CN104402821A - Nitrogen-oxygen free radical compound with anti-hypoxia injury activity and preparation and application thereof - Google Patents

Nitrogen-oxygen free radical compound with anti-hypoxia injury activity and preparation and application thereof Download PDF

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CN104402821A
CN104402821A CN201410726409.1A CN201410726409A CN104402821A CN 104402821 A CN104402821 A CN 104402821A CN 201410726409 A CN201410726409 A CN 201410726409A CN 104402821 A CN104402821 A CN 104402821A
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hypoxia
free radical
phenyl aldehyde
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phenyl
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景临林
马慧萍
樊鹏程
何蕾
蒙萍
贾正平
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/22—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention discloses a nitrogen-oxygen free radical compound with anti-hypoxia injury activity. The structural general formula of the nitrogen-oxygen free radical compound is shown as the following formula. Animal activity tests show that the nitrogen-oxygen free radical compound can enable the contents of H2O2, NO, MDA and LD in the brain tissue of an anoxic mouse to tend to be normal, enable the SOD, GSH-px and LDH activities to be significantly improved, enable the CAT activity to tend to be normal, and enable the anoxic mouse to have a remarkable anti-hypoxia activity; the nitrogen-oxygen free radical compound has a remarkable prevention and treatment effect on acute high altitude diseases, cerebral ischemia and hypoxia diseases and myocardial ischemia hypoxia diseases caused by hypobaric hypoxia on plateau.

Description

There is nitroxyl free radical compounds and the Synthesis and applications thereof of anti-hypoxia damagine activity
Technical field
The field of chemical synthesis of the present invention and medical applications field, relate to a kind of nitroxyl free radical compounds, particularly relates to the nitroxyl free radical compounds that a class has anti-hypoxia damagine activity; The present invention also relates to the synthetic method of this compound simultaneously and is preparing anti-hypoxia from the application damage medicine.
Background technology
Along with the continuous quickening of people's rhythm of life, anoxic has become the quite general pathological phenomenon of a class.Various factors, such as, in environment, in air, oxygen level or oxygen partial pressure reduce, and suffer from the systemic diseases such as breathing, blood, circulation and body oxygen consumption and are greater than feed rate body all can be caused to occur hypoxic conditions.Particularly the environment of the hypobaric hypoxia that highlands is special usually make just to the people of highland tour and work occur headache, palpitaition, uncomfortable in chest, breathe hard, the acute high altitude reaction such as weak, somnopathy, Nausea and vomiting, the fatal disease such as plateau pneumochysis, HACE is also there will be time serious, long term hypoxia also can cause chronic plateau sickness, has a strong impact on the healthy of high aborigines or sojourner.The control of prevention and therapy body anoxic of actively taking measures to the many diseases comprising acute high altitude sickness has a very important role.Current anti-hypoxia injury protection medicine is very deficient, in the urgent need to developing the anti-hypoxia injury protection medicine of efficient economy.
Research shows: anoxic can cause body oxidative stress, mitochondrial oxy-reduction pathway activation, and antioxidant system is lost compensatory, and free radical produces to be increased, thus causes the generation of Anoxic Phase related disorders.Nitroxyl free radical is a kind of new free-radical scavenger, has provide protection by removing the crossing polyradical of body generation to anoxia-induced apoptosis.Therefore, the nitroxyl free radical compounds of design and synthesis novel texture, to having anti-hypoxia damagine activity, and obtains application preparing in anti-hypoxia injury protection medicine.
Summary of the invention
The object of this invention is to provide the nitroxyl free radical compounds that a class has anti-hypoxia damagine activity;
Another object of the present invention is to provide a kind of synthetic method with the nitroxyl free radical compounds of anti-hypoxia damagine activity;
The prior object of the present invention, is just to provide this nitroxyl free radical compounds and is preparing the application in anti-hypoxia damage medicine.
One, nitroxyl free radical compounds
The present invention has the nitroxyl free radical compounds of anti-hypoxia damagine activity, and its general structure is as follows:
Wherein n=1 ~ 3; R is 1-(2-p-methoxy-phenyl) piperazine, 1-(2-pyrimidyl) piperazine, 1-(2-pyridyl) piperazine, 1; 2; 4-triazole, benzotriazole, dimethylamine, diethylamine, morpholine, Pyrrolidine, hexahydropyridine, 4-piperidone, 1-(2-hydroxyethyl) piperazine, 1-methylpiperazine, 1-ethyl piperazidine, 1-Acetylpiperazine, 1-benzyl diethylenediamine, 1-php, 1; 2,3-triazole, imidazoles.
Two, the synthesis of nitroxyl free radical compounds
The synthesis of nitroxyl free radical compounds of the present invention, take p-Hydroxybenzaldehyde as raw material, first replace alkane with dibromo to react, generate 4-(n-bromine alkoxyl group) phenyl aldehyde, make 4-(n-bromine alkoxyl group) phenyl aldehyde and amine carry out N-alkylated reaction again and obtain 4-(n-(alkylamino) alkoxyl group) phenyl aldehyde, then 4-(n-(alkylamino) alkoxyl group) phenyl aldehyde and 2 is made, 3-dimethyl-2, 3-dihydroxy amido butane carries out condensation reaction and obtains 4-(n-(substituted-amino) oxyethyl group) phenyl-1, 3-hydroxy imidazole, target product is obtained finally by sodium periodate oxidation.Its concrete synthesis technique is as follows:
(1) synthesis of 4-(n-bromine alkoxyl group) phenyl aldehyde: take acetone as solvent, K 2cO 3for catalyzer, p-Hydroxybenzaldehyde and dibromo replace alkane with the mol ratio back flow reaction 6 ~ 8h of 1:1 ~ 1:2, are cooled to room temperature, use CH after decompression removing acetone 2cl 2extraction, anhydrous Na 2sO 4drying, obtains 4-(n-bromine alkoxyl group) phenyl aldehyde; Structural formula is as follows:
It is glycol dibromide, 1,3-dibromopropane and Isosorbide-5-Nitrae-dibromobutane that above-mentioned dibromo replaces alkane; K 2cO 3consumption be 1 ~ 3 times of p-Hydroxybenzaldehyde molar weight.
(2) synthesis of 4-(n-(alkylamino) alkoxyl group) phenyl aldehyde: take acetonitrile as solvent, K 2cO 3for catalyzer, make 4-(n-bromine alkoxyl group) phenyl aldehyde and amine with the mol ratio back flow reaction 8 ~ 10h of 1:1 ~ 1:2; Cool to room temperature after reacting completely, filters, washing, column chromatography for separation, and obtain 4-(n-(alkylamino) alkoxyl group) phenyl aldehyde, its structural formula is as follows:
Above-mentioned amine is diethylamine, Pyrrolidine, hexahydropyridine, morpholine, piperidone, 1-(2-hydroxyl) piperazine, 1-methylpiperazine, 1-ethyl piperazidine, 1-Acetylpiperazine, 1-benzyl diethylenediamine, 1-php, 1-(2-p-methoxy-phenyl) piperazine, 1-(2-pyrimidyl) piperazine dihydrochloride, 1-(2-pyridyl) piperazine, imidazoles, 1,2,3-triazole, 1,2,4-triazole, benzotriazole; K 2cO 3consumption be 1 ~ 3 times of 4-(n-bromine alkoxyl group) phenyl aldehyde molar weight.
(3) 4-(n-(substituted-amino) oxyethyl group) phenyl-1, the synthesis of 3-hydroxy imidazole: take methyl alcohol as solvent, 4-(n-(alkylamino) alkoxyl group) phenyl aldehyde and 2,3-dimethyl-2,3-dihydroxy amido butane is with mol ratio back flow reaction 10 ~ 15 h of 1:0.8 ~ 1:1.2; Be cooled to removal of solvent under reduced pressure after room temperature, obtain 4-(n-(substituted-amino) oxyethyl group) phenyl-1,3-hydroxy imidazole, its structural formula is as follows:
(4) synthesis of target product: in methylene dichloride, 4-(n-(substituted-amino) oxyethyl group) phenyl-1,3-hydroxy imidazole and sodium periodate are with the mol ratio of 1:0.8 ~ 1:1.2, stopped reaction after-5 ~ 5 DEG C of vigorous stirring 10 ~ 20min, stratification, aqueous phase dichloromethane extraction, anhydrous Na 2sO 4drying, filters, and after removal of solvent under reduced pressure, rapid column chromatography is separated, and obtains target product.Structural formula is as follows:
In above steps; involved n=1 ~ 3; R is 1-(2-p-methoxy-phenyl) piperazine, 1-(2-pyrimidyl) piperazine, 1-(2-pyridyl) piperazine, 1; 2; 4-triazole, benzotriazole, dimethylamine, diethylamine, morpholine, Pyrrolidine, hexahydropyridine, 4-piperidone, 1-(2-hydroxyethyl) piperazine, 1-methylpiperazine, 1-ethyl piperazidine, 1-Acetylpiperazine, 1-benzyl diethylenediamine, 1-php, 1; 2,3-triazole, imidazoles.
Three, the anti-hypoxia damagine activity of nitroxyl free radical compounds
Below for the nitroxyl free radical compounds 5 of embodiment 5,12 preparation and compound 12, by experimentation on animals, its anti-hypoxia damagine activity is described.
1. pair mouse airtight anoxia tolerance experiment
1.1 experimental techniques: get healthy BALB/C mice 80, male, adaptability is divided into 8 groups after raising 3d at random: anoxia model group, acetazolamide group (200mg.kg -1), compound 5 high dose group (200mg.kg -1), middle dosage group (100mg.kg -1), low dose group (50mg.kg -1), compound 12 high dose group (200mg.kg -1), middle dosage group (100mg.kg -1), low dose group (50mg.kg -1), often organize 10.Single intraperitoneal injection administration, administration volume is 0.4 mL20g -1, anoxia model group gives isopyknic physiological saline.30min after administration, puts into the 250 mL wide-necked bottles (only putting 1 mouse for every bottle) filling 5 g sodica calxs respectively, smears bottleneck with Vaseline by mouse, sealing, makes it air tight, immediately timing, until breath stopped.With mouse in airtight wide-necked bottle the survival time for index, more each medicine group hypoxia endurance time.The results are shown in Table 1.
1.2 experimental results: as shown in table 1 result, compared with anoxia model group, compound 5 and middle and high group of compound 12 all can extend the survival time of mouse in atmospheric closed anaerobic environment, and there is certain dose-dependently, wherein the survival time of compound 5 and compound 12 high dose group is better than acetazolamide positive controls.
 
2. pair chmice acute hypobaric hypoxia tolerance experiment
2.1 experimental techniques: get healthy mice 80, male, raising property is divided into 4 groups after adapting to 3d at random: anoxia model group, acetazolamide control group (200mg.kg -1), compound 5 groups of (200mg.kg -1) and compound 12 groups of (200mg.kg -1) often organize 20.Single intraperitoneal injection administration, administration volume is 0.4 mL20g -1, anoxia model group gives isopyknic physiological saline.30min after administration, animal is put into hypobaric chamber, airtight hatch door, with the speed of 1000 m/min decompression rising sea level elevation to difference each stop 5min during 5000m and 8000m, finally rises to sea level elevation 10000m, after maintaining this height 1h, regulate inlet hole valve, be slowly down to normal sea level elevation, open hatch door, observe mortality of animals in statistics 1h, and variance analysis is carried out to experimental result.
2.2 experimental results: as shown in table 2 result, compare with acetazolamide group with anoxia model group, compound 5 and compound 12 can extend mouse decompression the airtight anoxia survival time ( p﹤ 0.01), in 1h, mortality ratio is respectively 40% and 50%, illustrates that compound 5 and compound 12 effectively can reduce the mortality ratio of mouse under Conditions of Acute Hypoxia in Human Body.
3. the provide protection of pair simulated high altitude hypoxia mice brain tissue impairment
3.1 experimental technique
Get healthy BABL/C mouse 40, male, adaptability is divided into 4 groups after raising 3d at random: Normal group, anoxia model group, acetazolamide group (200 mg/kg), compound 5 groups (200 mg/kg) and compound 12 groups (200 mg/kg), often organizes 10.Single intraperitoneal injection administration, administration volume is 0.4 mL20g -1anoxia model group gives isopyknic physiological saline, normal group mouse not anoxic, 20min after administration, all the other are respectively organized mouse and put into hypobaric hypoxia animal experimental chamber, airtight hatch door, with 10m/s speed decompression rising sea level elevation to 8000m, after maintaining this height 9h, regulate air inlet port valve, be down to sea level elevation identical with external atmosphere pressure (being equivalent to 1450m sea level elevation) with 20m/s speed, open hatch door, live rapidly and kill mouse, win brain, physiological saline washes three times, and filter paper blots, and-80 DEG C of refrigerator cold-storages are for subsequent use.Detecting for measuring biochemical indicator, all operating according to test kit specification sheets.The results are shown in Table 3,4,5.
3.2 experimental result
3.2.1 to simulated high altitude hypoxia mice cerebral tissue H 2o 2, NO and MDA impact
As shown in table 3, compared with Normal group, anoxia model group cerebral tissue H 2o 2, NO and MDA content significantly raises (P<0.01).Compared with anoxia model group, after using compound 5 and compound 12 administration process in advance, Mice brain tissues H 2o 2, NO and MDA content significantly reduces (P<0.01).
3.2.2 the impact of simulated high altitude hypoxia mice cerebral tissue LD and LDH
As shown in table 4 result, compared with Normal group, anoxia model group Mice brain tissues LD content significantly raises (P ﹤ 0.01), and LDH vigor obviously reduces (P ﹤ 0.05); Compared with anoxia model group, after using compound 5 and compound 12 administration process in advance, Mice brain tissues LD content significantly reduces (P ﹤ 0.01), and LDH vigor significantly rises (P ﹤ 0.01).
 
3.2.3 on the impact of simulated high altitude hypoxia mice cerebral tissue SOD, CAT and GSH-Px
As shown in table 5, compared with Normal group, anoxia model group Mice brain tissues SOD and GSH-Px vigor significantly reduce (P<0.01), and CAT vigor compensatory raises; Compared with anoxia model group, after using compound 5 and compound 12 administration process in advance, Mice brain tissues SOD and GSH-Px vigor significantly raise (P<0.01), and CAT is tending towards normal group (P<0.01).
Comprehensive above experimental result, shows that compound 5 and compound 12 make hypoxia mice cerebral tissue H 2o 2, NO, MDA and LD content is tending towards normal, SOD, GSH-px and LDH vigor significantly improves, CAT vigor is tending towards normal, show effectively to remove in hypoxia mice cerebral tissue the too much free radical produced, reduce lipid peroxidation, improve antioxidant ability of organism, alleviate the damage caused because of anoxic, there is good oxygen lack resistant function, and effect has and is better than acetazolamide.
A large amount of activity test confirms, other nitroxyl free radical compounds of the present invention's synthesis is the same with compound 12 with compound 5, all can make hypoxia mice cerebral tissue H 2o 2, NO, MDA and LD content is tending towards normal, SOD, GSH-px and LDH vigor significantly improves, CAT vigor is tending towards normal, have good hypoxia tolerance, acute high altitude sickness, cerebral ischemia/anoxia disease and the myocardial ischemia-anoxemia disease etc. that cause for plateau low-pressure hypoxia have obvious preventive and therapeutic effect.Can be used for preventing and treating hypoxic damage or treating the various anoxic pathological states caused because external environment oxygen level reduces, also can be used for prevention or treat because disease etc. causes extraneous normal oxygen amount fully not arrive in body, causing the anoxic pathological states such as the heart, brain and respiratory system; Can also be used for preventing or treating causing relative oxygen for not enough pathological state because body activities requisite oxygen consumption has exceeded the physiology ability of mobilization.
In actual applications, with the nitroxyl free radical compounds of said structure for activeconstituents, be combined with pharmaceutically conventional dressing, conventionally make tablet, capsule, dispersion agent, granule, injection liquid, injection freeze-dried powder injection etc.
Embodiment
Be described further below in conjunction with the synthesis of specific embodiment to nitroxyl free radical compounds of the present invention.
The synthesis of embodiment one, compound 1 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: by 1.22 g(10 mmol) 4-hydroxy benzaldehyde, 2.07g(15 mmol) K 2cO 3with 2.82 g(15 mmol) glycol dibromide is dissolved in 50 mL acetone, back flow reaction 8 h, stopped reaction, and after cool to room temperature, decompression removing acetone, adds 100 mL water, uses CH 2cl 2extraction (50 mL × 3), merges organic phase, anhydrous Na 2sO 4dried overnight, filters, and after removal of solvent under reduced pressure, rapid column chromatography is separated, and obtains 4-(2-bromine oxethyl) phenyl aldehyde.White solid 1.83 g, productive rate 80%. 1H-NMR（CDCl 3，400 MHz） δ: 9.89（s，1H），7.85（d， J=8.8 Hz，2H），7.02（d， J=8.4 Hz，2H），4.38（t， J=6.0 Hz，2H），3.68（t， J＝6.0 Hz，2H）。ESI-MS（m/z）: 230 [M+H] +。
(2) synthesis of 4-(2-(dimethyl amido) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol dimethylamine hydrochlorides, back flow reaction 10 h, after TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains 4-(2-(dimethyl amido) oxyethyl group) phenyl aldehyde.Pale yellow oil 1.37 g, productive rate 71%. 1H-NMR（CDCl 3，400 MHz） δ: 9.89（s，1H），7.83（d， J=8.4 Hz，2H），7.03（d， J=8.8 Hz，2H），4.15（t， J=5.6 Hz，2H），2.77（t， J=5.2 Hz，2H），2.36（s，6H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.8，163.9，131.9，129.8，114.8，66.4，58.0，45.9。ESI-MS（m/z）: 194 [M+H] +。Anal. Calcd for C 11H 15NO 2，C，68.37；H，7.82；N，7.25。Found: C，66.42；H，7.86。N，7.09。
(3) synthesis of compound 1: by 0.96 g(5.0 mmol) 4-(2-(dimethyl amido) oxyethyl group) phenyl aldehyde and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in 25 mL methyl alcohol, back flow reaction 12 h.Decompression removing methyl alcohol, resistates is scattered in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains blue oily matter 0.82 g, productive rate 51%.ESI-MS (m/z): 321 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.54G.IR（KBr）: 2929，1604，1454，1388，1361，1301，1253，1132，1036，839。Anal. Calcd for C 17H 26N 3O 3: C，63.73；H，8.18；N，13.11。Found: C，63.81；H，8.23；N，13.05。Its structural formula is as follows:
。
The synthesis of embodiment two, compound 2 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) synthesis of 4-(2-(diethyl amido) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol diethylamine, back flow reaction 11 h, after TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains 4-(2-(diethyl amido) oxyethyl group) phenyl aldehyde.Pale yellow oil 1.50 g, productive rate 68%. 1H-NMR（CDCl 3，400 MHz） δ: 9.88（s，1H），7.83（d， J=8.8 Hz，2H），7.01（d， J=8.4 Hz，2H），4.13（t， J=6.0 Hz，2H），2.90（t， J=6.0 Hz，2H）2.68~2.62（m，4H），1.08（t， J=6.8 Hz，6H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.8，163.9，131.9，129.8，114.8，67.1，51.5，47.9，11.8。ESI-MS（m/z）: 222 [M+H] +。Anal. Calcd for C 13H 19NO 2，C，70.56；H，8.65；N，6.33。Found: C，70.50；H，8.57。N，6.41。
(3) synthesis of compound 2: by 1.10 g(5.0 mmol) 4-(2-(diethyl amido) oxyethyl group) phenyl aldehyde and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in 25 mL methyl alcohol, back flow reaction 14 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains blue oily matter 0.92 g, productive rate 53%.ESI-MS (m/z): 349 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.77G.IR（KBr）: 2971，2934，1605，1470，1390，1362，1302，1257，1132，1040，835。Anal. Calcd for C 19H 30N 3O 3: C，65.49；H，8.68；N，12.06。Found: C，65.66；H，8.61；N，11.94。Its structural formula is:
。
Embodiment three: the synthesis of compound 3 and and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) synthesis of 4-(2-(Pyrrolidine base) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol Pyrrolidines, after back flow reaction 17 h, TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains pale yellow oil 1.35 g, productive rate 62%. 1H-NMR（CDCl 3，400 MHz） δ: 9.88（s，1H），7.83（d， J=8.4 Hz，2H），7.02（d， J=8.8 Hz，2H），4.21（t， J=5.6 Hz，2H），2.95（t， J=6.0 Hz，2H），2.65（s，4H），1.86（s，4H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.7，163.7，131.9，129.9，114.8，67.3，54.6，23.4。ESI-MS（m/z）: 220 [M+H] +。Anal. Calcd for C 13H 17NO 2，C，71.21；H，7.81；N，6.39。Found: C，71.28；H，7.76。N，6.35。
(3) synthesis of compound 3: by 5.0 mmol step (2) products therefroms and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 15 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains blue oily matter 0.95 g, productive rate 55%.ESI-MS (m/z): 347 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.74G.IR（KBr）: 2940，2780，1603，1477，1385，1361，1302，1258，1161，1026，831。Anal. Calcd for C 19H 28N 3O 3: C，65.87；H，8.15；N，12.13。Found: C，65.61；H，8.23；N，12.04。Its structural formula is as follows:
。
Embodiment four: the synthesis of compound 4 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) synthesis of 4-(2-(hexahydropyridine base) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol hexahydropyridines, after back flow reaction 16 h, TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains pale yellow oil 1.53 g, productive rate 66%. 1H-NMR（CDCl 3，400 MHz） δ: 9.88（s，1H），7.83（d， J=8.4 Hz，2H），7.01（d， J=8.4 Hz，2H），4.18（t， J=6.0 Hz，2H），2.80（t， J=6.0 Hz，2H），2.51（s，4H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.7，163.8，131.9，129.8，114.8，66.3，57.6，55.0，25.8，24.0。ESI-MS（m/z）: 234 [M+H] +。Anal. Calcd for C 14H 19NO 2，C，72.07；H，8.21；N，6.00。Found: C，72.12；H，8.16。N，6.05。
(3) synthesis of compound 4: by 5.0 mmol step (2) products therefroms and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 13 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains blue solid 0.90 g, productive rate 50%.ESI-MS (m/z): 361 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.76G.IR（KBr）: 2928，2788，1605，1470，1388，1361，1306，1255，1129，1027，842。Anal. Calcd for C 20H 30N 3O 3: C，66.64；H，8.39；N，11.66。Found: C，65.61；H，8.23；N，12.04。Its structure is as follows:
。
Embodiment five: the synthesis of compound 5 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) synthesis of 4-(2-(N-morpholinyl) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol morpholines, after back flow reaction 11 h, TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains pale yellow oil 1.43 g, productive rate 61%. 1H-NMR（CDCl 3，400 MHz） δ: 9.88（s，1H），7.84（d， J=8.8 Hz，2H），7.01（d， J=8.4 Hz，2H），4.20（t， J=6.0 Hz，2H），3.73（3，4H），2.82（t， J=5.6 Hz，2H），2.38（s，4H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.6，163.6，131.8，129.9，114.7，66.7，66.1，57.2，49.3。ESI-MS（m/z）: 236 [M+H] +。Anal. Calcd for C 13H 17NO 3，C，66.36；H，7.28；N，5.95。Found: C，66.31；H，7.19。N，6.08。
(3) synthesis of compound 3: by the above-mentioned product of 5.0 mmol and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 12 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains blue solid 0.87 g, productive rate 48%.ESI-MS (m/z): 363 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.78G.IR（KBr）: 2990，2933，1610，1493，1390，1363，1304，1260，1219，117,7，1040，836，799。Anal. Calcd for C 19H 28N 3O 4: C，62.96；H，7.79；N，11.59。Found: C，62.86；H，7.71；N，11.63。Its structural formula is as follows:
。
Embodiment six: the synthesis of compound 6 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) synthesis of 4-(2-(N-piperidone base) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol piperidone, after back flow reaction 12 h, TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains white solid 1.50 g, productive rate 62%. 1H-NMR（CDCl 3，400 MHz） δ: 9.89（s，1H），7.85（d， J=8.4 Hz，2H），7.03（d， J=8.4 Hz，2H），4.24（t， J=5.6 Hz，2H），2.98（t， J=5.6 Hz，2H），2.90（t， J=6.0 Hz，4H），2.49（t， J=6.0 Hz，4H）。 13C-NMR（CDCl 3，100 MHz） δ: 208.5，190.6，163.5，131.9，130.0，114.7，66.6，55.7，53.5，41.1。ESI-MS（m/z）: 248 [M+H] +。Anal. Calcd for C 14H 17NO 3，C，68.00；H，6.93；N，5.66。Found: C，68.11；H，6.96。N，5.59。
(3) synthesis of compound 6: by 5.0 mmol step (2) products therefroms and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 13 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains blue solid 0.84 g, productive rate 45%.ESI-MS (m/z): 375 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.74G.IR（KBr）: 2989，2957，1715，1606，1489，1386，1362，1305，1256，1134，1024，838。Anal. Calcd for C 20H 28N 3O 4: C，64.15；H，7.54；N，11.22。Found: C，64.06；H，7.55；N，11.29。Its structural formula is as follows:
。
Embodiment seven: the synthesis of compound 7 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) synthesis of 4-(2-(N-(4-hydroxyethyl) piperazinyl) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol1-(2-hydroxyethyl) piperazine, back flow reaction 16 h, after TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains pale yellow oil 1.53 g, productive rate 55%. 1H-NMR（CDCl 3，400 MHz） δ: 9.88（s，1H），7.83（d， J=8.8 Hz，2H），7.01（d， J=8.8 Hz，2H），4.19（t， J=5.6 Hz，2H），3.63（t， J=4.8 Hz，2H），2.85（t， J=5.6 Hz，4H），2.63,（s，2H），2.56（t， J=5.6 Hz，6H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.7，163.7，131.9，130.0，114.7，66.2，59.2，55.7，56.8，53.5，52.7。ESI-MS（m/z）: 279 [M+H] +。Anal. Calcd for C 15H 22N 2O 3，C，64.73；H，7.97；N，10.06。Found: C，64.68；H，7.89。N，10.12。
(3) synthesis of compound 6: by 5.0 mmol step (2) products therefroms and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 12 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains mazarine oily matter 1.07 g, productive rate 53%.ESI-MS (m/z): 406 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.77G.IR（KBr）: 3503，3412，2939，2829，1603，1459，1389，1359，1302，1255，1161，1136，960，834。Anal. Calcd for C 21H 33N 4O 4: C，62.20；H，8.20；N，13.82。Found: C，62.18；H，8.23；N，13.76。Its structural formula is as follows:
。
Embodiment eight: the synthesis of compound 8 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) synthesis of 4-(2-(N-(4-methyl) piperazinyl) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol1-methylpiperazines, after back flow reaction 12 h, TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains pale yellow oil 1.63 g, productive rate 66%. 1H-NMR（CDCl 3，400 MHz） δ: 9.88（s，1H），7.83（d， J=8.4 Hz，2H），7.01（d， J=8.4 Hz，2H），4.19（t， J=5.6 Hz，2H），2.85（t， J=5.2 Hz，2H），2.63,（s，4H），2.48（s，4H），2.29（s，3H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.6，163.6，131.8，129.8，114.7，66.2，56.7，54.8， 53.4，45.9。ESI-MS（m/z）: 249 [M+H] +。Anal. Calcd for C 14H 20N 2O 2，C，67.71；H，8.12；N，11.28。Found: C，67.67；H，8.06。N，11.15。
(3) synthesis of compound 8: by 5.0 mmol step (2) products therefroms and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 12 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains mazarine oily matter 1.03 g, productive rate 55%.ESI-MS (m/z): 376 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.67G.IR（KBr）: 3440，2938，2802，1603，1458，1361，1302，1257，1164，835。Anal. Calcd for C 20H 31N 4O 3: C，63.97；H，8.32；N，14.92。Found: C，63.89；H，8.41；N，14.97。Its structural formula is as follows:
。
Embodiment nine: the synthesis of compound 9 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) synthesis of 4-(2-(N-(4-ethyl) piperazinyl) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol1-ethyl piperazidines, after back flow reaction 13h, TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains yellow oil 1.86 g, productive rate 71%. 1H-NMR（CDCl 3，400 MHz） δ: 9.88（s，1H），7.83（d， J=8.8 Hz，2H），7.01（d， J=8.4 Hz，2H），4.19（t， J=5.6 Hz，2H），2.86（t， J=5.6 Hz，2H），2.65,（s，4H），2.52（s，4H），2.45~2.40（m，2H），1.09（t， J=7.2 Hz，3H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.7，163.8，131.9，129.9，114.8，66.2，56.9，53.6，52.6，52.2，11.9。ESI-MS（m/z）: 263 [M+H] +。Anal. Calcd for C 15H 22N 2O 2，C，68.67；H，8.45；N，10.68。Found: C，68.61；H，8.39。N，10.59。
(3) synthesis of compound 9: by 5.0 mmol step (2) products therefroms and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 12 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains blue solid 0.93 g, productive rate 48%.ESI-MS (m/z): 390 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.66G.IR（KBr）: 3443，2935，2819，1604，1456，1389，1360，1303，1257，1182，1133，838。Anal. Calcd for C 21H 33N 4O 3: C，64.75；H，8.54；N，14.38。Found: C，64.88；H，8.55；N，14.32。Its structural formula is as follows:
。
Embodiment ten: the synthesis of compound 10 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) synthesis (preferably can name) of 4-(2-(N-(4-ethanoyl) piperazinyl) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol1-Acetylpiperazine, after back flow reaction 11h, TLC monitoring reacts completely, by reaction system cool to room temperature; filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile; rapid column chromatography is separated, and obtains pale yellow oil 1.43 g, productive rate 52%. 1H-NMR（CDCl 3，400 MHz） δ: 9.89（s，1H），7.84（d， J=8.8 Hz，2H），7.01（d， J=8.4 Hz，2H），4.20（t， J=5.6 Hz，2H），3.65（t， J=4.8 Hz，2H），3.50（t， J=4.8 Hz，2H），2.87（t， J=5.6 Hz，2H），2.60（t， J=5.2 Hz，2H），2.56（t， J=5.2 Hz，2H），2.09（s，3H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.7，168.9，163.6，131.9，130.1，114.8，66.2，56.8，53.6，53.1，46.2，41.3，21.2。ESI-MS（m/z）: 277 [M+H] +。Anal. Calcd for C 15H 20N 2O 3，C，65.20；H，7.30；N，10.14。Found: C，65.12；H，7.36。N，10.18。
(3) synthesis of compound 10: by 5.0 mmol step (2) products therefroms and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 12 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains mazarine oily matter 0.90 g, productive rate 45%.ESI-MS (m/z): 404 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.74G.IR（KBr）: 3439，2938，2813，1605，1454，1361，1301，1255，1131，834。Anal. Calcd for C 21H 31N 4O 4: C，62.51；H，7.74；N，13.89。Found: C，62.63；H，7.69；N，13.94。Its structural formula is as follows:
。
Embodiment 11: the synthesis of compound 11 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) synthesis of 4-(2-(N-(4-benzyl) piperazinyl) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol1-benzyl diethylenediamines, after back flow reaction 13 h, TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains pale yellow oil 1.78 g, productive rate 55%. 1H-NMR（CDCl 3，400 MHz） δ: 9.87（s，1H），7.82（d， J=8.8 Hz，2H），7.32~7.24（m，5H），7.01（d， J=8.4 Hz，2H），4.18（t， J=6.0 Hz，2H），3.51（s，2H），3.50（t， J=4.8 Hz，2H），2.87（t， J=5.6 Hz，2H），2.62（s，2H），2.51（s，2H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.7，168.9，163.8，138.0，131.9，130.0，129.2，128.2，127.0，114.8，66.3，63.0，56.8，54.4，53.6，52.9，46.0。ESI-MS（m/z）: 325 [M+H] +。Anal. Calcd for C 20H 24N 2O 2，C，74.04；H，7.46；N，8.64。Found: C，74.15；H，7.33。N，8.73。
(3) synthesis of compound 11: by 5.0 mmol above-mentioned steps (2) products therefroms and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 16 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains mazarine oily matter 0.95 g, productive rate 42%.ESI-MS (m/z): 452 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.77G.IR（KBr）: 3439，2938，2813，1605，1454，1361，1301，1255，1131，834。Anal. Calcd for C 26H 35N 4O 3: C，69.15；H，7.81；N，12.41。Found: C，69.13；H，7.77；N，12.48。Its structural formula is as follows:
。
Embodiment 12: the synthesis of compound 12 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) synthesis of 4-(2-(N-(4-phenyl) piperazinyl) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol1-phenylpiperazines, after back flow reaction 12 h, TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains white solid 2.39 g, productive rate 70%. 1H-NMR（CDCl 3，400 MHz） δ: 9.88（s，1H），7.84（d， J=8.4 Hz，2H），7.29~7.25（m，2H），7.02（d， J=8.8 Hz，2H），6.93（d， J=8.0 Hz，2H），6.87（t， J=6.0 Hz，1H），4.23（t， J=5.6 Hz，2H），3.23（t， J=4.8 Hz，4H），2.90（t， J=5.6 Hz，2H），2.76（t， J=4.8 Hz，4H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.7，168.9，163.7，151.1，131.9，130.0，129.1，119.7，116.0，114.8，66.3，63.0，56.9，53.6，49.1。ESI-MS（m/z）: 311 [M+H] +。Anal. Calcd for C 19H 22N 2O 2，C，73.52；H，7.14；N，9.03。Found: C，73.63；H，7.17；N，8.94。
(3) synthesis of compound 12: by the above-mentioned product of 5.0 mmol and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 15 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains blue solid 1.11 g, productive rate 51%.ESI-MS (m/z): 438 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.74G.IR（KBr）: 2935，2828，1600，1505，1454，1387，1362，1301，1251，1184，1130，834，747，688。Anal. Calcd for C 25H 33N 4O 3: C，68.62；H，7.60；N，12.80。Found: C，68.76；H，7.67；N，12.73。Its structural formula is as follows:
。
Embodiment 13: the synthesis of compound 13 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) 4-(synthesis of 2-(N-(4-(2-p-methoxy-phenyl) piperazinyl) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3with 15 mmol1-(2-p-methoxy-phenyls) piperazine is dissolved in 50 mL acetonitriles, back flow reaction 16 h, after TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains pale yellow oil 2.00 g, productive rate 59%. 1H-NMR（CDCl 3，400 MHz） δ: 9.89（s，1H），7.84（d， J=8.8 Hz，2H），7.03（d， J=8.8 Hz，2H），7.00（s，1H），6.99~6.97（m，2H），6.87（d， J=8.0 Hz，1H），4.24（t， J=5.6 Hz，2H），3.87（s，3H），3.12（s，4H），2.93（t， J=5.6 Hz，2H），2.81（s，4H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.7，163.8，152.3，141.2，131.9，130.0，123.0，121.0，118.2，114.8，111.2，109.7，66.3，57.0，55.3，53.9，50.6。ESI-MS（m/z）: 341 [M+H] +。Anal. Calcd for C 20H 24N 2O 3，C，70.56；H，7.11；N，8.23。Found: C，70.60；H，7.15；N，8.07。
(3) synthesis of compound 13: by the above-mentioned product of 5.0 mmol and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 16 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains blue solid 1.01 g, productive rate 43%.ESI-MS (m/z): 468 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.74G.IR（KBr）: 2936，2815，1604，1501，1469，1383，1360，1301，1261，1129，1028，829，770。Anal. Calcd for C 26H 35N 4O 4: C，66.79；H，7.54；N，11.98。Found: C，66.76；H，7.63；N，12.05。Its structural formula is as follows:
。
Embodiment 14: the synthesis of compound 14 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) 4-(synthesis of 2-(N-(4-(2-pyrimidyl) piperazinyl) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol1-(2-pyrimidyl) piperazine dihydrochloride, back flow reaction 18 h, after TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains light yellow solid 1.99 g, productive rate 64%. 1H-NMR（CDCl 3，400 MHz） δ: 9.89（s，1H），8.31（d， J=4.8 Hz，2H），7.84（d， J=8.8 Hz，2H），7.03（d， J=8.4 Hz，2H），7.00（s，1H），6.49（t， J=4.4 Hz，1H），4.23（t， J=6.0 Hz，2H），3.86（t， J=4.4Hz，4H），2.89（t， J=5.6 Hz，2H），2.65（t， J=4.8Hz，4H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.7，163.7，161.6，157.7，131.9，130.0，114.8，109.9，66.3，57.0，53.5，43.6。ESI-MS（m/z）: 313 [M+H] +。Anal. Calcd for C 17H 20N 4O 2，C，65.37；H，6.45；N，17.94。Found: C，65.56；H，6.37；N，18.04。
(3) synthesis of compound 14: by 5.0 mmol above-mentioned steps (2) products therefroms and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 14 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains blue solid 1.21 g, productive rate 55%.ESI-MS (m/z): 440 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.77G.IR（KBr）: 2942，2840，1609，1584，1547，14,84，1388，1357，1304，1252，1133，1050，840，799。Anal. Calcd for C 23H 31N 6O 3: C，62.85；H，7.11；N，19.12。Found: C，62.79；H，7.04；N，19.18。Its structural formula is as follows:
。
Embodiment 15: the synthesis of compound 15 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) 4-(synthesis of 2-(N-(4-(2-pyridyl) piperazinyl) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3with 15 mmol1-(2-pyridyl) piperazine is dissolved in 50 mL acetonitriles, after back flow reaction 17 h, TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains pale yellow oil 1.87 g, productive rate 60%. 1H-NMR（CDCl 3，400 MHz） δ: 9.89（s，1H），8.19（d， J=3.6 Hz，1H），7.84（d， J=8.8 Hz，2H），7.50（t， J=2.4Hz，4H），7.50~7.46（m，1H），7.03（d， J=8.8 Hz，2H），6.66~6.61（m，2H），4.24（t， J=5.6 Hz，2H），3.58（t， J=4.8Hz，4H），2.90（t， J=5.6 Hz，2H），2.71（t， J=4.8Hz，4H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.7，163.7，159.4，147.9，137.4，131.9，130.0，114.8，113.3，107.0，66.3，57.0，53.5，45.1。ESI-MS（m/z）: 312 [M+H] +。Anal. Calcd for C 18H 21N 3O 2，C，69.43；H，6.80；N，13.49。Found: C，69.52；H，6.76；N，13.44。
(3) synthesis of compound 15: by 5.0 mmol step (2) products therefroms and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 14 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains blue solid 1.13 g, productive rate 52%.ESI-MS (m/z): 439 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.76G.IR（KBr）: 2942，2834，1594，1485，1438，1386，1357，1302，1251，1132，1025，1006，979，837，771。Anal. Calcd for C 24H 32N 5O 3: C，65.73；H，7.35；N，15.97。Found: C，65.74；H，7.42；N，15.89。Its structural formula is as follows:
。
Embodiment 16: the synthesis of compound 16 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) 4-(2-imidazolyl) oxyethyl group) synthesis of phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol imidazoles, after back flow reaction 18 h, TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains pale yellow oil 1.60 g, productive rate 74%. 1H-NMR（CDCl 3，400 MHz） δ: 9.88（s，1H），7.82（d， J=8.4 Hz，2H），7.60（s，1H），7.06（d， J=8.0 Hz，2H），6.97（d， J=8.4 Hz，2H），4.39（t， J=4.8 Hz，2H），4.30（t， J=4.8 Hz，2H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.6，162.7，137.4，131.9，130.4，114.8，129.6，114.6，67.3，46.1。ESI-MS（m/z）: 217 [M+H] +。Anal. Calcd for C 12H 12N 2O 2，C，66.65；H，5.59；N，12.96。Found: C，66.73；H，5.63；N，12.88。
(3) synthesis of compound 16: by 5.0 mmol step (2) products therefroms and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 13 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains blue solid 0.98 g, productive rate 57%.ESI-MS (m/z): 344 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.74G.IR（KBr）: 2989，2934，1611，1491，1460，1388，1361，1298，1260，1135，906，832。Anal. Calcd for C 18H 23N 4O 3: C，62.96；H，6.75；N，16.32。Found: C，63.04；H，6.69；N，16.36。Its structural formula is as follows:
Embodiment 17: the synthesis of compound 17 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) synthesis of 4-(2-(1,2,3-triazol radical) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol1,2,3-triazole, back flow reaction 18 h, after TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains white solid 1.55 g, productive rate 71%. 1H-NMR（CDCl 3，400 MHz） δ: 9.89（s，1H），7.93（d， J=8.4 Hz，2H），7.75（d， J=4.4 Hz，2H），6.98（d， J=8.4 Hz，2H），4.86（t， J=4.8 Hz，2H），4.48（t， J=4.8 Hz，2H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.6，162.6，134.0，132.0，130.7，124.5，114.6，66.6，49.3。ESI-MS（m/z）: 219 [M+H] +。Anal. Calcd for C 11H 11N 3O 2，C，60.82；H，5.10；N，19.34。Found: C，60.89；H，5.04；N，19.23。
(3) synthesis of compound 17: by 5.0 mmol step (2) products therefroms and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 14 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains blue solid 0.96 g, productive rate 56%.ESI-MS (m/z): 345 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.77G.IR（KBr）: 2983，2954，1606，1530，1472，1387，1364，1305，1257，1184，1118，1009，843。Anal. Calcd for C 17H 22N 5O 3: C，59.29；H，6.44；N，20.34。Found: C，59.18；H，6.37；N，20.43。Its structural formula is as follows:
。
Embodiment 18: the synthesis of compound 18 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) synthesis of 4-(2-(1,2,4-triazol radical) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol1,2,4-triazole, back flow reaction 19 h, after TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains pale yellow oil 1.48 g, productive rate 68%. 1H-NMR（CDCl 3，400 MHz） δ: 9.88（s，1H），8.25（s，1H），7.98（s，1H），7.82（d， J=8.8 Hz，2H），6.96（d， J=8.8 Hz，2H），4.63（t， J=4.8 Hz，2H），4.44（t， J=4.8 Hz，2H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.6，162.6，152.1，143.9，131.9，130.6，114.7，65.7，48.9。ESI-MS（m/z）: 219 [M+H] +。Anal. Calcd for C 11H 11N 3O 2，C，60.82；H，5.10；N，19.34。Found: C，60.78；H，5.14；N，19.38。
(3) synthesis of compound 18: by 5.0 mmol step (2) products therefroms and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 12 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains blue solid 0.89 g, productive rate 52%.ESI-MS (m/z): 345 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.74G.IR（KBr）: 3105，2980，2930，1605，1504，1463，1387，1361，1301，1253，1181，1130，1010，83,5。Anal. Calcd for C 17H 22N 5O 3: C，59.29；H，6.44；N，20.34。Found: C，59.33；H，6.42；N，20.29。Structural formula is as follows:
。
Embodiment 19: the synthesis of compound 19 and structural characterization
(1) synthesis of 4-(2-bromine oxethyl) phenyl aldehyde: with embodiment one.
(2) synthesis of 4-(2-(benzotriazole base) oxyethyl group) phenyl aldehyde: by 2.29 g(10 mmol) 4-(2-bromine oxethyl) phenyl aldehyde, 2.07g(15 mmol) K 2cO 3be dissolved in 50 mL acetonitriles with 15 mmol benzotriazoles, after back flow reaction 16 h, TLC monitoring reacts completely, by reaction system cool to room temperature, filter, a small amount of acetonitrile wash of filter cake, after decompression removing acetonitrile, rapid column chromatography is separated, and obtains white solid 1.52 g, productive rate 57%. 1H-NMR（CDCl 3，400 MHz） δ: 9.86（s，1H），8.07（d， J=8.0 Hz，1H），7.89（d， J=8.8 Hz，2H），7.78（d， J=8.8 Hz，2H），7.71（d， J=8.4 Hz，2H），7.55（t， J=7.2 Hz，1H），7.40（t， J=7.6 Hz，1H），6.92（d， J=8.4 Hz，2H），5.10（t， J=4.8 Hz，2H），4.58（t， J=5.2 Hz，2H）。 13C-NMR（CDCl 3，100 MHz） δ: 190.6，162.7，133.8，131.9，130.6，127.6，124.1，114.7，109.7，67.0，47.4。ESI-MS（m/z）: 268 [M+H] +。Anal. Calcd for C 15H 13N 3O 2，C，67.40；H，4.90；N，15.72。Found: C，67.29；H，5.05；N，15.76。
(3) synthesis of compound 19: by 5.0 mmol step (2) products therefroms and 0.74 g(5 mmol) 2,3-dimethyl-2,3-dihydroxy amido butane are dissolved in 25 mL methyl alcohol, back flow reaction 14 h.Decompression removing methyl alcohol, resistates is suspended in 25.0 mL CH 2cl 2in, low-temp reaction device is cooled to 0 ° of C, adds 15.0 mL NaIO 4(the 0.85 g) aqueous solution, stopped reaction after vigorous stirring 15 min.After stratification, aqueous phase CH 2cl 2extracting twice, merges organic phase, anhydrous Na 2sO 4dried overnight, filters, removal of solvent under reduced pressure, and resistates rapid column chromatography is separated, and obtains blue solid 0.83 g, productive rate 42%.ESI-MS (m/z): 395 [M+H] +; EPR(CH 3oH): quintet, g=2.0069, | aN|=7.74G.IR（KBr）: 2981，2933，1610，1490，1394，1365，1315，1258，1224，1165，1021，832，756。Anal. Calcd for C 21H 24N 5O 3: C，63.94；H，6.13；N，17.75。Found: C，63.99；H，6.22；N，17.70。Its structural formula is as follows:
。

Claims (10)

1. have the nitroxyl free radical compounds of anti-hypoxia damagine activity, its structural formula is:
Wherein n=1 ~ 3; R is 1-(2-p-methoxy-phenyl)-piperazine, 1-(2-pyrimidyl)-piperazine, 1-(2-pyridyl)-piperazine, 1; 2; 4-triazole, benzotriazole, dimethylamine, diethylamine, morpholine, Pyrrolidine, hexahydropyridine, 4-piperidone, 1-(2-hydroxyethyl) piperazine, 1-methylpiperazine, 1-ethyl piperazidine, 1-Acetylpiperazine, 1-benzyl diethylenediamine, 1-php, 1; 2,3-triazole or imidazoles.
2. there is the synthetic method of the nitroxyl free radical compounds of anti-hypoxia damagine activity as claimed in claim 1, take p-Hydroxybenzaldehyde as raw material, first replace alkane with dibromo to react, generate 4-(n-bromine alkoxyl group) phenyl aldehyde, make 4-(n-bromine alkoxyl group) phenyl aldehyde and amine carry out N-alkylated reaction again and obtain 4-(n-(alkylamino) alkoxyl group) phenyl aldehyde, then 4-(n-(alkylamino) alkoxyl group) phenyl aldehyde and 2 is made, 3-dimethyl-2, 3-dihydroxy amido butane carries out condensation reaction and obtains 4-(n-(substituted-amino) oxyethyl group) phenyl-1, 3-hydroxy imidazole, target product is obtained finally by sodium periodate oxidation.
3. there is the synthetic method of the nitroxyl free radical compounds of anti-hypoxia damagine activity as claimed in claim 2, it is characterized in that: comprise following processing step:
(1) synthesis of 4-(n-bromine alkoxyl group) phenyl aldehyde: take acetone as solvent, K 2cO 3for catalyzer, p-Hydroxybenzaldehyde and dibromo replace alkane with the mol ratio back flow reaction 6 ~ 8h of 1:1 ~ 1:2, are cooled to room temperature, use CH after decompression removing acetone 2cl 2extraction, anhydrous Na 2sO 4drying, obtains 4-(n-bromine alkoxyl group) phenyl aldehyde;
(2) synthesis of 4-(n-(alkylamino) alkoxyl group) phenyl aldehyde: take acetonitrile as solvent, K 2cO 3for catalyzer, make 4-(n-bromine alkoxyl group) phenyl aldehyde and amine with the mol ratio back flow reaction 8 ~ 10h of 1:1 ~ 1:2; Cool to room temperature after reacting completely, filters, washing, and column chromatography for separation, obtains 4-(n-(alkylamino) alkoxyl group) phenyl aldehyde;
(3) 4-(n-(substituted-amino) oxyethyl group) phenyl-1, the synthesis of 3-hydroxy imidazole: take methyl alcohol as solvent, 4-(n-(alkylamino) alkoxyl group) phenyl aldehyde and 2,3-dimethyl-2,3-dihydroxy amido butane is with mol ratio back flow reaction 10 ~ 15 h of 1:0.8 ~ 1:1.2; Be cooled to removal of solvent under reduced pressure after room temperature, obtain 4-(n-(substituted-amino) oxyethyl group) phenyl-1,3-hydroxy imidazole;
(4) synthesis of target product: in methylene dichloride, 4-(n-(substituted-amino) oxyethyl group) phenyl-1,3-hydroxy imidazole and sodium periodate are with the mol ratio of 1:0.8 ~ 1:1.2, stopped reaction after-5 ~ 5 DEG C of vigorous stirring 10 ~ 20min, stratification, aqueous phase dichloromethane extraction, anhydrous Na 2sO 4drying, filters, and after removal of solvent under reduced pressure, rapid column chromatography is separated, and obtains target product.
4. as described in Claims 2 or 3, have the synthetic method of the nitroxyl free radical compounds of anti-hypoxia damagine activity, it is characterized in that: in step (1), it is glycol dibromide, 1,3-dibromopropane or Isosorbide-5-Nitrae-dibromobutane that dibromo replaces alkane.
5. there is the synthetic method of the nitroxyl free radical compounds of anti-hypoxia damagine activity as described in Claims 2 or 3, it is characterized in that: in step (1), K 2cO 3consumption be 1 ~ 3 times of p-Hydroxybenzaldehyde molar weight.
6. as described in Claims 2 or 3, have the synthetic method of the nitroxyl free radical compounds of anti-hypoxia damagine activity, it is characterized in that: in step (2), described amine is diethylamine; Pyrrolidine, hexahydropyridine, morpholine; piperidone, 1-(2-hydroxyl) piperazine, 1-methylpiperazine; 1-ethyl piperazidine; 1-Acetylpiperazine, 1-benzyl diethylenediamine, 1-php; 1-(2-p-methoxy-phenyl) piperazine; 1-(2-pyrimidyl) piperazine dihydrochloride, 1-(2-pyridyl) piperazine, imidazoles; 1; 2,3-triazole, 1; 2,4-triazole or benzotriazole.
7. there is the synthetic method of the nitroxyl free radical compounds of anti-hypoxia damagine activity as described in Claims 2 or 3, it is characterized in that: in step (2), K 2cO 3consumption be 1 ~ 3 times of 4-(n-bromine alkoxyl group) phenyl aldehyde molar weight.
8. the nitroxyl free radical compounds as claimed in claim 1 with anti-hypoxia damagine activity is preparing the application in anti-anoxic medicine.
9. the nitroxyl free radical compounds as claimed in claim 1 with anti-hypoxia damagine activity is preparing the application in anti-anoxic medicine, it is characterized in that: described anoxia-induced apoptosis is the acute high altitude sickness that plateau low-pressure hypoxia causes, cerebral ischemia/anoxia disease, myocardial ischemia-anoxemia disease.
10. there is described in claim 1 synthetic method of the nitroxyl free radical compounds of anti-hypoxia damagine activity, it is characterized in that: with it for activeconstituents, be combined with pharmaceutically conventional auxiliary material, the tablet conventionally made, capsule, dispersion agent, granule, injection liquid, injection freeze-dried powder injection.
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