CN101787002B - 1-mustard acyl-4-benzylpiperazine derivative, preparation method thereof and application of anti-free radical or anti-inflammatory activity - Google Patents
1-mustard acyl-4-benzylpiperazine derivative, preparation method thereof and application of anti-free radical or anti-inflammatory activity Download PDFInfo
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- CN101787002B CN101787002B CN2010101129007A CN201010112900A CN101787002B CN 101787002 B CN101787002 B CN 101787002B CN 2010101129007 A CN2010101129007 A CN 2010101129007A CN 201010112900 A CN201010112900 A CN 201010112900A CN 101787002 B CN101787002 B CN 101787002B
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- benzyl diethylenediamine
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- acyl
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Abstract
The invention discloses a 1-mustard acyl-4-benzylpiperazine derivative with anti-free radical and anti-inflammatory activities. The structural formula of the 1-mustard acyl-4-benzylpiperazine derivative is shown as in the specification, wherein a substituent R1 is a hydrogen atom or hydrocarbyl or alkoxy or a halogen atom, R2 is the hydrogen atom or the hydrocarbyl or the alkoxy or the halogen atom, and R3 is the hydrogen atom or the hydrocarbyl or the alkoxy or the halogen atom, such as R1 and R3 are both hydrogen atoms and R2 is a chlorine atom. The constituted compound has the best anti-free radical and anti-inflammatory activities and can be used as a novel anti-inflammatory drug.
Description
Technical field
The invention belongs to chemical field of medicaments, be specifically related to a kind of benzylpiperazine derivative and preparation method thereof with Green Tea Extract and anti-inflammatory activity.
Background technology
Free-radical oxidn damage and inflammatory reaction may be one of the generation of a lot of diseases and development mechanism.R and D have the medicine of removing free radical, anti-inflammatory action, are one of important topics of field of medicaments always.In recent decades, the anti-inflammatory drug of multiple different chemical structures and formulation occurred, continually developing of new drug and eliminating of research and substandard drug can promote anti-inflammatory drug constantly to develop towards the direction that adapts to the human needs.
Under such background, the present invention researches and develops out a kind of new compound with good anti-inflammatory and Green Tea Extract pharmacologically active just.
Summary of the invention
The purpose of this invention is to provide a kind of new compound with good anti-inflammatory and Green Tea Extract pharmacologically active.
Another object of the present invention provides the preparation method of this compound.
A further object of the present invention provides this application of compound.
The present invention is achieved through the following technical solutions above-mentioned purpose:
A kind of 1-mustard acyl-4-benzylpiperazine derivative is provided, it is characterized in that its molecular structure is:
Substituent R wherein
1Be hydrogen atom or alkyl or alkoxy or halogen atom, R
2Be hydrogen atom or alkyl or alkoxy or halogen atom, R
3Be hydrogen atom or alkyl or alkoxy or halogen atom.R wherein
1Be preferably-H ,-CH
3,-OCH
3, or-Cl; R
2Be preferably-H ,-CH
3,-OCH
3, or-Cl; R
3Be preferably-H ,-CH
3,-OCH
3, or-Cl.
Work as R
1And R
3Be hydrogen atom, R
2Be the chlorine atomic time, the compound Green Tea Extract and the anti-inflammatory activity that are constituted are best.
The technological line for preparing this compound is:
(1) the synthetic and purifying of N-benzylpiperazine derivative
(2) 1-(O-acetyl-) mustard acyl-4-benzylpiperazine derivative is synthetic
(3) hydrolysis of 1-(O-acetyl-) mustard acyl-4-benzylpiperazine derivative
The key step for preparing this compound is: (1) Uricida and two hydrochloric acid, one water piperazine, benzyl chloride or synthetic purified N-benzylpiperazine derivative and the O-acetyl mustard seed acyl chloride reaction of N-benzylpiperazine derivative (2) of replacement benzyl chloride reaction become 1-(O-acetyl-) mustard acyl-4-benzylpiperazine derivative; (3) 1-(O-acetyl-) mustard acyl-4-benzylpiperazine derivative further hydrolysis becoming 1-mustard acyl-4-benzylpiperazine derivative.
The building-up process of N-benzylpiperazine derivative is in the step (1): with Uricida, two hydrochloric acid, one water piperazine and benzyl chloride or replacement benzyl chloride is that raw material reacts, suction filtration obtains N-benzylpiperazine derivative mono-hydrochloric salts crude product, boils off solvent and obtains N-benzylpiperazine derivative crude product through alkalization and ethyl acetate extraction again.The molecular formula of described N-benzylpiperazine derivative is:
The name of its R substituting group and the synthetic N-of institute benzylpiperazine derivative is as shown in table 1:
Table 1 a synthetic N-benzylpiperazine derivative
Specifically, the operation of step (1) is as follows: Uricida and two hydrochloric acid, one water piperazine stirring and dissolving in dehydrated alcohol, 65～80 ℃ are stirred 10～30min down, add benzyl chloride or replace benzyl chloride, temperature sharply rises to 80～90 ℃, separate out a large amount of white solids, insulation continues to stir, suction filtration, filtrate decompression steam desolventize N-benzylpiperazine derivative mono-hydrochloric salts crude product, use water dissolution, regulating the pH value with NaOH under the ice bath is 10, use ethyl acetate extraction, concentrated ethyl acetate layer gets faint yellow oily thing, gets N-benzylpiperazine derivative crude product.
The synthetic N-benzylpiperazine derivative of step (1) institute synthetic had also passed through purifying before entering the reaction of (2) step, its method is to separate the pure product of N-benzylpiperazine derivative that obtain with column chromatography.
The building-up process of step (2) 1-(O-acetyl-) mustard acyl-4-benzylpiperazine derivative is: the pure product of N-benzylpiperazine derivative are dissolved in the chloroform; add triethylamine; stir; drip the O-acetyl mustard seed acyl chlorides chloroformic solution of new system; the control rate of addition; make temperature of reaction be lower than 30 ℃, continue under the room temperature to stir 1～2h, reaction solution is with 5%NaHCO
3Washing, the chloroform layer solvent evaporated gets red-brown oily matter, is 1-(O-acetyl-) mustard acyl-4-benzylpiperazine derivative crude product.
The hydrolytic process of step (3) 1-(O-acetyl-) mustard acyl-4-benzylpiperazine derivative is: red-brown oily 1-(O-acetyl-) mustard acyl-4-benzylpiperazine derivative crude product adds the 2molL of new system with the ethanol heating for dissolving during 50 ℃ of left and right sides
-1The ethanolic soln of NaOH is separated out yellow solid, and reaction solution is yellow suspension liquid, backflow 15min, and solvent evaporated gets yellow solid, uses water dissolution, and ice bath drips concentrated hydrochloric acid down to pH5～6, again with 5%NaHCO
3Regulate about pH7～8, separate out faint yellow solid and filter, dry 1-mustard acyl-4-benzylpiperazine derivative crude product.Get 1-mustard acyl-4-benzylpiperazine derivative elaboration with chloroform-ethyl acetate mixed solvent recrystallization.
It is as shown in table 2 to utilize benzyl chloride or different replacement benzyl chlorides can obtain following ten compounds (SA1-SA10) as raw material:
The various 1-mustard acyl-4-benzylpiperazine derivatives of table 2 gained of the present invention
A series of 1-mustard acyl-4-benzylpiperazine derivative provided by the invention can be applied to remove free radical, also can be applicable to the anti-inflammatory anti-inflammatory.
Compared with prior art, the present invention has following beneficial effect:
The a series of 1-mustard acyl-4-benzylpiperazine derivatives of synthetic of the present invention have good Green Tea Extract and antiphlogistic pharmacologically active; The productive rate height of 1-mustard acyl-4-benzylpiperazine derivative in the synthetic method that invention is provided; For the medicament research and development for the treatment of relative disease provides another approach.
Embodiment
Below further specify technical scheme of the present invention by specific embodiment.
Embodiment 1
Get 1.94g Uricida and 2.12g two hydrochloric acid, one water piperazine stirring and dissolving in the 10ml dehydrated alcohol, 65 ℃ are stirred 10min, add the 1.15ml benzyl chloride, temperature sharply rises to 78 ℃, separate out a large amount of white solids, insulation continues to stir suction filtration, filtrate decompression steam desolventize N-benzyl diethylenediamine mono-hydrochloric salts crude product, with the 25ml water dissolution, regulate pH10 with NaOH under the ice bath, use ethyl acetate extraction, concentrated ethyl acetate layer gets faint yellow oily thing, gets 1.30g N-benzyl diethylenediamine crude product.Crude product gets the pure product of 0.76g N-benzyl diethylenediamine after column chromatography is separated.
0.76g the N-benzyl diethylenediamine dissolves in the 10ml chloroform, adds the 2ml triethylamine, stirs, and drips the O-acetyl mustard seed acyl chlorides chloroformic solution of new system, the control rate of addition makes temperature of reaction be lower than 30 ℃, dropwises, and continues under the room temperature to stir 1h, and reaction solution is with 5%NaHCO
3Washing, the chloroform layer solvent evaporated gets red-brown oily matter, is 1-(O-acetyl-) mustard acyl-4-benzylpiperazine crude product.
Red-brown oily 1-(O-acetyl-) mustard acyl-4-benzylpiperazine crude product adds the 2molL of 20ml new system with 20ml ethanol heating for dissolving during 50 ℃ of left and right sides
-1The ethanolic soln of NaOH is separated out yellow solid, and reaction solution is yellow suspension liquid, backflow 15min, and solvent evaporated gets yellow solid, and with the 50ml water dissolution, ice bath drips concentrated hydrochloric acid down to pH5～6, again with 5%NaHCO
3Regulate about pH7～8, separate out a large amount of faint yellow solids and filter, dry 1-mustard acyl-4-benzylpiperazine crude product.Get 1-mustard acyl-4-benzylpiperazine elaboration with chloroform-ethyl acetate mixed solvent recrystallization.
Embodiment 2
Get 1.94g Uricida and 2.12g two hydrochloric acid, one water piperazine stirring and dissolving in the 10ml dehydrated alcohol, 65 ℃ are stirred 10min, add 1.15ml 3-chlorobenzyl chloride, temperature sharply rises to 78 ℃, separate out a large amount of white solids, insulation continues to stir, suction filtration, filtrate decompression steam desolventize N-(3 '-Cl-) benzyl diethylenediamine mono-hydrochloric salts crude product, with the 25ml water dissolution, regulate pH10 with NaOH under the ice bath, use ethyl acetate extraction, concentrated ethyl acetate layer gets faint yellow oily thing, gets 1.65g N-(3 '-Cl-) benzyl diethylenediamine crude product.Crude product gets 0.96g N-(the pure product of 3 '-Cl-) benzyl diethylenediamine after column chromatography is separated.
0.96g (3 '-Cl) benzyl diethylenediamine dissolves in the 15ml chloroform N-, adds the 3ml triethylamine, stirs, drip the O-acetyl mustard seed acyl chlorides chloroformic solution of new system, the control rate of addition makes temperature of reaction be lower than 30 ℃, dropwise, continue under the room temperature to stir 1h, reaction solution is with 5%NaHCO
3Washing, the chloroform layer solvent evaporated gets red-brown oily matter, is 1-(O-acetyl-) mustard acyl-4-(3 '-Cl-)-benzyl diethylenediamine crude product.
(3 '-Cl-) benzyl diethylenediamine crude product adds the 2molL of 28ml new system with 20ml ethanol heating for dissolving to red-brown oily 1-(O-acetyl-) mustard acyl-4-during 50 ℃ of left and right sides
-1The ethanolic soln of NaOH is separated out yellow solid, and reaction solution is yellow suspension liquid, backflow 15min, and solvent evaporated gets yellow solid, and with the 50ml water dissolution, ice bath drips concentrated hydrochloric acid down to pH5～6, again with 5%NaHCO
3Regulate about pH7～8, separate out a large amount of faint yellow solids and filter, dry 1-mustard acyl-4-(3 '-Cl-) benzyl diethylenediamine crude product.Get 1-mustard acyl-4-(3 '-Cl-) benzyl diethylenediamine elaboration with methanol-water mixed solvent recrystallization.
Embodiment 3
(3 '-Cl-) benzyl diethylenediamine is formulated as 6mmolL to 1-mustard acyl-4-
-1Solution and to carry out gradient dilution be 3mmolL
-1, 1.5mmolL
-1, 0.75mmolL
-1, 0.38mmolL
-1, 0.19mmolL
-1, 0.10mmolL
-1, 0.05mmolL
-1Solution add DPPH solution respectively, the feature purple of DPPH solution shoals, and at the 517nm place maximum absorption is arranged.Variation according to absorbancy can record 1-mustard acyl-4-(IC of 3 '-Cl)-benzyl diethylenediamine removing DPPH free radical
50Be 0.044.
Embodiment 4
Use phenanthroline-Fe
2+Oxidation style is measured 1-mustard acyl-4-, and (3 '-Cl-) benzyl diethylenediamine is to the removing ability of hydroxy radical qiao OH.(3 '-Cl-) benzyl diethylenediamine is formulated as 6mmolL to 1-mustard acyl-4-
-1Solution and to carry out gradient dilution be 3mmolL
-1, 1.5mmolL
-1, 0.75mmolL
-1, 0.38mmolL
-1, 0.19mmolL
-1Solution, respectively to phenanthroline-Fe
2+Add above-mentioned each concentration solution in the system, add H again
2O
2, the OH that produces through the Fenton reaction partly is eliminated, and makes it in the 536nm absorbancy.Utilize the variation of reaction front and back absorbance Δ A to measure and calculate clearance rate, (3 '-Cl) benzyl diethylenediamine is removed the IC of OH free radical to calculate 1-mustard acyl-4-
50Be 0.215.
Embodiment 5
Kunming mouse
The mouse stomach administration is given respectively and 50mgkg
-1, 100mgkg
-1, 200mgkg
-11-mustard acyl-4-(3 '-Cl-) benzyl diethylenediamine behind the administration 1hr, mixes 50 μ L Oleum Tigliis causing scorching liquid and be evenly coated in the mouse right ear tow sides and cause inflammation, and left ear compares.Behind the 4hr, mouse is put to death, cut two ears, each beats next auricle to the punch tool of usefulness diameter 8mm respectively in same position, weighs, and the difference of calculating two auricle weight is the swelling degree.Calculate 1-mustard acyl-4-(ED of 3 '-Cl-) benzyl diethylenediamine anti-inflammatory action
50Be 398.5mgkg
-1
Claims (2)
1.1-mustard acyl-4-benzylpiperazine derivative is characterized in that its molecular structure is:
Substituent R wherein
1Be hydrogen atom, R
2Be chlorine atom, R
3Be hydrogen atom.
2. the preparation method of the described compound of claim 1 is characterized in that may further comprise the steps:
(1) gets 1.94g Uricida and 2.12g two hydrochloric acid, one water piperazine stirring and dissolving in the 10ml dehydrated alcohol, 65 ℃ are stirred 10min, add 1.15ml 3-chlorobenzyl chloride, temperature sharply rises to 78 ℃, separate out a large amount of white solids, insulation continues to stir, suction filtration, filtrate decompression steam desolventize N-(3 '-Cl-) benzyl diethylenediamine mono-hydrochloric salts crude product with the 25ml water dissolution, is regulated pH10 with NaOH under the ice bath, use ethyl acetate extraction, concentrated ethyl acetate layer gets faint yellow oily thing, and (3 '-Cl-) benzyl diethylenediamine crude product, crude product get 0.96g N-(the pure product of 3 '-Cl-) benzyl diethylenediamine after column chromatography is separated to get 1.65g N-;
(2) (3 '-Cl) benzyl diethylenediamine dissolves in the 15ml chloroform 0.96g N-, adds the 3ml triethylamine, stirs, drip the O-acetyl mustard seed acyl chlorides chloroformic solution of new system, the control rate of addition makes temperature of reaction be lower than 30 ℃, dropwise, continue under the room temperature to stir 1h, reaction solution is with 5%NaHCO
3Washing, the chloroform layer solvent evaporated gets red-brown oily matter, is 1-(O-acetyl-) mustard acyl-4-(3 '-Cl-)-benzyl diethylenediamine crude product;
(3) (3 '-Cl-) benzyl diethylenediamine crude product adds the 2molL of 28ml new system with 20ml ethanol heating for dissolving to red-brown oily 1-(O-acetyl-) mustard acyl-4-during 50 ℃ of left and right sides
-1The ethanolic soln of NaOH is separated out yellow solid, and reaction solution is yellow suspension liquid, backflow 15min, and solvent evaporated gets yellow solid, and with the 50ml water dissolution, ice bath drips concentrated hydrochloric acid down to pH5～6, again with 5%NaHCO
3Regulate about pH7～8, separate out a large amount of faint yellow solids and filter, dry 1-mustard acyl-4-(3 '-Cl-) benzyl diethylenediamine crude product gets 1-mustard acyl-4-(3 '-Cl-) benzyl diethylenediamine elaboration with methanol-water mixed solvent recrystallization.
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| CN102416016B (en) * | 2011-12-31 | 2013-08-21 | 汕头大学医学院 | Use of 1-erucic acyl-4-(3'-chloro-)benzylpiperazine in medicine preparation |
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| FR3000742A1 (en) * | 2013-01-08 | 2014-07-11 | Pharmasynthese | NEW DERIVATIVES OF SINAPINIC ACID |
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