Mp:152.9-153.1 DEG C of .1H NMR (400MHz, CDCl3):3.056-3.080(m,4H),3.152-3.176(m,4H),4.344-4.385(m,4H),5.164(s,2H),6.885-6.919(m,2H),6.975-7.027(m,3H),7.469-7.496(m,2H)。
Embodiment 7
The preparation of 5-(2,3-dihydrobenzo [b] [1,4] dioxine-6-base)-3-((4-(2-fluorophenyl) piperazine-1-base) methyl)-1,3,4-diazole-2 (3H)-thioketone.
Preparation method is with embodiment 1.Replace p-methoxyphenyl piperazine with adjacent fluorophenyl piperazine, obtain target compound.
White powder, productivity is 80%, Mp:147.8-148.9 DEG C of .1H NMR (400MHz, CDCl3): 3.086-3.109 (m, 4H), 3.147-3.160 (d, J=9.2Hz, 4H), 4.359-4.386 (m, 4H), 5.169 (s, 2H), (6.994-7.015 m, 3H), 7.082-7.102 (d, J=8.0Hz, 2H), 7.476-7.502 (m, 2H).
Embodiment 8
The preparation of 3-((4-(4-chlorphenyl) piperazine-1-base) methyl)-5-(2,3-dihydrobenzo [b] [1,4] dioxine-6-base)-1,3,4-diazole-2 (3H)-thioketone.
Preparation method is with embodiment 1.Replace p-methoxyphenyl piperazine with rubigan piperazine, obtain target compound.
White powder, productivity is 85%, Mp:149.2-150.7 DEG C of .1H NMR (400MHz, CDCl3):2.444(s,4H),2.898-2.922(m,4H),4.357-4.396(m,4H),5.090(s,2H),7.012-7.032(m,1H),7.354-7.380(m,4H),7.490-7.523(m,2H)。
Embodiment 9
The preparation of 3-((4-benzhydryl piperazidine-1-base) methyl)-5-(2,3-dihydrobenzo [b] [1,4] dioxine-6-base)-1,3,4-diazole-2 (3H)-thioketone.
Preparation method is with embodiment 1.Replace p-methoxyphenyl piperazine with diphenylmethyl piperazine, obtain target compound.
White powder, productivity is 78%, Mp:160.4-161.0 DEG C of .1H NMR (400MHz, CDCl3): 2.468 (s, 3H), 2.747 (s, 1H), 2.916 (s, 3H), 3.261 (s, 1H), 4.358-4.371 (m, 4H), 5.093 (s, 2H), (5.592-5.606 m, 1H), 6.998-7.044 (m, 2H), 7.199-7.216 (m, 2H), (7.269 s, 1H), 7.410-7.429 (d, J=7.6Hz, 4H), 7.471 (s, 1H), (7.491-7.516 d, J=10.0Hz, 3H).
Embodiment 10
5-(2,3-dihydrobenzo [b] [1,4] dioxine-6-base) preparation of-3-((4-(3-(trifluoromethyl) phenyl) piperazine-1-base) methyl)-1,3,4-diazole-2 (3H)-thioketone.
Preparation method is with embodiment 1.Replace p-methoxyphenyl piperazine with m-trifluoromethyl phenylpiperazine, obtain target compound.
White powder, productivity is 83%, Mp:132.4-132.8 DEG C of .1H NMR (400MHz, CDCl3):3.061-3.086(m,4H),3.282-3.306(m,4H),4.343-4.383(m,4H),5.170(s,2H),6.993-7.132(m,5H),7.471-7.503(m,2H)。
Embodiment 11
The preparation of 3-((4-(2,3-Dichlorobenzene base) piperazine-1-base) methyl)-5-(2,3-dihydrobenzo [b] [1,4] dioxine-6-base)-1,3,4-diazole-2 (3H)-thioketone.
Preparation method is with embodiment 1.With 2,3-dichlorophenylpiperazine replaces p-methoxyphenyl piperazine, obtains target compound.
White powder, productivity is 85%, Mp:148.5-149.9 DEG C of .1H NMR (400MHz, CDCl3):3.102(s,4H),3.438-3.489(m,4H),4.344-4.385(m,4H),5.164(s,1H),5.590-5.611(m,1H),7.003-7.044(m,2H),7.185-7.240(m,2H),7.491-7.519(m,2H)。
Embodiment 12
The preparation of 5-(2,3-dihydrobenzo [b] [1,4] dioxine-6-base)-3-((4-(3-methoxyphenyl) piperazine-1-base) methyl)-1,3,4-diazole-2 (3H)-thioketone.
Preparation method is with embodiment 1.Replace p-methoxyphenyl piperazine with m-methoxyphenyl piperazine, obtain target compound.
White powder, productivity is 80%, Mp:155.4-155.8 DEG C of .1H NMR (400MHz, CDCl3):3.046-3.070(m,4H),3.232-3.257(m,4H),3.813-3.845(m,3H),4.342-4.382(m,4H),5.161(s,2H),6.458-6.491(m,2H),6.556-6.576(m,1H),6.990-7.011(m,1H),7.184-7.225(m,1H),7.468-7.500(m,2H)。
Embodiment 13
The preparation of 3-((4-(3,4-Dichlorobenzene base) piperazine-1-base) methyl)-5-(2,3-dihydrobenzo [b] [1,4] dioxine-6-base)-1,3,4-diazole-2 (3H)-thioketone.
Preparation method is with embodiment 1.With 3,4-dichlorophenylpiperazine replaces p-methoxyphenyl piperazine, obtains target compound.
White powder, productivity is 85%, Mp:159.2-159.9 DEG C of .1H NMR (400MHz, CDCl3): 3.031-3.056 (m, 2H), 3.212-3.237 (m, 2H), 3.431 (s, 2H), 3.520-3.534 (m, 2H), 4.343-4.384 (m, 4H), 5.154 (s, 1H), 5.590-5.611 (m, 1H), 6.773 (s, 1H), 6.971-7.041 (m, 2H), 7.373-7.395 (d, J=8.8Hz, 1H), 7.466-7.493 (m, 2H).
Embodiment 14
3 (4-benzyl diethylenediamine-1-base) methyl) preparation of-5-(2,3-dihydrobenzo [b] [1,4] dioxine-6-base)-1,3,4-diazole-2 (3H)-thioketone.
Preparation method is with embodiment 1.Replace p-methoxyphenyl piperazine with benzyl piperazine, obtain target compound.
White powder, productivity is 85%, Mp:97.8-98.2 DEG C of .1H NMR (400MHz, CDCl3):2.544(s,4H),2.967(s,4H),3.578-3.588(m,2H),4.341-4.382(m,4H),5.093(s,2H),6.984-7.044(m,1H),7.349(s,3H),7.380-7.393(m,2H),7.451-7.482(m,2H)。
Embodiment 15
The product obtaining embodiment 1-14 carries out following Anticancer Activities:
1, experiment material
1.1 cell strain
Human liver cancer cell (human hepatocellular liver carcinoma cell line)；HepG2
Human cervical carcinoma cell (human cervical cancer cells)；HELA
Human colon cancer cell (human colon cancer cells)；SW1116
Gastric carcinoma cells (human gastric cancer cells)；BGC823
1.2 reagent
RPMI 1640 culture medium (GIBCO), new-born calf serum (Hangzhou Ilex purpurea Hassk.[I.chinensis Sims biological engineering material), trypsin Sigma), MTT (Sigma), (the Shandong auspicious sun pharmacy of injection streptomycin, 1g 1,000,000 unit /), benzylpenicillin sodium for injection (the anti-medicine in Shandong, Shandong, 800,000 units /).Other conventional chemical reagent is domestic analytical pure.
2, experimental technique
The preparation of 2.1 culture medium
RPMI 1640 culture medium (Gibcio USA) one bag adds water one liter, adds 2g sodium bicarbonate, 100,000 units of Penicillin and 100mg streptomycin, and regulation pH value is to 7.4, degerming with the degerming membrane filtration of 0.22mm.90mL culture medium adds inactivation new-born calf serum 10mL and is complete culture solution.Trypsin D-hanks buffer is made into 0.25% solution, and after filtration sterilization, 4 DEG C save backup.
The preparation of 2.2 medicinal liquids
Accurately weigh sample 1.0mg, be added in the 1.5mL centrifuge tube of sterilizing, add DMSO 1mL, be made into 1mg/mL stock solution ,-40 DEG C of freezen protective.It is diluted to respective concentration application with appropriate D-hanks after melting before use.
2.3 cells are cultivated and pass on
The equal adhere-wall culture of cell is in containing in 10mL complete culture solution Tissue Culture Flask, in 37 DEG C, 5%CO2, cultivate under saturated humidity.Cell cover with bottle at the bottom of after wash twice with sterilizing D-hanks liquid, add 0.25% trypsin digestion and cell 2min, outwell trypsin, after jog cell can completely fall off, after adding complete culture solution 30mL, dispel cell with pipet, it is sub-packed in 3 new Tissue Culture Flasks, continues to cultivate.
2.4 active anticancer tests
Take one bottle of the cell just growing up to intact monolayer, cell is collected after trypsinization, with pipet piping and druming uniformly, take two cell suspension trypan blue (Trypan Blue) dyeing, in counted under microscope number of viable cells (dead cell number must not exceed 5%), adjust cell number to 1 × 10 with complete culture solution4Individual cell/mL.In 96 porocyte culture plates, every hole adds 100 μ L cell suspension, and culture plate is placed in CO2Incubator is cultivated 24h, in every hole, the 11 μ L solution containing variable concentrations sample is added after taking out culture plate, medicine final concentration is made to be respectively 100,50,25,12.5,6.25 and 3.125 μ g/mL, each concentration sets 3 parallel holes, separately sets 6 porocytes and makees normal control hole and positive cisplatin control wells.After adding medicine, culture plate vibrates mixing on microwell plate agitator, is placed in CO2Incubator continues cultivate 24h.Taking out culture plate, every hole adds the MTT liquid of 25 μ L 5mg/mL, vibration mixing, continues to cultivate 4h.10min is cultivated after adding every hole 100 μ L DMSO.Microplate reader measures each hole light and absorbs (OD value), measures wavelength 490nm.According to each hole OD value by the CalcuSyn computed in software medicine suppression ratio to four kinds of cell proliferation, i.e. IC50Value, experimental result is shown in Table 1.
Table 1 medicine inhibiting tumor cell proliferation experiment
aThree parallel laboratory tests, experimental result averages, and error is between 5%-10%.
Claims (9)
1. the bridged piperazine derivatives containing diazole, it is characterised in that its structural formula is as follows:
Wherein, the one during R is following group:
2. the preparation method of the bridged piperazine derivatives containing diazole described in a claim 1, it is characterised in that include following step
Rapid:
(1) PCA, concentrated sulphuric acid, methanol being carried out back flow reaction, TLC detection, until raw material disappears, obtains
Solid product；
(2) solid product that step (1) obtained, acetone, Bromofume, potassium carbonate carry out back flow reaction, obtain solid
Product；
(3) solid product that step (2) obtained, ethanol, hydrazine hydrate carry out back flow reaction, obtain solid product；
(4) solid product that step (3) obtained, ethanol, Carbon bisulfide, potassium hydroxide carry out back flow reaction, then steam
Dry, add distilled water and dissolve, filter, the filtrate obtained adjusts its pH value to 4～5 with dilute hydrochloric acid, filters, separates out to obtain solid product；
(5) solid product that step (4) obtained, the phenylpiperazine of substituent group, ethanol, formaldehyde through stirring at normal temperature, filtration,
Obtain the bridged piperazine derivatives containing diazole.
The preparation method of the bridged piperazine derivatives containing diazole the most according to claim 2, it is characterised in that: step (1)
In, PCA, concentrated sulphuric acid, the usage ratio of methanol are 1:0.1:5, and wherein, PCA is with mmol
Meter, concentrated sulphuric acid, methanol are all in terms of mL.
The preparation method of the bridged piperazine derivatives containing diazole the most according to claim 2, it is characterised in that: step (2)
In, solid product that step (1) obtains, acetone, Bromofume, the usage ratio of potassium carbonate are 1:20:1:1.5, wherein,
Solid product that step (1) obtains, Bromofume, potassium carbonate all in terms of mmol, acetone in terms of mL, reflux time
For 15h.
The preparation method of the bridged piperazine derivatives containing diazole the most according to claim 2, it is characterised in that: step (3)
In, solid product that step (2) obtains, ethanol, the usage ratio of hydrazine hydrate are 0.1:2:0.5, wherein, step (2)
To solid product in terms of mmol, ethanol, hydrazine hydrate are all in terms of mL, and reflux time is 15h.
The preparation method of the bridged piperazine derivatives containing diazole the most according to claim 2, it is characterised in that: step (4)
In, solid product that step (3) obtains, ethanol, Carbon bisulfide, the usage ratio of potassium hydroxide are 1:20:1:1, wherein,
Solid product that step (3) obtains, Carbon bisulfide, potassium hydroxide are all in terms of mmol, and ethanol is in terms of mL, during back flow reaction
Between be 24h.
The preparation method of the bridged piperazine derivatives containing diazole the most according to claim 2, it is characterised in that: step (5)
In, solid product that step (4) obtains, the phenylpiperazine of substituent group, ethanol, the usage ratio of formaldehyde are 1:1:20:1.5,
Wherein, the phenylpiperazine of solid product, phenylpiperazine or substituent group that step (4) obtains, formaldehyde all in terms of mmol, ethanol
In terms of mL, stirring at normal temperature 12h.
The preparation method of the bridged piperazine derivatives containing diazole the most according to claim 2, it is characterised in that: step (5)
In, substituted phenylpiperazine be Chloro-O-Phenyl piperazine, benzyl piperazine, o-methoxyphenyl piperazine, p-methoxyphenyl piperazine,
To fluorophenyl piperazine, Pyridylpiperazine, adjacent fluorophenyl piperazine, p-nitrophenyl piperazine, rubigan piperazine, 2,3-Dichlorobenzene base
In piperazine, 3,4-dichlorophenylpiperazine, m-methoxyphenyl piperazine, diphenylmethyl piperazine or m-trifluoromethyl phenylpiperazine one
Kind.
9. the purposes of the bridged piperazine derivatives containing diazole described in a claim 1, it is characterised in that: containing diazole
Bridged piperazine derivatives is used for preparing cancer therapy drug.
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