CN109928896A - Resveratrol amino-acid ester analog derivative and preparation method thereof - Google Patents
Resveratrol amino-acid ester analog derivative and preparation method thereof Download PDFInfo
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- CN109928896A CN109928896A CN201910298268.0A CN201910298268A CN109928896A CN 109928896 A CN109928896 A CN 109928896A CN 201910298268 A CN201910298268 A CN 201910298268A CN 109928896 A CN109928896 A CN 109928896A
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Abstract
The invention discloses a kind of resveratrol amino-acid ester analog derivatives and preparation method thereof, belong to fine chemical synthesis technical field.The structure of the resveratrol amino-acid ester analog derivative is shown below:
Description
Technical field
The invention belongs to fine chemical synthesis technical fields, and in particular to a kind of resveratrol amino acid esters are derivative
Object and preparation method thereof.
Background technique
Resveratrol is a kind of natural products found from white black false hellebore from 1938 by Japanese Scientists, is primarily present in
In the plants such as peanut, grape (red wine), polygonum cuspidate.Modern research shows that resveratrol is a kind of very important food
Product additive and prevention medical supplies, have good effect to inflammation, cardiovascular disease, antifatigue aspect.
Alanine is one of the 20 kinds of amino acid for forming human body protein, helps mitigation hypoglycemia, improves body energy shape
Condition.γ-aminobutyric acid is a kind of naturally occurring non-protein composition amino acid, has extremely important physiological function, it can promote
Into the reactivity of brain, brain tonic and intelligence development, anti-epileptic promotes sleep, and beauty moisturizing delays brain aging function, can supplement human body inhibition
Nerve mediator has good blood pressure reduction effect.
In the prior art, often resveratrol, alanine or γ-aminobutyric acid are used alone, for beauty product or
As antifatigue, blood pressure lowering drug.Due to the presence of activity hydroxy in resveratrol, so that resveratrol is right at normal temperature
Light, temperature, soda acid are unstable, by hydroxyl by chemically reacting, are protected, can greatly improve resveratrol
Stability.However, the substituent group newly increased often increases the pharmacological toxicity of resveratrol, the medicinal effect of resveratrol is influenced
Fruit.Therefore, it is necessary to a kind of new derivative of resveratrol is synthesized, to reduce the introduced pharmacological toxicity of substituent group, and
The medicinal effects that resveratrol maintains resveratrol are played simultaneously.
Summary of the invention
In view of this, the present invention provides a kind of derivative of new resveratrol, i.e. resveratrol amino acid esters spread out
Biology.
The present invention also provides a kind of new synthetic methods of above-mentioned resveratrol amino-acid ester analog derivative.
The technical solution adopted by the present invention to solve the technical problems is:
A kind of resveratrol amino-acid ester analog derivative, structure is as shown in formula I:
Wherein, R is selected from-CH2-CH2-、Or-CH2-CH2-CH2, R ' be selected from-CH3 ,-CH2CH3 or-
CH2CH2CH3。
A kind of preparation method of resveratrol amino-acid ester analog derivative as described above, with resveratrol, R amino acid,
R ' alcohol, thionyl chloride, two (p-nitrophenyl) carbonic esters are raw material, with 4-dimethylaminopyridine (DMAP) for catalyst, with acetonitrile
For solvent, synthesizing resveratrol amino acid esters derivative；
Wherein, R amino acid is selected from one of α-alanine, Beta-alanine or γ-aminobutyric acid, R ' alcohol be selected from methanol,
One of ethyl alcohol or normal propyl alcohol.
Specifically, comprising the following steps:
A. thionyl chloride is added into R ' alcohol, is sufficiently stirred under ice-water bath, R amino acid is added, in 20 DEG C~80 DEG C temperature
Under, after 6h~12h is sufficiently stirred, excessive R ' alcohol is distilled off, obtains the R amino acid R ' ester derivant of solid-like；Wherein, R
Amino acid is selected from one of α-alanine, Beta-alanine or γ-aminobutyric acid, and R ' alcohol is selected from methanol, ethyl alcohol or normal propyl alcohol
One of；
B. excessive second is added in R amino acid R ' ester derivant, two (p-nitrophenyl) carbonic esters and DMAP step a obtained
In nitrile solvent, wherein the amount of the substance of two (p-nitrophenyl) carbonic esters is 1 times~5 times of R amino acid R ' ester derivant；20
DEG C~90 DEG C of reaction temperature under, reaction 2h~6h is sufficiently stirred, obtains intermediate product mixed solution；
C. hydrochloric acid is added into the intermediate product mixed solution that step b is obtained to be washed, dichloro is added into cleaning solution
Methane carries out standing extraction, and extraction phase successively through drying, revolving and column chromatographic runs, obtains solid-like intermediate product；
D. the obtained solid-like intermediate product of resveratrol, step c and DMAP are added in excessive acetonitrile solvent,
In, the amount of the substance for the solid-like intermediate product that step c is obtained is 3 times~7 times of resveratrol, in 20 DEG C~90 DEG C of reaction
At a temperature of, reaction 12h~36h is sufficiently stirred, obtains final product mixed solution；
E. hydrochloric acid is added into the final product mixed solution that step d is obtained to be washed, dichloro is added into cleaning solution
Methane carries out standing extraction, and extraction phase successively through drying, revolving and column chromatographic runs, obtains solid product.
The present invention by adopting the above technical scheme, the beneficial effect is that: provide a kind of completely new resveratrol amino acid
Ester derivative will not allowed resveratrol and alanine or γ-aminobutyric acid easy to maintain to synthesize new compound, be solved white
While veratryl alcohol technical problem not easy to maintain, the introduced pharmacological toxicity of resveratrol substituent group is reduced.Resveratrol
The amino in hydroxyl and alanine or γ-aminobutyric acid having in structure is dehydrated, and is connected in the form of amido bond, is worked as derivative
After being entered in vivo by way of oral, the chemical bond of formation can be hydrolyzed by intracorporal enzyme, release resveratrol and phase
The amino acid monomer answered, and then play respective physiological action, avoid introducing other substituent groups and the poison that makes resveratrol
Side effect enhancing.It is contemplated that the new compound can be played in beauty and in terms of preparing antifatigue, blood pressure lowering drug
Important function.The present invention also provides a kind of preparation method of above-mentioned resveratrol amino-acid ester analog derivative, with resveratrol,
Alanine or γ-aminobutyric acid, methanol/ethanol or normal propyl alcohol, thionyl chloride, two (p-nitrophenyl) carbonic esters are raw material, with 4-
Dimethylamino naphthyridine (DMAP) is catalyst, using acetonitrile as solvent, synthesizing resveratrol amino acid esters derivative, and work
Skill process is simple, resveratrol high conversion rate, and product yield is stablized.
Detailed description of the invention
Fig. 1 is product P1Nucleus magnetic hydrogen spectrum figure.
Fig. 2 is product P2Nucleus magnetic hydrogen spectrum figure.
Fig. 3 is product P3Nucleus magnetic hydrogen spectrum figure.
Fig. 4 is product P8Nucleus magnetic hydrogen spectrum figure.
Fig. 5 is product P9Nucleus magnetic hydrogen spectrum figure.
Specific embodiment
In order to illustrate the technical solution of the embodiments of the present invention more clearly, will be done furtherly to the method for the present invention below
It is bright.
The embodiment of the invention provides a kind of resveratrol amino-acid ester analog derivatives, and structure is as shown in formula I:
Wherein, R is selected from-CH2-CH2-、Or-CH2-CH2-CH2, R ' be selected from-CH3 ,-CH2CH3 or-
CH2CH2CH3。
Preferably, the resveratrol amino-acid ester analog derivative is resveratrol-α-alanine methyl esters, structure is such as
Shown in formula II:
Preferably, the resveratrol amino-acid ester analog derivative is resveratrol-Beta-alanine methyl esters, structure is such as
Shown in formula III:
Preferably, the resveratrol amino-acid ester analog derivative is resveratrol-γ-aminobutyric acid methyl esters or white Chenopodiaceae
Reed alcohol-γ-aminobutyric acid ethyl ester or resveratrol-γ-aminobutyric acid propyl ester, structure is as shown in formula IV:
Wherein, R ' is selected from-CH3 ,-CH2CH3 or-CH2CH2CH3.
In one preferred embodiment, a kind of preparation method of resveratrol amino-acid ester analog derivative as described above, with
Resveratrol, R amino acid, R ' alcohol, thionyl chloride, two (p-nitrophenyl) carbonic esters are raw material, with 4-dimethylaminopyridine
It (DMAP) is catalyst, using acetonitrile as solvent, synthesizing resveratrol amino acid esters derivative.Wherein, R amino acid selects
From one of α-alanine, Beta-alanine or γ-aminobutyric acid, R ' alcohol be selected from methanol, ethyl alcohol or normal propyl alcohol one of.
Specifically, comprising the following steps:
A. thionyl chloride is added into R ' alcohol, is sufficiently stirred under ice-water bath, R amino acid is added, in 20 DEG C~80 DEG C temperature
Under, after 6h~12h is sufficiently stirred, excessive R ' alcohol is distilled off, obtains the R amino acid R ' ester derivant of solid-like；Wherein, R
Amino acid is selected from one of α-alanine, Beta-alanine or γ-aminobutyric acid, and R ' alcohol is selected from methanol, ethyl alcohol or normal propyl alcohol
One of；
Its reaction process includes:
A1. thionyl chloride and R ' alcohol substitution reaction generate acyl chlorides, such as formula (1):
A2. acyl chlorides is reacted with R amino acid substitution, generates R amino acid R ' ester, such as formula (2):
Preferably, addition thionyl chloride is slowly added dropwise to R ' alcohol, is sufficiently stirred under ice-water bath to improve raw material availability
It mixes, to obtain alcohol acyl chlorides.
B. excessive second is added in R amino acid R ' ester derivant, two (p-nitrophenyl) carbonic esters and DMAP step a obtained
In nitrile solvent, wherein the amount of the substance of two (p-nitrophenyl) carbonic esters is 1 times~5 times of R amino acid R ' ester derivant.20
DEG C~90 DEG C of reaction temperature under, reaction 2h~6h is sufficiently stirred, obtains intermediate product mixed solution.
Shown in its reaction process such as formula (3):
C. hydrochloric acid is added into the intermediate product mixed solution that step b is obtained to be washed, dichloro is added into cleaning solution
Methane carries out standing extraction, and extraction phase successively through drying, revolving and column chromatographic runs, obtains solid-like intermediate product.
Wherein, the raffinate phase of extraction is operated through revolving, solvent is removed, to recycle DMAP.
Wherein, it selects in anhydrous sodium sulfate, silica gel, anhydrous calcium chloride, montmorillonite, anhydrous calcium chloride or aluminium oxide at least
Operation is dried in a kind of pair of extraction phase.
D. the obtained solid-like intermediate product of resveratrol, step c and DMAP are added in excessive acetonitrile solvent,
In, the amount of the substance for the solid-like intermediate product that step c is obtained is 3 times~7 times of resveratrol, in 20 DEG C~90 DEG C of reaction
At a temperature of, reaction 12h~36h is sufficiently stirred, obtains final product mixed solution.
Preferably, the amount of the substance for the solid-like intermediate product that step c is obtained is 4 times~6 times of resveratrol.
Shown in its reaction process such as formula (4):
E. hydrochloric acid is added into the final product mixed solution that step d is obtained to be washed, dichloro is added into cleaning solution
Methane carries out standing extraction, and extraction phase successively through drying, revolving and column chromatographic runs, obtains solid product.
Wherein, the raffinate phase of extraction is operated through revolving, solvent is removed, to recycle DMAP.
Wherein, it selects in anhydrous sodium sulfate, silica gel, anhydrous calcium chloride, montmorillonite, anhydrous calcium chloride or aluminium oxide at least
Operation is dried in a kind of pair of extraction phase.
Below by way of specific embodiment, further the embodiment of the present invention is explained.
The preparation of embodiment monoamino-acid ester derivative
Specific embodiment 1
The methanol of 40ml and the thionyl chloride of 3ml are added in 100ml three-neck flask, reaction vessel is opened under ice-water bath
Begin to stir, so that reactant is sufficiently mixed, and then sufficiently generates acyl chlorides, reacts 2h, obtain corresponding alcohol acyl chlorides.Then wherein
The α-alanine of 0.01mol (0.8909g) is added, at a temperature of 80 DEG C, reacts 6h, obtains corresponding α-alanine methyl esters
0.0184mol (1.8975g), yield reaches 92%.
Specific embodiment 2
The methanol of 60ml and the thionyl chloride of 5ml are added in 100ml three-neck flask, reaction vessel is opened under ice-water bath
Begin to stir, so that reactant is sufficiently mixed, and then sufficiently generates acyl chlorides, reacts 4h, obtain corresponding alcohol acyl chlorides.Then wherein
The α-alanine of 0.02mol (1.7826g) is added, at a temperature of 20 DEG C, reacts 12h, obtains corresponding α-alanine methyl esters
0.0194mol (2.0002g), yield reaches 97%.
Specific embodiment 3
The methanol of 60ml and the thionyl chloride of 5ml are added in 100ml three-neck flask, reaction vessel is opened under ice-water bath
Begin to stir, so that reactant is sufficiently mixed, and then sufficiently generates acyl chlorides, reacts 6h, obtain corresponding alcohol acyl chlorides.Then wherein
The α-alanine of 0.02mol (1.7823g) is added, at a temperature of 60 DEG C, reacts 8h, obtains corresponding α-alanine methyl esters
0.0099mol (1.0210g), yield reaches 99%.
Specific embodiment 4
The ethyl alcohol of 60ml and the thionyl chloride of 5ml are added in 100ml three-neck flask, reaction vessel is opened under ice-water bath
Begin to stir, so that reactant is sufficiently mixed, and then sufficiently generates acyl chlorides, reacts 4h, obtain corresponding alcohol acyl chlorides.Then wherein
The α-alanine of 0.02mol (1.7826g) is added, at a temperature of 60 DEG C, reacts 8h, obtains corresponding α-alanine ethyl ester
0.019mol (2.2263g), yield reaches 95%.
Specific embodiment 5
The normal propyl alcohol of 60ml and the thionyl chloride of 5ml are added in 100ml three-neck flask, by reaction vessel under ice-water bath
Start to stir, so that reactant is sufficiently mixed, and then sufficiently generates acyl chlorides, reacts 4h, obtain corresponding alcohol acyl chlorides.Then at it
The middle α-alanine that 0.02mol (1.7826g) is added reacts 8h, obtains corresponding α-alanine propyl ester at a temperature of 60 DEG C
0.018mol (2.363g), yield reaches 90%.
Specific embodiment 6
The methanol of 40ml and the thionyl chloride of 3ml are added in 100ml three-neck flask, reaction vessel is opened under ice-water bath
Begin to stir, so that reactant is sufficiently mixed, and then sufficiently generates acyl chlorides, reacts 2h, obtain corresponding alcohol acyl chlorides.Then wherein
The Beta-alanine of 0.01mol (0.89091g) is added, at a temperature of 80 DEG C, reacts 6h, obtains corresponding Beta-alanine methyl esters
0.0091mol (0.9385g), yield reaches 91%.
Specific embodiment 7
The methanol of 60ml and the thionyl chloride of 5ml are added in 100ml three-neck flask, reaction vessel is opened under ice-water bath
Begin to stir, so that reactant is sufficiently mixed, and then sufficiently generates acyl chlorides, reacts 4h, obtain corresponding alcohol acyl chlorides.Then wherein
The Beta-alanine of 0.02mol (1.7818g) is added, at a temperature of 20 DEG C, reacts 12h, obtains corresponding Beta-alanine methyl esters
0.018mol (1.8565g), yield reaches 90%.
Specific embodiment 8
The methanol of 60ml and the thionyl chloride of 5ml are added in 100ml three-neck flask, reaction vessel is opened under ice-water bath
Begin to stir, so that reactant is sufficiently mixed, and then sufficiently generates acyl chlorides, reacts 6h, obtain corresponding alcohol acyl chlorides.Then wherein
The Beta-alanine of 0.02mol (1.7818g) is added, at a temperature of 60 DEG C, reacts 8h, obtains corresponding Beta-alanine methyl esters
0.019mol (1.9596g), yield reaches 95%.
Specific embodiment 9
The ethyl alcohol of 60ml and the thionyl chloride of 5ml are added in 100ml three-neck flask, reaction vessel is opened under ice-water bath
Begin to stir, so that reactant is sufficiently mixed, and then sufficiently generates acyl chlorides, reacts 4h, obtain corresponding alcohol acyl chlorides.Then wherein
The Beta-alanine of 0.02mol (1.7818g) is added, at a temperature of 60 DEG C, reacts 8h, obtains corresponding Beta-alanine ethyl ester
0.0192mol (2.2497g), yield reaches 96%.
Specific embodiment 10
The normal propyl alcohol of 60ml and the thionyl chloride of 5ml are added in 100ml three-neck flask, by reaction vessel under ice-water bath
Start to stir, so that reactant is sufficiently mixed, and then sufficiently generates acyl chlorides, reacts 4h, obtain corresponding alcohol acyl chlorides.Then at it
The middle Beta-alanine that 0.02mol (1.7818g) is added reacts 8h, obtains corresponding Beta-alanine propyl ester at a temperature of 60 DEG C
0.0178mol (2.3351g), yield reaches 89%.
Specific embodiment 11
The methanol of 40ml and the thionyl chloride of 3ml are added in 100ml three-neck flask, reaction vessel is opened under ice-water bath
Begin to stir, so that reactant is sufficiently mixed, and then sufficiently generates acyl chlorides, reacts 2h, obtain corresponding alcohol acyl chlorides.Then wherein
The γ-aminobutyric acid of 0.01mol (1.031g) is added, at a temperature of 80 DEG C, reacts 6h, obtains corresponding γ-aminobutyric acid first
Ester 0.0092mol (1.0785g), yield reaches 92%.
Specific embodiment 12
The methanol of 60ml and the thionyl chloride of 5ml are added in 100ml three-neck flask, reaction vessel is opened under ice-water bath
Begin to stir, so that reactant is sufficiently mixed, and then sufficiently generates acyl chlorides, reacts 4h, obtain corresponding alcohol acyl chlorides.Then wherein
The γ-aminobutyric acid of 0.02mol (2.0621g) is added, at a temperature of 20 DEG C, reacts 12h, obtains corresponding γ-aminobutyric acid
Methyl esters 0.018mol (2.1143g), yield reaches 90%.
Specific embodiment 13
The methanol of 60ml and the thionyl chloride of 5ml are added in 100ml three-neck flask, reaction vessel is opened under ice-water bath
Begin to stir, so that reactant is sufficiently mixed, and then sufficiently generates acyl chlorides, reacts 6h, obtain corresponding alcohol acyl chlorides.Then wherein
The γ-aminobutyric acid of 0.02mol (2.0621g) is added, at a temperature of 60 DEG C, reacts 8h, obtains corresponding γ-aminobutyric acid first
Ester 0.0194mol (2.2735g), yield reaches 97%.
Specific embodiment 14
The ethyl alcohol of 60ml and the thionyl chloride of 5ml are added in 100ml three-neck flask, reaction vessel is opened under ice-water bath
Begin to stir, so that reactant is sufficiently mixed, and then sufficiently generates acyl chlorides, reacts 4h, obtain corresponding alcohol acyl chlorides.Then wherein
The γ-aminobutyric acid of 0.02mol (2.0621g) is added, at a temperature of 60 DEG C, reacts 8h, obtains corresponding γ-aminobutyric acid second
Ester 0.0184mol (2.4146g), yield reaches 92%.
Specific embodiment 15
The normal propyl alcohol of 60ml and the thionyl chloride of 5ml are added in 100ml three-neck flask, by reaction vessel under ice-water bath
Start to stir, so that reactant is sufficiently mixed, and then sufficiently generates acyl chlorides, reacts 4h, obtain corresponding alcohol acyl chlorides.Then at it
The middle γ-aminobutyric acid that 0.02mol (2.0621g) is added reacts 8h, obtains corresponding γ-aminobutyric acid at a temperature of 60 DEG C
Propyl ester 0.018mol (2.6148g), yield reaches 90%.
The preparation of two intermediate product of embodiment
Specific embodiment 16
α-alanine methyl esters 0.005mol (0.5162g) is added into the acetonitrile of 50ml, two (p-nitrophenyl) carbonic esters
0.025mol (7.6073g) and 4-dimethylaminopyridine (DMAP) 0.3g, be sufficiently stirred at 20 DEG C reaction 6h.End of reaction
Afterwards, reaction liquid is washed through 300ml dilute hydrochloric acid first, is then extracted through 300ml methylene chloride, extraction phase anhydrous sodium sulfate
It is dry, and removing solvent is rotated, column chromatographs to obtain intermediate product A0.004mol (1.0734g), and yield reaches 80%.
Specific embodiment 17
α-alanine methyl esters 0.01mol (1.0315g) is added into the acetonitrile of 100ml, two (p-nitrophenyl) carbonic esters
0.01mol (3.0432g) and 4-dimethylaminopyridine (DMAP) 0.6g, be sufficiently stirred at 60 DEG C reaction 3.5h.It has reacted
Reaction liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, extraction phase anhydrous slufuric acid by Bi Hou
Sodium is dry, and rotates removing solvent, and column chromatographs to obtain intermediate product A0.009mol (2.4143g), and yield reaches 90%.
Specific embodiment 18
α-alanine methyl esters 0.01mol (1.0316g) is added into the acetonitrile of 100ml, two (p-nitrophenyl) carbonic esters
0.03mol (9.1283g) and 4-dimethylaminopyridine (DMAP) 0.5g, be sufficiently stirred at 90 DEG C reaction 2h.End of reaction
Afterwards, reaction liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, extraction phase anhydrous sodium sulfate
It is dry, and removing solvent is rotated, column chromatographs to obtain intermediate product A0.0082mol (2.1993g), and yield reaches 82%.
Specific embodiment 19
α-alanine ethyl ester 0.01mol (1.1721g) is added into the acetonitrile of 100ml, two (p-nitrophenyl) carbonic esters
0.01mol (3.0432g) and 4-dimethylaminopyridine (DMAP) 0.6g, be sufficiently stirred at 60 DEG C reaction 3.5h.It has reacted
Reaction liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, extraction phase anhydrous slufuric acid by Bi Hou
Sodium is dry, and rotates removing solvent, and column chromatographs to obtain intermediate product B0.0085mol (2.3993g), and yield reaches 85%.
Specific embodiment 20
α-alanine propyl ester 0.01mol (1.3121g) is added into the acetonitrile of 100ml, two (p-nitrophenyl) carbonic esters
0.01mol (3.0432g) and 4-dimethylaminopyridine (DMAP) 0.6g, be sufficiently stirred at 60 DEG C reaction 3.5h.It has reacted
Reaction liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, extraction phase anhydrous slufuric acid by Bi Hou
Sodium is dry, and rotates removing solvent, and column chromatographs to obtain intermediate product C 0.0082mol (2.4295g), and yield reaches 82%.
Specific embodiment 21
Beta-alanine methyl esters 0.01mol (1.0311g) is added into the acetonitrile of 100ml, two (p-nitrophenyl) carbonic esters
0.01mol (3.0432g) and 4-dimethylaminopyridine (DMAP) 0.4g, be sufficiently stirred at 60 DEG C reaction 3.5h.It has reacted
Reaction liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, extraction phase anhydrous slufuric acid by Bi Hou
Sodium is dry, and rotates removing solvent, and column chromatographs to obtain intermediate product D 0.0087mol (2.3333g), and yield reaches 87%.
Specific embodiment 22
Beta-alanine ethyl ester 0.01mol (1.1721g) is added into the acetonitrile of 100ml, two (p-nitrophenyl) carbonic esters
0.01mol (3.0433g) and 4-dimethylaminopyridine (DMAP) 0.5g, be sufficiently stirred at 60 DEG C reaction 3.5h.It has reacted
Reaction liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, extraction phase anhydrous slufuric acid by Bi Hou
Sodium is dry, and rotates removing solvent, and column chromatographs to obtain intermediate product E 0.009mol (2.544g), and yield reaches 90%.
Specific embodiment 23
Beta-alanine propyl ester 0.01mol (1.3123g) is added into the acetonitrile of 100ml, two (p-nitrophenyl) carbonic esters
0.01mol (3.0431g) and 4-dimethylaminopyridine (DMAP) 0.5g, be sufficiently stirred at 60 DEG C reaction 3.5h.It has reacted
Reaction liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, extraction phase anhydrous slufuric acid by Bi Hou
Sodium is dry, and rotates removing solvent, and column chromatographs to obtain intermediate product F0.0088mol (2.6075g), and yield reaches 88%.
Specific embodiment 24
γ-aminobutyric acid methyl esters 0.01mol (1.1721g) is added into the acetonitrile of 100ml, two (p-nitrophenyl) carbonic esters
0.01mol (3.0432g) and 4-dimethylaminopyridine (DMAP) 0.5g, be sufficiently stirred at 60 DEG C reaction 3.5h.It has reacted
Reaction liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, extraction phase anhydrous slufuric acid by Bi Hou
Sodium is dry, and rotates removing solvent, and column chromatographs to obtain intermediate product G 0.0091mol (2.5683g), and yield reaches 91%.
Specific embodiment 25
γ-aminobutyric acid ethyl ester 0.01mol (1.3121g) is added into the acetonitrile of 100ml, two (p-nitrophenyl) carbonic esters
0.01mol (3.0432g) and 4-dimethylaminopyridine (DMAP) 0.5g, be sufficiently stirred at 60 DEG C reaction 3.5h.It has reacted
Reaction liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, extraction phase anhydrous slufuric acid by Bi Hou
Sodium is dry, and rotates removing solvent, and column chromatographs to obtain intermediate product H 0.0087mol (2.5776g), and yield reaches 87%.
Specific embodiment 26
γ-aminobutyric acid propyl ester 0.01mol (1.4521g) is added into the acetonitrile of 100ml, two (p-nitrophenyl) carbonic esters
0.01mol (3.0432g) and 4-dimethylaminopyridine (DMAP) 0.5g, be sufficiently stirred at 60 DEG C reaction 3.5h.It has reacted
Reaction liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, extraction phase anhydrous slufuric acid by Bi Hou
Sodium is dry, and rotates removing solvent, and column chromatographs to obtain intermediate product J 0.008mol (2.2821g), and yield reaches 80%.
The preparation of three resveratrol amino-acid ester analog derivative of embodiment
Specific embodiment 27
Addition gained intermediate product A 0.003mol (0.8053g), resveratrol 0.001mol into the acetonitrile of 50ml
(0.2283g) and 4-dimethylaminopyridine (DMAP) 0.5g, reaction 36h is sufficiently stirred at 20 DEG C will react after completion of the reaction
Liquid is washed through 300ml dilute hydrochloric acid first, is then extracted through 300ml methylene chloride, and extraction phase is dry with anhydrous sodium sulfate, and revolves
Solvent is evaporated off, column chromatographs to obtain product P10.00081mol (0.5373g), yield reaches 81%.Product P1Nucleus magnetic hydrogen spectrum figure
As shown in Figure 1.
Specific embodiment 28
Addition gained intermediate product D 0.004mol (1.0732g), resveratrol 0.001mol into the acetonitrile of 100ml
(0.2281g) and 4-dimethylaminopyridine (DMAP) 0.6g is sufficiently stirred reaction for 24 hours at 60 DEG C, after completion of the reaction, will react
Liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, and extraction phase is dry with anhydrous sodium sulfate, and revolves
Solvent is evaporated off, column chromatographs to obtain product P20.00083mol (0.5631g), yield reaches 83%.Product P2Nucleus magnetic hydrogen spectrum figure
As shown in Figure 2.
Specific embodiment 29
Addition gained intermediate product G 0.006mol (1.6943g), resveratrol 0.001mol into the acetonitrile of 100ml
(0.2282g) and 4-dimethylaminopyridine (DMAP) 0.6g, reaction 12h is sufficiently stirred at 90 DEG C will react after completion of the reaction
Liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, and extraction phase is dry with anhydrous sodium sulfate, and revolves
Solvent is evaporated off, column chromatographs to obtain product P30.00079mol (0.5231g), yield reaches 79%.Product P3Nucleus magnetic hydrogen spectrum figure
As shown in Figure 3.
Specific embodiment 30
Addition gained intermediate product B 0.005mol (1.4113g), resveratrol 0.001mol into the acetonitrile of 100ml
(0.2282g) and 4-dimethylaminopyridine (DMAP) 0.5g is sufficiently stirred reaction for 24 hours at 60 DEG C, after completion of the reaction, will react
Liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, and extraction phase is dry with anhydrous sodium sulfate, and revolves
Solvent is evaporated off, column chromatographs to obtain product P40.0008mol (0.5383g), yield reaches 80%.
Specific embodiment 31
Addition gained intermediate product C 0.005mol (1.4813g), resveratrol 0.001mol into the acetonitrile of 100ml
(0.2282g) and 4-dimethylaminopyridine (DMAP) 0.5g is sufficiently stirred reaction for 24 hours at 60 DEG C, after completion of the reaction, will react
Liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, and extraction phase is dry with anhydrous sodium sulfate, and revolves
Solvent is evaporated off, column chromatographs to obtain product P50.00082mol (0.5856g), yield reaches 82%.
Specific embodiment 32
Addition gained intermediate product D 0.005mol (1.3413g), resveratrol 0.001mol into the acetonitrile of 100ml
(0.2282g) and 4-dimethylaminopyridine (DMAP) 0.5g is sufficiently stirred reaction for 24 hours at 60 DEG C, after completion of the reaction, will react
Liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, and extraction phase is dry with anhydrous sodium sulfate, and revolves
Solvent is evaporated off, column chromatographs to obtain product P20.00075mol (0.4656g), yield reaches 75%.
Specific embodiment 33
Addition gained intermediate product E 0.005mol (1.4115g), resveratrol 0.001mol into the acetonitrile of 100ml
(0.2285g) and 4-dimethylaminopyridine (DMAP) 0.5g is sufficiently stirred reaction for 24 hours at 60 DEG C, after completion of the reaction, will react
Liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, and extraction phase is dry with anhydrous sodium sulfate, and revolves
Solvent is evaporated off, column chromatographs to obtain product P60.00079mol (0.5413g), yield reaches 79%.
Specific embodiment 34
Addition gained intermediate product F 0.005mol (1.4817g), resveratrol 0.001mol into the acetonitrile of 100ml
(0.2287g) and 4-dimethylaminopyridine (DMAP) 0.5g is sufficiently stirred reaction for 24 hours at 60 DEG C, after completion of the reaction, will react
Liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, and extraction phase is dry with anhydrous sodium sulfate, and revolves
Solvent is evaporated off, column chromatographs to obtain product P70.00085mol (0.6573g), yield reaches 85%.
Specific embodiment 35
Addition gained intermediate product G 0.005mol (1.4110g), resveratrol 0.001mol into the acetonitrile of 100ml
(0.2282g) and 4-dimethylaminopyridine (DMAP) 0.5g is sufficiently stirred reaction for 24 hours at 60 DEG C, after completion of the reaction, will react
Liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, and extraction phase is dry with anhydrous sodium sulfate, and revolves
Solvent is evaporated off, column chromatographs to obtain product P30.00077mol (0.5649g), yield reaches 77%.
Specific embodiment 36
Addition gained intermediate product H 0.005mol (1.4813g), resveratrol 0.001mol into the acetonitrile of 100ml
(0.2282g) and 4-dimethylaminopyridine (DMAP) 0.5g is sufficiently stirred reaction for 24 hours at 60 DEG C, after completion of the reaction, will react
Liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, and extraction phase is dry with anhydrous sodium sulfate, and revolves
Solvent is evaporated off, column chromatographs to obtain product P80.00088mol (0.6158g), yield reaches 88%.The nucleus magnetic hydrogen spectrum of product P8
Figure is as shown in Figure 4.
Specific embodiment 37
Addition gained intermediate product J 0.005mol (1.4263g), resveratrol 0.001mol into the acetonitrile of 100ml
(0.2282g) and 4-dimethylaminopyridine (DMAP) 0.5g is sufficiently stirred reaction for 24 hours at 60 DEG C, after completion of the reaction, will react
Liquid is washed through 500ml dilute hydrochloric acid first, is then extracted through 500ml methylene chloride, and extraction phase is dry with anhydrous sodium sulfate, and revolves
Solvent is evaporated off, column chromatographs to obtain product P90.0008mol (0.5932g), yield reaches 80%.Product P9Nucleus magnetic hydrogen spectrum figure
As shown in Figure 5.
The above disclosure is only the preferred embodiments of the present invention, cannot limit the right model of the present invention with this certainly
It encloses, those skilled in the art can understand all or part of the processes for realizing the above embodiment, and wants according to right of the present invention
Made equivalent variations is sought, is still belonged to the scope covered by the invention.
Claims (10)
1. a kind of resveratrol amino-acid ester analog derivative, which is characterized in that its structure is as shown in formula I:
Wherein, R is selected from-CH2-CH2-、Or-CH2-CH2-CH2, R ' is selected from-CH3、-CH2CH3Or-CH2CH2CH3。
2. resveratrol amino-acid ester analog derivative as described in claim 1, which is characterized in that its structure is as shown in formula II:
3. resveratrol amino-acid ester analog derivative as described in claim 1, which is characterized in that its structure is as shown in formula III:
4. resveratrol amino-acid ester analog derivative as described in claim 1, which is characterized in that its structure is as shown in formula IV:
Wherein, R ' is selected from-CH3、-CH2CH3Or-CH2CH2CH3。
5. a kind of preparation method of resveratrol amino-acid ester analog derivative as described in claim 1, which is characterized in that with white
Veratryl alcohol, R amino acid, R ' alcohol, thionyl chloride, two (p-nitrophenyl) carbonic esters are with acetonitrile using DMAP as catalyst for raw material
Solvent, synthesizing resveratrol amino acid esters derivative；Wherein, R amino acid be selected from α-alanine, Beta-alanine or
One of γ-aminobutyric acid, R ' alcohol be selected from methanol, ethyl alcohol or normal propyl alcohol one of.
6. the preparation method of resveratrol amino-acid ester analog derivative as claimed in claim 5, which is characterized in that including following
Step:
A. thionyl chloride is added into R ' alcohol, is sufficiently stirred under ice-water bath, R amino acid is added and is filled at a temperature of 20 DEG C~80 DEG C
After dividing stirring 6h~12h, excessive R ' alcohol is distilled off, obtains the R amino acid R ' ester derivant of solid-like；Wherein, R amino acid
Selected from one of α-alanine, Beta-alanine or γ-aminobutyric acid, R ' alcohol in methanol, ethyl alcohol or normal propyl alcohol one
Kind；
B. it is molten that excessive acetonitrile is added in R amino acid R ' ester derivant, two (p-nitrophenyl) carbonic esters and DMAP step a obtained
In agent, wherein the amount of the substance of two (p-nitrophenyl) carbonic esters is 1 times~5 times of R amino acid R ' ester derivant；20 DEG C~
Under 90 DEG C of reaction temperature, reaction 2h~6h is sufficiently stirred, obtains intermediate product mixed solution；
C. hydrochloric acid is added into the intermediate product mixed solution that step b is obtained to be washed, methylene chloride is added into cleaning solution
Standing extraction is carried out, extraction phase successively through drying, revolving and column chromatographic runs, obtains solid-like intermediate product；
D. the obtained solid-like intermediate product of resveratrol, step c and DMAP are added in excessive acetonitrile solvent, wherein step
The amount of the substance for the solid-like intermediate product that rapid c is obtained is 2 times~8 times of resveratrol, in 20 DEG C~90 DEG C of reaction temperature
Under, reaction 12h~36h is sufficiently stirred, obtains final product mixed solution；
E. hydrochloric acid is added into the final product mixed solution that step d is obtained to be washed, methylene chloride is added into cleaning solution
Standing extraction is carried out, extraction phase successively through drying, revolving and column chromatographic runs, obtains solid product.
7. the preparation method of resveratrol amino-acid ester analog derivative as claimed in claim 6, which is characterized in that in step d,
The amount of the substance for the solid-like intermediate product that step c is obtained is 4 times~6 times of resveratrol.
8. the preparation method of resveratrol amino-acid ester analog derivative as claimed in claim 6, which is characterized in that in step a,
Addition thionyl chloride is slowly added dropwise to R ' alcohol, is sufficiently stirred under ice-water bath, to obtain alcohol acyl chlorides.
9. the preparation method of resveratrol amino-acid ester analog derivative as claimed in claim 6, which is characterized in that step c with
In step e, the raffinate phase of extraction is operated through revolving, solvent is removed, to recycle DMAP.
10. the preparation method of resveratrol amino-acid ester analog derivative as claimed in claim 6, which is characterized in that step c with
In step e, at least one of anhydrous sodium sulfate, silica gel, anhydrous calcium chloride, montmorillonite, anhydrous calcium chloride or aluminium oxide are selected
Operation is dried to extraction phase.
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| US20130090298A1 (en) * | 2010-06-18 | 2013-04-11 | Green Cross Corporation | Thiazole Derivatives as SGLT2 Inhibitors and Pharmaceutical Composition Comprising Same |
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