CN106866418B - Beta-elemene dimer derivate, Its Preparation Method And Use - Google Patents
Beta-elemene dimer derivate, Its Preparation Method And Use Download PDFInfo
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- CN106866418B CN106866418B CN201710038980.8A CN201710038980A CN106866418B CN 106866418 B CN106866418 B CN 106866418B CN 201710038980 A CN201710038980 A CN 201710038980A CN 106866418 B CN106866418 B CN 106866418B
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Abstract
The present invention relates to natural drugs and medicinal chemistry art, specifically disclose a kind of β elemenes dimer derivate (I), (II), (III) or (IV), wherein X, R1、R2、R3、R4、R5、R6With the same specification of definition of Y.The invention also discloses the preparation method of these β elemene dimer derivates, and the pharmaceutical composition containing the β elemenes dimer derivate or its pharmaceutically acceptable salt and its anti-oxidant aspect application.Pharmaceutical research shows that the derivative of the present invention has the effective antioxidation of low toxicity.
Description
Technical field
The present invention relates to a kind of elemene dimer derivates, and in particular to a kind of beta-elemene dimer derivate, its
Preparation method and its usage.
Background technology
Atherosclerosis (AS) is the common pathophysiological basis that cardiocerebrovasculaevents events occur, and is to cause cardiovascular and cerebrovascular disease
Disease and a dead key factor.Studies have shown that the occurrence and development of AS and oxidative stress close relation.The danger that AS occurs
Dangerous factor, such as hypercholesterolemia, diabetes, hypertension, smoking all can the productions such as inducing endothelial cell, vascular smooth muscle cells
Raw excess oxygen radical (ROS), and these ROS participate in entire evolutions of the AS from fat line lesion to plaque rupture, and mediate
Vascular endothelial cell, smooth muscle cell and mononuclear macrophage function change and damage, while promoting inflammatory reaction again.Cause
It is still the top priority for preventing AS that this, which finds novel antioxidant with strong points,.Synthetized oxidation preventive agent is due to its clinical poison
Side effect is just gradually eliminated, and natural is increasingly increased with its use of exclusive safety clinically.
Beta-elemene is the sesquiterpenoid separated from the rhizome of Curcuma wenyujin (C.Wenchowensis), is
The main active of elemene.Studies have shown that beta-elemene has anti oxidative damage, there is potential anti-artery congee
Sample induration (gross profit flies, and Huo Weimin, Liu Jun wait Chinese Clinicals pharmacology and acology, and 2012,17:727.).By to β-
Elemene carries out structural modification, finds two 13- beta-elemenes dimer derivates (5r and 5s) relative to monomer derived object pair
The human endothelial cells of oxidative damage have higher antioxidant activity, while being shown to normal human's endothelial cell lower
Toxic effect (Chen J.C., Duan W.L., Bai R.R., et al.Bioorg Med Chem Lett.2014,24:
3407.).In consideration of it, the beta-elemene dimer derivate of design composite structure novelty, wide variety, analysis and summary structure effect are closed
System finds that antioxidation is stronger, the lower lead compound of toxicity, has to treatment atherosclerosis relevant disease important
Meaning.
Invention content
The technical problem to be solved by the present invention is to be directed to the deficiencies in the prior art, a kind of new, antioxygen is provided
Change acts on stronger, the lower beta-elemene dimer derivate of toxicity or its pharmaceutically acceptable salt.
Another technical problem to be solved by this invention there is provided containing above-mentioned beta-elemene dimer derivate or
The oxidation resistant pharmaceutical composition of its pharmaceutically acceptable salt.
There is provided above-mentioned beta-elemene dimer derivate or its medicines for another technical problem to be solved by this invention
The purposes of acceptable salt on.
The technical problem to be solved by the present invention is to what is be achieved through the following technical solutions.
The present invention provides a kind of with the beta-elemene dimer derivate that beta-elemene is raw material preparation, pharmaceutical research
Show that the derivative of the present invention has the effective antioxidation of low toxicity.
Technical scheme is as follows：
With logical formula (I), (II), (III) or (IV) beta-elemene dimer derivate or its is pharmaceutically acceptable
Salt：
Wherein X is selected from-OC (O)-,-O- ,-S- ,-N (R)-, and R is selected from H, unsubstituted or substituted C1-5Straight chained alkyl or not
The C of substitution or substitution3-5Branched alkyl；
Y is selected from-OC (O)-,-O- or-S-；
R1Selected from unsubstituted or substituted C1-10Straight chained alkyl, unsubstituted or substituted C3-10It is branched alkyl, unsubstituted or take
The C in generation2-10Straight-chain alkenyl, unsubstituted or substituted C3-10Branched-chain alkenyl, unsubstituted or substituted C2-10It is straight-chain alkynyl, unsubstituted
Or the C of substitution4-10Branch alkynyl or unsubstituted or substituted C6-12Naphthenic base or aryl；
R2Selected from unsubstituted or substituted C1-10Straight chained alkyl, unsubstituted or substituted C3-10It is branched alkyl, unsubstituted or take
The C in generation2-10Straight-chain alkenyl or unsubstituted or substituted C3-10Branched-chain alkenyl；
R3Selected from unsubstituted or substituted C1-10Straight chained alkyl, unsubstituted or substituted C3-10It is branched alkyl, unsubstituted or take
The C in generation1-10Straight chain acyl, unsubstituted or substituted C3-10Branched chain acyl, unsubstituted or substituted C6-12Cycloalkanoyl or fragrant acyl
Base, unsubstituted or substituted C2-10Straight-chain alkenyl, unsubstituted or substituted C3-10Branched-chain alkenyl, unsubstituted or substituted C3-10Directly
Alkenoyl or unsubstituted or substituted C4-10Branch alkenoyl；
R4Selected from H, unsubstituted or substituted C1-5Straight chained alkyl or unsubstituted or substituted C3-5Branched alkyl；
R5Selected from (CH2)n, n=0-10 or unsubstituted or substituted C3-10Branched alkyl；
R6Selected from unsubstituted or substituted C1-10Straight chained alkyl, unsubstituted or substituted C3-10It is branched alkyl, unsubstituted or take
The C in generation2-10Straight-chain alkenyl or unsubstituted or substituted C3-10Branched-chain alkenyl.
Derivative of the present invention or its pharmaceutically acceptable salt, wherein X preferably-OC (O)-,-O- ,-NH- ,-N (CH2)-
Or-NCH3-；
Y preferably-OC (O)-or-O-；
R1It is preferred that (CH2)2、(CH2)3、(CH2)4、(CH2)5、(CH2)6, CH=CH or C6H4；
R2It is preferred that (CH2)2、(CH2)3、(CH2)4、(CH2)5Or (CH2)6；
R3It is preferred that (CH2)2、(CH2)3、(CH2)4、(CH2)2CO、(CH2)3CO、CH2(CH3)2CH2CO, CH=CHCO or
C6H4CO；
R4It is preferred that H, CH2Or CH3；
R5It is preferred that (CH2)n, n=0-5；
R6It is preferred that (CH2)2、(CH2)3、(CH2)4、(CH2)5Or (CH2)6。
Derivative of the present invention or its pharmaceutically acceptable salt, wherein X more preferably-OC (O)-or-O-；
Y more preferably-OC (O)-；
R1More preferably (CH2)3、(CH2)4、(CH2)5Or CH=CH；
R2More preferably (CH2)2、(CH2)3Or (CH2)4；
R3More preferably (CH2)2、(CH2)3、(CH2)2CO or (CH2)3CO；
R4More preferable CH2Or CH3；
R5More preferably (CH2)n, n=0-1；
R6More preferably (CH2)4、(CH2)5Or (CH2)6。
Partial derivatives of the present invention or its pharmaceutically acceptable salt：
Ethanedioic acid two (13- β-elemol) ester；
1,3- malonic acid two (13- β-elemol) ester；
1,4- maleics two (13- β-elemol) ester；
1,5- glutaric acids two (13- β-elemol) ester；
Diglycolic acid two (13- β-elemol) ester；
M-phthalic acid two (13- β-elemol) ester；
Terephthalic acid (TPA) two (13- β-elemol) ester；
1,8- naphthalenedicarboxylic acids two (13- β-elemol) ester；
Cis- 1,2- cyclohexyl dicarboxylic acids two (13- β-elemol) ester；
Cis- 5- norbornene-external form -2,3- dioctyl phthalate two (13- β-elemol) ester；
1,4- bis- (beta-elemene -13- oxygen) butane；
L-Aspartic acid two (13- β-elemol) ester；
Pidolidone two (13- β-elemol) ester；
1,2- bis- (N- methyl-N-13- beta-elemenes) ethylenediamine；
1,4- bis- (N-13- beta-elemenes) piperazine；
1,2- bis- (N- methyl-N-3- propionic acid -13- β-elemi alcohol ester) ethylenediamine；
1,2- bis- (N- methyl-N-4- butyric acid -13- β-elemi alcohol ester) ethylenediamine；
1,4- bis- (N-3- propionic acid -13- β-elemi alcohol ester) piperazine；
1,4- bis- (N-4- butyric acid -13- β-elemi alcohol ester) piperazine；
1,4- bis- (N-4- butyric acid -13- β-elemol monoesters) piperazine diamides；
1- (4 butyric acid -13- β-elemi alcohol ester) -4- (formic acid -13- β-elemi alcohol ester) -1- hydrogen -1,2,3- triazoles；
1- (5- valeric acids -13- β-elemi alcohol ester) -4- (formic acid -13- β-elemi alcohol ester) -1- hydrogen -1,2,3- triazoles；
1- (6- caproic acids -13- β-elemi alcohol ester) -4- (formic acid -13- β-elemi alcohol ester) -1- hydrogen -1,2,3- triazoles；
1- (8- octanoic acids -13- β-elemi alcohol ester) -4- (formic acid -13- β-elemi alcohol ester) -1- hydrogen -1,2,3- triazoles；
1- (4 butyric acid -13- β-elemi alcohol ester) -4- (methylene -13- beta-elemenes ether) -1- hydrogen -1,2,3- triazoles；
1- (5- valeric acids -13- β-elemi alcohol ester) -4- (methylene -13- beta-elemenes ether) -1- hydrogen -1,2,3- triazoles；
1- (6- caproic acids -13- β-elemi alcohol ester) -4- (methylene -13- beta-elemenes ether) -1- hydrogen -1,2,3- triazoles；
1- (8- octanoic acids -13- β-elemi alcohol ester) -4- (methylene -13- beta-elemenes ether) -1- hydrogen -1,2,3- triazoles；
1,4- bis- (4- (formic acid -13- β-elemi alcohol ester) -1- hydrogen -1,2,3- triazol-1-yls) butane；
1,4- bis- (6- (formic acid -13- β-elemi alcohol ester) -1- hydrogen -1,2,3- triazol-1-yls) hexane；
1,4- bis- (4- (methylene -13- beta-elemenes ether) -1- hydrogen -1,2,3- triazol-1-yls) butane；
1,4- bis- (6- (methylene -13- beta-elemenes ether) -1- hydrogen -1,2,3- triazol-1-yls) hexane.
Here is that beta-elemene dimer derivate leads to formula (I), (II), compound shown in (III) and (IV) in the present invention
Preparation method.
The preparation of logical formula (I), (II), compound shown in (III) and (IV), is respectively required for by among 13- β-elemol
Body.
The preparation method includes the following steps：Beta-elemene is with sodium hypochlorite in dichloromethane and glacial acetic acid mixed solution
In, it is reacted under condition of ice bath and 13- chloros-beta-elemene is made；Then 13- chloros-beta-elemene is using anhydrous DMF as solvent and nothing
Water acetic acid sodium reacts in a heated condition generates 13- β-elemi alcohol acetic ester, then obtains intermediate 13- through potassium hydroxide hydrolysis
β-elemol.
Part of compounds can be prepared according to reaction one in logical formula (I).13- β-elemol is with corresponding ring dicarboxylic anhydride in DMAP
In Et under being catalyzed with EDCI or with corresponding diacid chloride3Reaction is carried out under N catalysis as solvent using dichloromethane to can be prepared by accordingly
Product.Reaction one：
Part of compounds can be prepared according to reaction two in logical formula (I), and 13- β-elemol is with Boc- acidic amino acids in EDCI
Reacted by solvent of dichloromethane under being catalyzed with DMAP, gained intermediate using dichloromethane as solvent under condition of ice bath and
Trifluoroacetic acid reaction sloughs Boc and can be prepared by corresponding product.
Reaction two：
Part of compounds can be prepared according to reaction three in logical formula (I), and 13- β-elemol is solvent in sodium hydrogen using anhydrous DMF
Effect is lower to can be prepared by corresponding product to dibromo alkane reaction.
Reaction three：
Part of compounds can be prepared according to reaction four in logical formula (I), and 13- β-elemol passes through NBS/Ph3P is in dichloromethane
Middle bromo, then from different diamines with Et3N is that acid binding agent back flow reaction in anhydrous acetonitrile can be prepared by corresponding product.
Reaction four：
Part of compounds can be prepared according to reaction five in logical formula (II), and 13- β-elemol is with dichloromethane with acrylic acid
Solvent is reacted under EDCI and DMAP catalysis, 13- β-elemol acrylate is made, then from different diamines in tetrahydrochysene
Back flow reaction can be prepared by corresponding product in furans.
Reaction five：
Part of compounds can be prepared according to reaction six in logical formula (II), and 13- β-elemol is with bromo carboxylic acid with dichloromethane
It is reacted under DCC and DMAP catalysis for solvent, gained intermediate is then from different diamines with Et3N is acid binding agent in nothing
Heating reaction can be prepared by corresponding product in water DMF.
Reaction six：
Part of compounds can be prepared according to reaction seven in logical formula (II), and 13- β-elemol is with ring dicarboxylic anhydride with dichloromethane
It is solvent in DMAP and Et3It is reacted under N catalysis, gained intermediate is solvent under the action of thionyl chloride using dichloromethane
Acid chloride intermediate is generated, then from different diamines with Et3N, which reacts for acid binding agent in anhydrous methylene chloride, can be prepared by accordingly
Product.Reaction seven：
Compound can be prepared according to reaction eight in logical formula (III) and (IV), 13- β-elemol and bromo carboxylic acid in DCC and
It is reacted by solvent of dichloromethane under DMAP catalysis, the 80 DEG C of heating in anhydrous DMF with sodium azide again of gained intermediate
Intermediate 1 is made in lower reaction；13- β-elemol and different acetylenic acids under DCC and DMAP catalysis using dichloromethane as solvent or with
Different bromo alkyl alkynes are reacted as solvent under the effect of sodium hydrogen using anhydrous DMF is made intermediate 2 and intermediate 3 respectively；Then in
Mesosome 2 and intermediate 3 are respectively with intermediate 1 or with two nitrine alkane in dichloromethane and water mixed solution, in five water sulfuric acid
Corresponding product is made in copper and the lower reaction of sodium ascorbate effect.
Reaction eight：
A kind of oxidation resistant pharmaceutical composition, wherein containing logical formula (I), the beta-elemene dimerization of (II), (III) or (IV)
Syntaxy object or its pharmaceutically acceptable salt.
Further, the oxidation resistant pharmaceutical composition, wherein containing pharmaceutically acceptable carrier.
The beta-elemene dimer derivate or its pharmaceutically acceptable salt use of logical formula (I), (II), (III) or (IV)
In the purposes for preparing anti-oxidation medicine.
The present invention has been synthetically prepared serial beta-elemene dimer derivate, and discloses it and preparing antioxidant drug object space
The purposes in face.
The a kind of of the present invention with beta-elemene is that raw material prepares a series of beta-elemene dimer derivates, activity height,
Toxicity is low, and pharmaceutical research shows that the derivative of the present invention has low toxicity and an effective antioxidation, bioavilability higher,
Potentiality with exploitation treatment atherosclerosis relevant disease drug.
Description of the drawings
The general formula of Fig. 1 beta-elemenes dimer derivates or its pharmaceutically acceptable salt.
In conjunction with drawings and examples, the invention will be further described.
Specific implementation mode
The preparation of intermediate 13- β-elemol
100mmol beta-elemenes are dissolved in (V in 20mL dichloromethane and acetic acid mixed solution:V=2:1), condition of ice bath
Under be slowly dropped into the liquor natrii hypochloritis containing 180mmol Active Chlorines, ice bath reacts 4h.Dichloromethane layer is separated, water layer is with two
Chloromethanes extracts 3 times, and combined dichloromethane is concentrated to give weak yellow liquid crude product, and liquid crude product is dissolved in the anhydrous N of 15mL, N- dimethyl
In formamide (DMF), 200mmol anhydrous sodium acetates are added with stirring, react 7h in 100 DEG C.Reaction solution is taken out with 200 mesh silica gel
15mL saturated salt solutions are added in filter, filtrate, and with petroleum ether extraction 3 times.Inspissated oil ether obtains yellow liquid, with 8mL methanol and
The mixed solution of 8mL chloroforms dissolves, and 200mmol potassium hydroxide back flow reactions 2h is added.Filtering, filtrate concentration, with petroleum ether：Second
Acetoacetic ester=10:1(V:V) column chromatography obtains colorless liquid product, gross production rate 15%.1H NMR(CDCl3,300MHz)δ:
1.01(s,3H),1.41-1.67(m,6H),1.71(s,3H),1.97-2.05(m,2H),4.13(s,2H),4.59(s,1H),
4.82 (t, J=1.7Hz, 1H), 4.88 (s, 1H), 4.91-4.94 (m, 2H), 5.05 (d, J=1.3Hz, 1H), 5.81 (dd, J1
=17.8Hz, J2=10.5Hz, 1H)13C NMR(CDCl3,300MHz)δ:153.7,150.0,147.4,112.1,109.9,
107.9,65.1,52.7,41.4,39.8,39.7,33.2,27.2,24.7,16.5.
Embodiment 1
The preparation of ethanedioic acid two (13- β-elemol) ester
1mmol 13- β-elemol is dissolved in 10mL anhydrous methylene chlorides, sequentially add 0.5mmol oxalyl chlorides,
1.5mmolEt3N and 0.1mmol DMAP, normal-temperature reaction 1h.Reaction solution is obtained with 10% salt acid elution 3 times, concentration dichloromethane layer
Weak yellow liquid.With petroleum ether：Ethyl acetate=100:1(V:V) column chromatography obtains colorless liquid product, yield 70%.1H
NMR(300MHz,CDCl3) δ 5.74 (dd, J=17.8,10.5Hz, 2H), 5.08 (s, 2H), 5.02 (s, 2H), 4.86 (d, J=
3.2Hz,2H),4.81(s,2H),4.76(s,2H),4.72(s,4H),4.51(s,2H),2.07–1.89(m,4H),1.64(s,
6H),1.61–1.49(m,6H),1.47–1.34(m,6H),0.94(s,6H).13C NMR(75MHz,CDCl3)δ156.98,
149.40,146.75,146.33,112.28,111.85,109.62,67.91,52.10,41.23,39.24(2),32.46,
26.50,24.33,16.09.
Embodiment 2
The preparation of 1,3- malonic acid two (13- β-elemol) ester
With reference to the synthetic method of embodiment 1, oxalyl chloride replaces with malonyl chloride, obtains colorless liquid product, and yield is
73%.1H NMR(300MHz,CDCl3) δ 5.74 (dd, J=17.7,10.5Hz, 2H), 5.00 (s, 2H), 4.95 (s, 2H),
4.86 (d, J=3.7Hz, 2H), 4.81 (s, 2H), 4.76 (s, 2H), 4.59 (s, 4H), 4.52 (s, 2H), 3.39 (s, 2H),
2.00–1.90(m,4H),1.64(s,6H),1.60–1.50(m,3H),1.46–1.32(m,6H),0.93(s,6H).13C NMR
(75MHz,CDCl3)δ165.61,149.46,147.23,146.81,111.80,110.98,109.56,66.62,52.15,
41.19,41.14,39.29,39.23,32.50,26.53,24.30,16.10.
Embodiment 3
The preparation of 1,4- maleic acids two (13- β-elemol) ester
1mmol 13- β-elemol is dissolved in 10mL anhydrous methylene chlorides, 0.5mmol maleic acids are sequentially added
Acid anhydride, 1.5mmol Et3N and 0.1mmol DMAP, normal-temperature reaction 2h.Reaction solution concentrates dichloromethane with 10% salt acid elution 3 times
Layer obtains colourless liquid.With petroleum ether：Ethyl acetate=100:1(V:V) column chromatography obtains colorless liquid product, yield 76%
。1H NMR(300MHz,CDCl3) δ 6.85 (s, 2H), 5.75 (dd, J=17.8,10.5Hz, 2H), 5.02 (s, 2H), 4.98 (s,
2H), 4.86 (d, J=3.7Hz, 2H), 4.81 (s, 2H), 4.76 (s, 2H), 4.64 (s, 4H), 4.52 (s, 2H), 2.04-1.90
(m,4H),1.64(s,6H),1.61–1.48(m,6H),1.47–1.36(m,6H),0.94(s,6H).13C NMR(75MHz,
CDCl3)δ164.12,149.42,147.27,146.79,133.19,111.83,111.24,109.60,66.49,52.15,
41.29,39.28,39.24,32.53,26.54,24.31,16.10.
Embodiment 4
The preparation of 1,5- glutaric acids two (13- β-elemol) ester
With reference to the synthetic method of embodiment 3, maleic anhydride replaces with glutaric anhydride, obtains colorless liquid product, produces
Rate is 82%.1H NMR(300MHz,CDCl3) δ 5.74 (dd, J=17.8,10.5Hz, 2H), 4.97 (s, 2H), 4.93 (s,
2H), 4.86 (d, J=4.0Hz, 2H), 4.81 (s, 2H), 4.75 (s, 2H), 4.52 (s, 6H), 2.37 (t, J=7.3Hz, 4H),
2.02–1.87(m,6H),1.64(s,6H),1.60–1.47(m,6H),1.46–1.34(m,6H),0.94(s,6H).13C NMR
(75MHz,CDCl3)δ172.06,149.49,147.87,146.84,111.78,110.44,109.54,65.60,52.18,
41.34,39.31,39.24,32.84,32.55,26.55,24.29,19.63,16.10.
Embodiment 5
The preparation of diglycolic acid two (13- β-elemol) ester
With reference to the synthetic method of embodiment 3, maleic anhydride replaces with anhydride diethylene glycol, obtains colorless liquid product,
Yield is 68%.1H NMR(300MHz,CDCl3) δ 5.74 (dd, J=17.8,10.5Hz, 2H), 4.99 (s, 2H), 4.96 (s,
2H), 4.86 (d, J=4.3Hz, 2H), 4.81 (s, 2H), 4.76 (s, 2H), 4.60 (s, 4H), 4.51 (s, 2H), 4.22 (s,
4H),2.07–1.89(m,4H),1.64(s,6H),1.60–1.47(m,6H),1.45–1.34(m,6H),0.93(s,6H).13C
NMR(75MHz,CDCl3)δ168.94,149.42,147.33,146.79,111.81,111.18,109.58,67.65,
66.08,52.16,41.28,39.27,39.22,32.54,26.53,24.29,16.10.
Embodiment 6
The preparation of M-phthalic acid two (13- β-elemol) ester
With reference to the synthetic method of embodiment 1, oxalyl chloride replaces with m-phthaloyl chloride, obtains colorless liquid product, yield
It is 72%.1H NMR(300MHz,CDCl3) δ 8.75 (s, 1H), 8.28 (d, J=1.6Hz, 1H), 8.25 (d, J=1.6Hz,
1H), 7.56 (t, J=7.8Hz, 1H), 5.82 (dd, J=17.8,10.5Hz, 2H), 5.17 (s, 2H), 5.08 (s, 2H), 4.93
(d, J=4.4Hz, 2H), 4.88 (s, 2H), 4.87 (s, 4H), 4.83 (s, 2H), 4.59 (s, 2H), 2.20-2.07 (m, 2H),
2.06–2.00(m,2H),1.71(s,6H),1.70–1.62(m,6H),1.60–1.45(m,6H),1.02(s,6H).13C NMR
(75MHz,CDCl3)δ164.92,149.47,147.68,146.81,133.41,130.29,128.21,111.82,110.84,
109.56,66.37,52.19,41.54,39.32,39.26,32.61,26.63,24.29,16.13.
Embodiment 7
The preparation of terephthalic acid (TPA) two (13- β-elemol) ester
With reference to the synthetic method of embodiment 1, oxalyl chloride replaces with paraphthaloyl chloride, obtains colorless liquid product, yield
It is 80%.1H NMR(300MHz,CDCl3) δ 8.06 (s, 4H), 5.74 (dd, J=17.7,10.5Hz, 2H), 5.09 (s, 2H),
5.01 (s, 2H), 4.86 (d, J=4.2Hz, 2H), 4.81 (s, 2H), 4.78 (s, 4H), 4.76 (s, 2H), 4.52 (s, 2H),
2.15–1.99(m,2H),1.99–1.90(m,2H),1.63(s,6H),1.62–1.54(m,6H),1.47–1.34(m,6H),
0.94(s,6H).13CNMR(300MHz,CDCl3)δ164.95,149.43,147.65,146.81,133.59,129.14,
111.82,111.07,109.59,66.52,52.21,41.58,39.32,39.25,32.66,26.61,24.29,16.13.
Embodiment 8
The preparation of 1,8- naphthalenedicarboxylic acids two (13- β-elemol) ester
With reference to the synthetic method of embodiment 3, maleic anhydride replaces with 1,8- naphthalic anhydrides, obtains colourless liquid production
Object, yield 61%.1H NMR(300MHz,CDCl3) δ 7.94 (t, J=7.4Hz, 4H), 7.47 (t, J=7.7Hz, 2H),
5.73 (dd, J=17.8,10.5Hz, 2H), 5.08 (s, 2H), 4.97 (s, 2H), 4.84 (d, J=3.9Hz, 2H), 4.80 (s,
2H),4.75(s,6H),4.49(s,2H),2.13–1.99(m,2H),1.98–1.90(m,2H),1.62(s,6H),1.60–
1.47(m,6H),1.46–1.34(m,6H),0.91(s,6H).13C NMR(75MHz,CDCl3)δ167.93,149.56,
147.69,146.88,133.90,131.89,129.63,129.41,127.07,124.79,111.75,110.72,109.48,
66.29,52.19,41.37,39.34,39.26,32.64,26.58,24.29,16.10.
Embodiment 9
The preparation of cis- 1,2- cyclohexyl dicarboxylic acids two (13- β-elemol) ester
With reference to the synthetic method of embodiment 3, maleic anhydride replaces with cis- 1,2- cyclohexyl dicarboxylic acids acid anhydride, obtains colourless
Product liquid, yield 82%.1H NMR(300MHz,CDCl3) δ 5.82 (dd, J=17.8,10.5Hz, 2H), 5.04 (s,
2H), 4.99 (s, 2H), 4.93 (d, J=4.3Hz, 2H), 4.88 (s, 2H), 4.83 (s, 2H), 4.67-4.51 (m, 6H),
2.95–2.85(s,2H),2.14–1.96(m,6H),1.87–1.72(m,2H),1.71(s,6H),1.65–1.54(m,6H),
1.52–1.40(m,10H),1.01(s,6H).13C NMR(75MHz,CDCl3)δ172.78,149.52,147.97,146.84,
111.75,110.27,109.48,65.66,65.63,52.25,42.25,41.33,39.35,39.24,32.56,26.54,
25.84,24.25,23.31,16.13.
Embodiment 10
The preparation of cis- 5- norbornene-external form -2,3- dioctyl phthalate two (13- β-elemol) ester
With reference to the synthetic method of embodiment 3, maleic anhydride replaces with cis- 5- norbornene-external form -2,3- dioctyl phthalate
Acid anhydride obtains colorless liquid product, yield 74%.1H NMR(300MHz,CDCl3) δ 6.26 (s, 2H), 5.81 (dd, J=
17.8,10.5Hz, 2H), 5.02 (s, 2H), 4.97 (s, 2H), 4.92 (d, J=4.1Hz, 2H), 4.88 (s, 2H), 4.82 (s,
2H),4.65–4.55(m,4H),4.44–4.35(m,2H),3.35(s,2H),3.19(s,2H),2.06–1.95(m,4H),
1.70(s,6H),1.68–1.53(m,6H),1.51–1.41(m,6H),1.00(s,6H).13C NMR(75MHz,CDCl3)δ
171.59,149.52,147.99,146.82,134.45,134.40,111.78,110.26,110.18,109.50,65.68,
52.27,48.24,47.82,45.91,41.28,39.37,39.24,32.52,26.55,24.25,16.13.
Embodiment 11
The preparation of 1,4- bis- (13-O- beta-elemenes) butane
1mmol 13- β-elemol is dissolved in 10mL anhydrous DMFs, 1.2mmol NaH are added, reacts 0.5h, is added
0.5mmol Isosorbide-5-Nitraes-dibromobutane, room temperature the reaction was continued 1h.Reaction solution adds water quenching to go out, and dichloromethane extraction concentrates dichloromethane
Layer obtains weak yellow liquid.With petroleum ether：Ethyl acetate=100:1(V:V) column chromatography, obtains colorless liquid product, and yield is
63%.1H NMR(300MHz,CDCl3) δ 5.82 (dd, J=17.8,10.5Hz, 2H), 5.03 (s, 2H), 4.95 (s, 2H),
4.92 (dd, J=5.3,1.2Hz, 2H), 4.88 (s, 2H), 4.82 (s, 2H), 4.58 (s, 2H), 3.95 (s, 4H), 3.42 (s,
4H),2.13–1.97(m,4H),1.71(s,6H),1.69–1.54(m,10H),1.52–1.41(m,6H),1.01(s,6H).13C
NMR(75MHz,CDCl3)δ150.33,149.74,147.14,111.63,109.41,109.27,72.61,69.51,52.26,
40.85,39.46,39.34,32.65,26.57,26.06,24.34,16.09.
Embodiment 12
The preparation of L-Aspartic acid two (13- β-elemol) ester
1mmol 13- β-elemol is dissolved in 10mL anhydrous methylene chlorides, 1.2mmol EDCI, 0.1mmol is added
DMAP and 0.5mmol Boc-L- aspartic acids, normal-temperature reaction 2h.Reaction solution concentrates dichloromethane with 10% salt acid elution 3 times
Layer obtains weak yellow liquid.Gained liquid is dissolved in dichloromethane, and under condition of ice bath, trifluoroacetic acid is slowly added dropwise, keeps ice bath anti-
0.5h is answered, room temperature is moved to the reaction was continued 2h.It is spin-dried for reaction solution, with petroleum ether：Ethyl acetate=6:1(V:V) column chromatography obtains light
Yellow liquid product, gross production rate 62%.1H NMR(300MHz,CDCl3) δ 5.74 (dd, J=17.8,10.5Hz, 2H), 4.98
(s, 2H), 4.95 (d, J=3.7Hz, 2H), 4.86 (d, J=3.5Hz, 2H), 4.81 (s, 2H), 4.76 (s, 2H), 4.58 (s,
2H),4.55(s,2H),4.51(s,2H),3.90–3.80(m,1H),2.90–2.71(m,2H),1.99–1.89(m,4H),
1.64(s,6H),1.61–1.47(m,6H),1.45–1.34(m,6H),0.93(s,6H).13C NMR(75MHz,CDCl3)δ
172.75,170.31,149.46,149.41,147.50,147.39,146.82,146.79,111.82,111.79,110.96,
110.72,109.60,109.56,66.58,66.09,52.15,50.65,41.29,41.22,39.29,39.23,37.91,
32.53,26.54,24.31,16.10.
Embodiment 13
The preparation of Pidolidone two (13- β-elemol) ester
With reference to the synthetic method of embodiment 12, Boc-L- aspartic acids replace with Boc-L- glutamic acid, obtain colourless liquid
Product, gross production rate 65%.1H NMR(300MHz,CDCl3) δ 5.74 (dd, J=17.8,10.5Hz, 2H), 4.98 (d, J=
1.9Hz, 2H), 4.94 (d, J=7.0Hz, 2H), 4.86 (d, J=3.9Hz, 2H), 4.81 (s, 2H), 4.75 (s, 2H), 4.56
(s, 2H), 4.52 (s, 4H), 3.50-3.40 (m, 2H), 2.46 (t, J=7.5Hz, 2H), 2.15-2.01 (m, 1H), 2.00-
1.90(m,4H),1.88–1.77(m,1H),1.64(s,6H),1.62–1.48(m,6H),1.46–1.35(m,6H),0.93(s,
6H).13C NMR(75MHz,CDCl3)δ174.61,172.23,149.48,149.41,147.85,147.57,146.83,
146.79,111.80,111.78,110.81,110.38,109.58,109.53,66.13,65.66,53.32,52.17,
41.35,41.33,39.31,39.28,39.23,32.54,30.13,26.54,24.29,16.10.
Embodiment 14
The preparation of 1,2- bis- (N- methyl-N-13- beta-elemenes) ethylenediamine
2mmol 13- β-elemol is dissolved in 10mL anhydrous methylene chlorides, 3.0mmol Ph are added3P, then be added portionwise
3.0mmol NBS, normal-temperature reaction 10min, are spin-dried for reaction solution, with pure petroleum ether column chromatography, gained intermediate 13- bromos-β-olive
Fragrant alkene (1mmol) again with 0.5mmol N, N '-dimethyl ethylenediamine and 1.5mmol Et3N back flow reaction 4h in anhydrous acetonitrile,
It is spin-dried for reaction solution, with petroleum ether：Ethyl acetate=15:1(V:V) column chromatography obtains colorless liquid product, gross production rate 68%.1H NMR(300MHz,CDCl3) δ 5.82 (dd, J=17.8,10.5Hz, 2H), 4.94-4.92 (m, 3H), 4.91-4.88 (m,
3H),4.87(s,2H),4.81(s,2H),4.58(s,2H),2.99–2.86(m,4H),2.44(s,4H),2.17(s,6H),
2.11–1.98(m,4H),1.70(s,6H),1.67–1.54(m,6H),1.53–1.39(m,6H),1.00(s,6H).13C NMR
(75MHz,CDCl3)δ151.51,149.87,147.26,111.53,109.80,109.27,62.94,54.99,52.30,
42.42,41.12,39.56,39.39,32.83,26.84,24.31,16.13.
Embodiment 15
The preparation of 1,4- bis- (N-13- beta-elemenes) piperazine
With reference to the synthetic method in embodiment 14, N, N '-dimethyl ethylenediamine replaces with piperazine, obtains colourless liquid production
Object, gross production rate 71%.1H NMR(300MHz,CDCl3) δ 5.75 (dd, J=17.8,10.5Hz, 2H), 4.86 (s, 3H),
4.84–4.81(m,3H),4.80(s,2H),4.75(s,2H),4.52(s,2H),2.92–2.77(m,4H),2.32(s,8H),
2.05–1.91(m,4H),1.64(s,6H),1.58–1.45(m,6H),1.45–1.32(m,6H),0.94(s,6H).13C NMR
(75MHz,CDCl3)δ150.61,149.89,147.35,111.53,110.04,109.29,62.96,52.91,52.25,
41.75,39.52,39.40,32.80,26.73,24.33,16.11.
Embodiment 16
The preparation of 1,2- bis- (N- methyl-N-3- propionic acid -13- β-elemi alcohol ester) ethylenediamine
2mmol 13- β-elemol is dissolved in 10mL anhydrous methylene chlorides, 2.4mmol EDCI, 0.2mmol is added
DMAP and 2.4mmol acrylic acid, normal-temperature reaction 4h.Handle intermediate 13- β-elemol acrylate (1mmol) obtained by reaction solution
It is spin-dried for reaction solution, with 0.5mmol N, N '-dimethyl ethylenediamine back flow reaction 2h in tetrahydrofuran with petroleum ether again：Acetic acid
Ethyl ester=2:1(V:V) column chromatography obtains colorless liquid product, gross production rate 42%.1H NMR(300MHz,CDCl3)δ5.82
(dd, J=17.8,10.5Hz, 2H), 5.05 (s, 2H), 5.00 (s, 2H), 4.93 (d, J=3.8Hz, 2H), 4.88 (s, 2H),
4.82 (s, 2H), 4.59 (s, 6H), 2.74 (t, J=7.3Hz, 4H), 2.51 (t, J=7.3Hz, 4H), 2.49 (s, 4H), 2.25
(s,6H),2.09–1.96(m,4H),1.71(s,6H),1.69–1.54(m,6H),1.52–1.41(m,6H),1.01(s,6H)
.13C NMR(75MHz,CDCl3)δ171.75,149.49,147.89,146.82,111.78,110.41,109.53,65.61,
54.69,52.74,52.21,41.76,41.34,39.33,39.23,32.55,32.02,26.55,24.27,16.12.
Embodiment 17
The preparation of 1,2- bis- (N- methyl-N-4- butyric acid -13- β-elemi alcohol ester) ethylenediamine
2mmol 13- β-elemol is dissolved in 10mL anhydrous methylene chlorides, 2.2mmol DCC, 0.2mmol is added
DMAP and 2.4mmol 4- bromo-butyric acids, normal-temperature reaction 8h.Handle intermediate 13- β-elemol -4- bromobutanoates obtained by reaction solution
(1mmol) again with 0.5mmol N, N '-dimethyl ethylenediamine and 1.5mmol Et3N is heated to 100 DEG C of reaction 4h in DMF.Instead
It answers liquid with water washing 3 times, dichloromethane layer is concentrated, with petroleum ether：Ethyl acetate=2:1(V:V) column chromatography obtains colourless liquid
Product, gross production rate 40%.1H NMR(300MHz,CDCl3) δ 5.81 (dd, J=17.8,10.5Hz, 2H), 5.04 (s, 2H),
5.00 (s, 2H), 4.93 (d, J=3.4Hz, 2H), 4.88 (s, 2H), 4.83 (s, 2H), 4.58 (s, 6H), 2.58 (s, 4H),
2.48 (t, J=7.3Hz, 4H), 2.40 (t, J=7.3Hz, 4H), 2.30 (s, 6H), 2.08-1.94 (m, 4H), 1.91-1.78
(m,4H),1.71(s,6H),1.70–1.54(m,6H),1.53–1.41(m,6H),1.01(s,6H).13C NMR(75MHz,
CDCl3)δ172.63,149.48,147.91,146.85,111.78,110.36,109.55,65.56,56.54,54.40,
52.17,41.66,41.32,39.30,39.24,32.53,31.42,26.54,24.30,21.61,16.09.
Embodiment 18
The preparation of 1,4- bis- (N-3- propionic acid -13- β-elemi alcohol ester) piperazine
Intermediate 13- β-elemol acrylate (1mmol) and 0.5mmol piperazines are obtained according to the method in embodiment 16
The back flow reaction 2h in tetrahydrofuran, is spin-dried for reaction solution, with petroleum ether：Ethyl acetate=2:1(V:V) column chromatography obtains colourless
Product liquid, gross production rate 44%.1H NMR(300MHz,CDCl3) δ 5.81 (dd, J=17.8,10.5Hz, 2H), 5.06 (s,
2H), 5.00 (s, 2H), 4.93 (d, J=3.3Hz, 2H), 4.88 (s, 2H)), 4.83 (s, 2H), 4.59 (s, 6H), 2.71 (t, J
=7.2Hz, 4H), 2.58-2.42 (m, 12H), 2.09-1.95 (m, 4H), 1.71 (s, 6H), 1.69-1.55 (m, 6H), 1.52-
1.41(m,6H),1.01(s,6H).13C NMR(75MHz,CDCl3)δ171.64,149.49,147.86,146.84,111.80,
110.45,109.56,65.66,52.99,52.34,52.21,41.32,39.32,39.23,32.55,31.89,26.54,
24.29,16.11.
Embodiment 19
The preparation of 1,4- bis- (N-4- butyric acid -13- β-elemi alcohol ester) piperazine
Intermediate 13- β-elemol -4- bromobutanoates (1mmol) and 0.5mmol are obtained according to the method in embodiment 17
Piperazine and 1.5mmol Et3N is heated to 100 DEG C of reaction 4h in DMF.Reaction solution concentrates dichloromethane layer with water washing 3 times,
With petroleum ether：Ethyl acetate=2:1(V:V) column chromatography obtains colorless liquid product, gross production rate 38%.1H NMR
(300MHz,CDCl3) δ 5.81 (dd, J=17.8,10.5Hz, 2H), 5.04 (s, 2H), 5.00 (s, 2H), 4.93 (d, J=
3.8Hz, 2H), 4.88 (s, 2H), 4.82 (s, 2H), 4.58 (s, 6H), 2.45 (s, 8H), 2.38 (t, J=7.5Hz, 4H),
2.35 (t, J=7.5Hz, 4H), 2.08-1.98 (m, 4H), 1.88-1.76 (m, 4H), 1.71 (s, 6H), 1.69-1.55 (m,
6H),1.52–1.40(m,6H),1.01(s,6H).13C NMR(75MHz,CDCl3)δ172.71,149.48,148.00,
146.82,111.78,110.35,109.52,65.50,57.13,52.64,52.24,41.41,39.33,39.23,32.58,
31.80,26.57,24.25,21.69,16.13.
Embodiment 20
The preparation of 1,4- bis- (N-4- butyric acid -13- β-elemol monoesters) piperazine diamides
2mmol 13- β-elemol is dissolved in 10mL anhydrous methylene chlorides, 0.2mmol DMAP, 3.0mmol is added
Et3N and 2.4mmol succinic anhydrides, normal-temperature reaction 2h.Handle intermediate 13- β-elemol succinate monoester obtained by reaction solution
(1mmol) in thionyl chloride solution reflux generate acyl chlorides, then with 0.5mmol piperazines in anhydrous methylene chloride with 1.5mmol
Et3N is that acid binding agent reacts 2h, and reaction solution concentrates dichloromethane layer, products therefrom crude product, with oil with 10% salt acid elution 3 times
Ether：Ethyl acetate=1:1(V:V) column chromatography obtains weak yellow liquid product, gross production rate 54%.1H NMR(300MHz,
CDCl3) δ 5.74 (dd, J=17.8,10.5Hz, 2H), 4.99 (s, 2H), 4.93 (s, 2H), 4.86 (d, J=3.4Hz, 2H),
4.81(s,2H),4.75(s,2H),4.54(s,4H),4.51(s,2H),3.73–3.34(m,8H),2.70–2.52(m,8H),
2.04–1.88(m,4H),1.63(s,4H),1.62–1.47(m,8H),1.46–1.34(m,6H),0.93(s,6H).13C NMR
(75MHz,CDCl3)δ172.71,170.00,169.78,150.01,148.30,147.37,112.26,110.86,110.04,
66.31,52.61,45.18,45.00,41.70,41.57,39.78,39.74,33.00,29.20,27.85,27.03,
24.83,16.57.
Embodiment 21
The preparation of 1- (4 butyric acid -13- β-elemi alcohol ester) -4- (formic acid -13- β-elemi alcohol ester) -1- hydrogen -1,2,3- triazoles
2mmol 13- β-elemol, 2.2mmol propiolic acids and 0.2mmol DMAP is dissolved in 10mL anhydrous methylene chlorides
In, it is slowly dropped into the dichloromethane solution of 2.2mmol DCC, normal-temperature reaction 5h.Reaction solution concentrates dichloromethane with water washing 3 times
Alkane layer, with petroleum ether：Ethyl acetate=30:1(V:V) column chromatography obtains intermediate 13- β-elemol propiolate；With reference to real
Apply intermediate 13- β made from the synthetic method of example 17-elemol-4- bromobutanoates (1.5mmol) and sodium azide
(3.0mmol) is heated to 80 DEG C of reaction 2h in DMF, and dichloromethane is added in reaction solution, with water washing 3 times, concentrates dichloromethane
Layer, with petroleum ether：Ethyl acetate=100:1(V:V) column chromatography obtains intermediate 13- β-elemol -4- azido butyrates；
Then 1mmol 13- β-elemol propiolate and 1mmol 13- β-elemol -4- azido butyrates are in dichloromethane and water
Mixed solution in stir, the aqueous solution of 0.2mmol sodium ascorbates and 0.1mmol cupric sulfate pentahydrates is added dropwise successively, room temperature is anti-
Answer 10h, dichloromethane is added in reaction solution, with water washing 3 times, dichloromethane layer is concentrated, with petroleum ether：Ethyl acetate=4:1(V:
V) column chromatography obtains weak yellow liquid product, gross production rate 30%.1H NMR(300MHz,CDCl3)δ8.04(s,1H),5.74
(dd, J=17.8,10.5Hz, 2H), 5.09 (s, 1H), 5.00 (s, 1H), 4.96 (s, 1H), 4.95 (s, 1H), 4.88-4.83
(m, 2H), 4.80 (d, J=2.5Hz, 4H), 4.75 (s, 2H), 4.53 (s, 2H), 4.51 (s, 2H), 4.45 (t, J=6.8Hz,
2H), 2.35 (t, J=6.8Hz, 2H), 2.28-2.16 (m, 2H), 2.08-1.90 (m, 4H), 1.63 (s, 6H), 1.61-1.48
(m,6H),1.45–1.35(m,6H),0.94(s,3H),0.93(s,3H).13C NMR(75MHz,CDCl3)δ171.30,
159.87,149.50,149.41,147.60,147.37,146.88,146.83,139.61,127.06,111.79,111.76,
111.13,110.79,109.60,109.53,66.15,65.99,52.14,49.04,41.29,39.27,39.22,32.55,
30.01,26.54,24.85,24.29,16.10.
Embodiment 22
The preparation of 1- (5- valeric acids -13- β-elemi alcohol ester) -4- (formic acid -13- β-elemi alcohol ester) -1- hydrogen -1,2,3- triazoles
With reference to the synthetic method of embodiment 21,4- bromo-butyric acids replace with 5- bromine valeric acids, obtain weak yellow liquid product, total yield
Rate is 26%.1H NMR(300MHz,CDCl3) δ 8.02 (s, 1H), 5.74 (dd, J=17.8,10.5Hz, 2H), 5.09 (s,
1H), 5.00 (s, 1H), 4.95 (d, J=4.9Hz, 2H), 4.88-4.83 (m, 2H), 4.80 (d, J=3.1Hz, 4H), 4.75
(s, 2H), 4.51 (s, 4H), 4.37 (t, J=7.1Hz, 2H), 2.35 (t, J=7.2Hz, 2H), 2.12-1.81 (m, 6H),
1.63(s,8H),1.60–1.49(m,6H),1.48–1.34(m,6H),0.94(s,3H),0.93(s,3H).13C NMR
(75MHz,CDCl3)δ171.94,159.92,149.50,149.42,147.78,147.40,146.88,146.83,139.55,
126.80,111.78,111.76,111.10,110.58,109.58,109.52,66.12,65.73,52.19,52.15,
49.76,41.40,41.30,39.29,39.25,32.78,32.56,28.98,26.55,24.28,21.14,16.11.
Embodiment 23
The preparation of 1- (6- caproic acids -13- β-elemi alcohol ester) -4- (formic acid -13- β-elemi alcohol ester) -1- hydrogen -1,2,3- triazoles
With reference to the synthetic method of embodiment 21,4- bromo-butyric acids replace with 6- bromocaproic acids, obtain weak yellow liquid product, total yield
Rate is 34%.1H NMR(300MHz,CDCl3) δ 8.01 (s, 1H), 5.74 (dd, J=17.8,10.5Hz, 2H), 5.09 (s,
1H), 5.00 (s, 1H), 4.96 (s, 1H), 4.93 (s, 1H), 4.89-4.84 (m, 2H), 4.80 (d, J=2.9Hz, 4H), 4.75
(s, 2H), 4.51 (s, 4H), 4.35 (t, J=7.2Hz, 2H), 2.29 (t, J=7.3Hz, 2H), 2.09-1.85 (m, 6H),
1.63(s,8H),1.62–1.48(m,6H),1.47–1.28(m,8H),0.94(s,3H),0.93(s,3H).13C NMR
(75MHz,CDCl3)δ172.40,159.97,149.49,149.45,147.88,147.39,146.89,146.85,139.50,
126.79,111.78,111.76,111.09,110.48,109.57,109.53,66.12,65.61,52.19,52.14,
49.89,41.39,41.30,39.29,39.24,33.35,32.55,29.38,26.54,25.36,24.29,23.62,
16.11.
Embodiment 24
The preparation of 1- (8- octanoic acids -13- β-elemi alcohol ester) -4- (formic acid -13- β-elemi alcohol ester) -1- hydrogen -1,2,3- triazoles
With reference to the synthetic method of embodiment 21,4- bromo-butyric acids replace with 8- bromine octanoic acids, obtain weak yellow liquid product, total yield
Rate is 41%.1H NMR(300MHz,CDCl3) δ 8.08 (s, 1H), 5.82 (dd, J=17.8,10.5Hz, 2H), 5.16 (s,
1H), 5.07 (s, 1H), 5.04 (s, 1H), 5.00 (s, 1H), 4.95-4.90 (m, 2H), 4.88 (d, J=2.1Hz, 4H), 4.82
(s, 2H), 4.58 (s, 4H), 4.41 (t, J=7.2Hz, 2H), 2.34 (t, J=7.4Hz, 2H), 2.17-1.89 (m, 6H),
1.71(s,6H),1.70–1.55(m,8H),1.54–1.41(m,6H),1.33(s,6H),1.01(s,3H),1.00(s,3H)
.13C NMR(75MHz,CDCl3)δ172.82,160.01,149.49,149.48,147.97,147.38,146.90,146.85,
139.47,126.74,111.77,111.08,110.36,109.56,66.11,65.48,52.18,52.11,50.13,
41.36,41.27,39.30,39.27,33.69,32.53,29.60,28.32,28.10,26.52,25.70,24.32,
24.23,16.09.
Embodiment 25
The system of 1- (4 butyric acid -13- β-elemi alcohol ester) -4- (methylene -13- beta-elemenes ether) -1- hydrogen -1,2,3- triazoles
It is standby
2mmol 13- β-elemol is dissolved in 10mL anhydrous DMFs, 2.4mmol NaH are added, reacts 0.5h, is added
2.2mmol propargyl bromides, room temperature the reaction was continued 1h.Reaction solution adds water quenching to go out, and with water washing 3 times, dichloromethane layer is concentrated, with stone
Oily ether：Ethyl acetate=30:1(V:V) column chromatography, gained intermediate 13- propargyl alcoholates-beta-elemene (1mmol) with according to reality
Mixing of the intermediate 13- β-elemol -4- azidos butyrate (1mmol) that the method for applying example 22 obtains in dichloromethane and water
It is stirred in solution, successively the aqueous solution of dropwise addition 0.2mmol sodium ascorbates and 0.1mmol cupric sulfate pentahydrates, normal-temperature reaction 10h,
Dichloromethane is added in reaction solution, with water washing 3 times, dichloromethane layer is concentrated, with petroleum ether：Ethyl acetate=4:1(V:V) column layer
Analysis, obtains colorless liquid product, gross production rate 38%.1H NMR(300MHz,CDCl3) δ 7.56 (s, 1H), 5.81 (dd, J=
17.8,10.5Hz,2H),5.07(s,1H),5.04(s,1H),5.02–4.99(m,2H),4.96–4.91(m,2H),4.90–
4.85 (m, 2H), 4.82 (s, 2H), 4.68-4.54 (m, 6H), 4.44 (t, J=6.9Hz, 2H), 4.07 (s, 2H), 2.41 (t, J
=7.0Hz, 2H), 2.32-2.18 (m, 2H), 2.11-1.90 (m, 4H), 1.70 (s, 6H), 1.69-1.54 (m, 6H), 1.53-
1.41(m,6H),1.00(s,6H).13C NMR(75MHz,CDCl3)δ171.49,149.63,149.41,147.65,147.04,
146.81,145.00,121.93,111.79,111.64,110.67,110.17,109.58,109.42,72.33,65.87,
62.99,52.21,52.13,48.67,41.27,40.86,39.39,39.26,39.22,32.62,32.53,30.21,
26.56,26.53,24.94,24.30,16.09.
Embodiment 26
The system of 1- (5- valeric acids -13- β-elemi alcohol ester) -4- (methylene -13- beta-elemenes ether) -1- hydrogen -1,2,3- triazoles
It is standby
With reference to the synthetic method of embodiment 25,4- bromo-butyric acids replace with 5- bromine valeric acids, obtain colorless liquid product, gross production rate
It is 41%.1H NMR(300MHz,CDCl3) δ 7.54 (s, 1H), 5.81 (dd, J=17.8,10.5Hz, 2H), 5.08 (s, 1H),
5.03(s,1H),5.01(s,2H),4.94–4.91(m,2H),4.90–4.85(m,2H),4.82(s,2H),4.62(s,2H),
4.58 (s, 4H), 4.37 (t, J=7.2Hz, 2H), 4.06 (s, 2H), 2.41 (t, J=7.2Hz, 2H), 2.12-1.90 (m,
6H),1.71(s,6H),1.69–1.54(m,8H),1.52–1.41(m,6H),1.00(s,6H).13C NMR(75MHz,CDCl3)
δ172.12,149.66,149.45,147.78,147.09,146.85,144.93,121.73,111.79,111.64,
110.52,110.17,109.59,109.44,72.31,65.69,63.02,52.20,52.14,49.39,41.33,40.83,
39.39,39.28,39.24,32.88,32.62,32.53,29.11,26.54,26.52,24.33,21.27,16.08.
Embodiment 27
The system of 1- (6- caproic acids -13- β-elemi alcohol ester) -4- (methylene -13- beta-elemenes ether) -1- hydrogen -1,2,3- triazoles
It is standby
With reference to the synthetic method of embodiment 25,4- bromo-butyric acids replace with 6- bromocaproic acids, obtain colorless liquid product, gross production rate
It is 43%.1H NMR(300MHz,CDCl3) δ 7.53 (s, 1H), 5.81 (dd, J=17.8,10.5Hz, 2H), 5.08 (s, 1H),
5.03(s,1H),5.00(s,2H),4.95–4.91(m,2H),4.90–4.85(m,2H),4.82(s,2H),4.62(s,2H),
4.58 (s, 4H), 4.35 (t, J=7.2Hz, 2H), 4.06 (s, 2H), 2.36 (t, J=7.4Hz, 2H), 2.10-1.88 (m,
6H),1.70(s,6H),1.68–1.54(m,8H),1.53–1.33(m,8H),1.00(s,6H).13C NMR(75MHz,CDCl3)
δ172.48,149.64,149.45,147.88,147.06,146.83,144.87,121.68,111.78,111.64,
110.43,110.15,109.57,109.43,72.29,65.56,63.04,52.20,52.16,49.52,41.34,40.85,
39.39,39.29,39.23,33.42,32.62,32.53,29.51,26.53,25.49,24.32,23.72,16.08.
Embodiment 28
The system of 1- (8- octanoic acids -13- β-elemi alcohol ester) -4- (methylene -13- beta-elemenes ether) -1- hydrogen -1,2,3- triazoles
It is standby
With reference to the synthetic method of embodiment 25,4- bromo-butyric acids replace with 8- bromine octanoic acids, obtain colorless liquid product, gross production rate
It is 38%.1H NMR(300MHz,CDCl3) δ 7.52 (s, 1H), 5.82 (dd, J=17.8,10.5Hz, 2H), 5.07 (s, 1H),
5.04(s,1H),5.01(s,2H),4.96–4.89(m,2H),4.88–4.84(m,2H),4.82(s,2H),4.62(s,2H),
4.58 (s, 4H), 4.34 (t, J=7.2Hz, 2H), 4.06 (s, 2H), 2.34 (t, J=7.5Hz, 2H), 2.10-1.94 (m,
4H),1.95–1.83(m,2H),1.70(s,6H),1.69–1.52(m,8H),1.51–1.40(m,6H),1.34(s,6H),
1.01(s,3H),1.00(s,3H).13C NMR(75MHz,CDCl3)δ172.85,149.66,149.49,147.99,147.08,
146.85,144.85,121.60,111.78,111.64,110.35,110.15,109.56,109.43,72.29,65.47,
63.08,52.21,52.19,49.77,41.36,40.87,39.40,39.31,39.24,33.73,32.62,32.54,
29.74,28.37,28.17,26.54,25.83,24.31,24.28,16.09.
Embodiment 29
The preparation of 1,4- bis- (4- (formic acid -13- β-elemi alcohol ester) -1- hydrogen -1,2,3- triazol-1-yls) butane
Intermediate 13- β-elemol propiolate (1mmol) with reference to made from the synthetic method of embodiment 21 and 1,4- bis-
Azido butane (0.5mmol) stirs in the mixed solution of dichloromethane and water, successively be added dropwise 0.2mmol sodium ascorbates and
Dichloromethane is added in the aqueous solution of 0.1mmol cupric sulfate pentahydrates, normal-temperature reaction 10h, reaction solution, with water washing 3 times, concentrates dichloro
Methane layer, with petroleum ether：Ethyl acetate=2:1(V:V) column chromatography obtains white solid product, gross production rate 63%.1HNMR
(300MHz,CDCl3) δ 7.27 (s, 2H), 5.81 (dd, J=17.8,10.5Hz, 2H), 5.15 (s, 2H), 5.07 (s, 2H),
4.93 (d, J=3.7Hz, 2H), 4.88 (s, 2H), 4.86 (s, 4H), 4.82 (s, 2H), 4.58 (s, 2H), 4.48 (s, 4H),
2.18–1.95(m,8H),1.70(s,6H),1.69–1.60(m,6H),1.59–1.40(m,6H),1.01(s,6H).13C NMR
(75MHz,CDCl3)δ159.78,149.46,147.33,146.88,139.74,126.96,111.76,111.12,109.55,
66.18,52.15,49.09,41.31,39.28,39.24,32.55,26.54,26.47,24.28,16.12.
Embodiment 30
The preparation of 1,4- bis- (4- (formic acid -13- β-elemi alcohol ester) -1- hydrogen -1,2,3- triazol-1-yls) hexane
With reference to the synthetic method of embodiment 29, Isosorbide-5-Nitrae-diazido butane replaces with 1,6- diazido hexanes, obtains white
Color solid product, gross production rate 58%.1H NMR(300MHz,CDCl3) δ 8.11 (s, 2H), 5.81 (dd, J=17.8,
10.5Hz, 2H), 5.15 (s, 2H), 5.07 (s, 2H), 4.93 (d, J=3.3Hz, 2H), 4.90-4.84 (m, 6H), 4.82 (s,
2H), 4.58 (s, 2H), 4.43 (t, J=7.0Hz, 4H), 2.19-1.86 (m, 10H), 1.70 (s, 6H), 1.69-1.60 (m,
6H),1.59–1.40(m,6H),1.38(s,4H),1.01(s,6H).13C NMR(75MHz,CDCl3)δ159.77,149.46,
147.33,146.88,139.74,126.96,111.76,111.11,109.55,66.18,52.15,49.09,41.31,
39.28,39.24,32.55,29.19,26.54,26.47,24.28,16.12.
Embodiment 31
The preparation of 1,4- bis- (4- (methylene -13- beta-elemenes ether) -1- hydrogen -1,2,3- triazol-1-yls) butane
Intermediate 13- propargyl alcoholates-beta-elemene (1mmol) is made for synthetic method with reference to embodiment 25 and 1,4- bis- is folded
Nitrogen base butane (0.5mmol) stirs in the mixed solution of dichloromethane and water, successively be added dropwise 0.2mmol sodium ascorbates and
Dichloromethane is added in the aqueous solution of 0.1mmol cupric sulfate pentahydrates, normal-temperature reaction 10h, reaction solution, with water washing 3 times, concentrates dichloro
Methane layer, with petroleum ether：Ethyl acetate=2:1(V:V) column chromatography obtains white solid product, gross production rate 70%.1HNMR
(300MHz,CDCl3) δ 7.51 (s, 2H), 5.81 (dd, J=17.8,10.5Hz, 2H), 5.07 (s, 2H), 5.00 (s, 2H),
4.92 (d, J=4.1Hz, 2H), 4.87 (s, 2H), 4.81 (s, 2H), 4.61 (s, 4H), 4.58 (s, 2H), 4.38 (s, 4H),
4.06(s,4H),2.13–1.97(m,4H),1.95(s,4H),1.70(s,6H),1.68–1.54(m,6H),1.52–1.41(m,
6H),1.00(s,6H).13C NMR(75MHz,CDCl3)δ149.62(2),147.06,145.16,121.80,111.64,
110.16,109.43,72.40,63.00,52.25,48.76,40.91,39.40,39.28,32.66,26.58(2),24.27,
16.11.
Embodiment 32
The preparation of 1,4- bis- (4- (methylene -13- beta-elemenes ether) -1- hydrogen -1,2,3- triazol-1-yls) hexane
With reference to the synthetic method of embodiment 31, Isosorbide-5-Nitrae-diazido butane replaces with 1,6- diazido hexanes, obtains white
Color solid product, gross production rate 64%.1H NMR(300MHz,CDCl3) δ 7.52 (s, 2H), 5.81 (dd, J=17.8,
10.5Hz, 2H), 5.07 (s, 2H), 5.00 (s, 2H), 4.92 (d, J=3.6Hz, 2H), 4.87 (s, 1H), 4.81 (s, 2H),
4.62 (s, 4H), 4.57 (s, 2H), 4.33 (t, J=7.0Hz, 4H), 4.06 (s, 4H), 2.13-1.97 (m, 4H), 1.90 (s,
4H),1.70(s,6H),1.68–1.54(m,6H),1.52–1.41(m,6H),1.36(s,4H),1.00(s,6H).13C NMR
(75MHz,CDCl3)δ149.64(2),147.08,144.92,121.72,111.64,110.16,109.44,72.34,
63.01,52.22,49.53,40.88,39.39,39.29,32.63,29.51,26.56,25.33,24.31,16.09.
Here be the compounds of this invention pharmacodynamics test and as a result, in pharmacodynamics test compound used therefor code name chemistry
Structure is shown in embodiment, with document (Chen J.C., Duan W.L., Bai R.R., et al.Bioorg Med Chem
Lett.2014,24:3407.) two 13- beta-elemene dimer derivates disclosed in are reference substance (5r and 5s).
Test example 1
Influence to oxidative damage Human umbilical vein endothelial cell (HUVECs) vigor
The good HUVECs had digestive transfer cultures of growth conditions are taken, with 5 × 103A/hole is inoculated in 96 well culture plates, in 37
DEG C, 5%CO2It is cultivated in incubator.Experiment divides Normal group, model group, various concentration compound group and reference substance group.Just
Often after culture for 24 hours, it is separately added into after the various pharmaceutical interventions of a concentration of 1 μm of ol/L, 10 μm of ol/L in 37 DEG C, 5%CO2Incubator
After middle culture for 24 hours, washed 1 time with PBS buffer solution, the normal group of culture medium for using serum-free instead, other groups 0.5mmol/LH2O2Thorn
Swash 2h.Culture solution is abandoned in suction, and the 180 μ L of 20 μ L of MTT solution and serum free medium of a concentration of 5mg/ml are added per hole, continue to cultivate
After 4 hours, culture supernatant is abandoned in suction, and 200 μ L DMSO shaking tables are added per hole and shake 10min, and wavelength 570nm is measured with microplate reader
Locate absorbance (OD values), calculates cell viability.
Cell viability (%)=administration group/normal group × 100%
Experimental result is shown in Table 1.
Influence of the 1 beta-elemene dimer derivate of table to oxidative damage endotheliocyte viability
Antioxidation activity in vitro evaluation display, beta-elemene dimer derivate show preferably HUVECs after damage
Antioxidant activity, and be significantly better than that beta-elemene, reference substance 5r and 5s.
Test example 2
Influence to normal human's huve cell vigor
Take the good HUVECs of growth conditions, had digestive transfer culture, with 5 × 103A/hole is inoculated in 96 well culture plates, in 37
DEG C, 5%CO2It is cultivated in incubator.Experiment divides Normal group, various concentration to test compound group and reference substance group, each
Concentration sets 6 multiple holes.After normal culture for 24 hours, washed 2 times with PBS buffer solution, the normal group of culture medium for using serum-free instead, other groups
It is separately added into the culture medium containing respective concentration drug, 96 well culture plates are placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator
Afterwards, the 20 μ L of MTT solution of a concentration of 5mg/ml are added per hole, after continuing culture 4 hours, culture supernatant is abandoned in suction, is added per hole
200 μ L DMSO, shaking table shake 10min, measure absorbance (OD values) at wavelength 570nm with microplate reader, calculate cell viability.
Cell viability (%)=administration group/normal group × 100%
Experimental result is shown in Table 2.
Influence of the 2 beta-elemene dimer derivate of table to normal endothelial cell vigor
Vitro Cytotoxicity Evaluation shows that beta-elemene dimer derivate shows normal HUVECs lower thin
Cellular toxicity acts on, and is below beta-elemene, reference substance 5r and 5s.
Test example 3
The evaluation of antioxidation in vitro relevant biological activity material effect
The HUVEC cells of logarithmic growth phase, with 105The cell suspension inoculation of a/mL is in 6 well culture plates, and culture is for 24 hours
Afterwards, it inhales and abandons culture solution, fresh serum-free DMEM high glucose mediums, routine culture is added in blank group and damage group.Administration group and
Reference substance group is separately added into the various drugs of a concentration of 1 μm of ol/L or 10 μm of ol/L on this basis, after continuing culture for 24 hours, adds
Enter to contain H2O2The DMEM serum free mediums of final concentration of 0.5mmol/L, after handling 2h, detection reactive oxygen species (ROS), third
The content of dialdehyde (MDA) and superoxide dismutase (SOD).
ROS reduced rates=(model group-administration group)/model group × 100%
SOD increment rates=(administration group-model group)/model group × 100%
MDA reduced rates=(model group-administration group)/model group × 100%
Experimental result is shown in Table 3.
Influence of the 3 part beta-elemene dimer derivate of table to oxidative damage endothelial cell oxidation index
The evaluation of external oxidation relevant biological activity material effect is shown, after beta-elemene dimer derivate is to damage
The variation of HUVECs internal oxidition relevant biological activity substances shows good inhibiting effect, and is significantly better than that β-elemi
Alkene, reference substance 5r and 5s.Experimental data also further confirms to prepare beta-elemene dimer derivate the present invention provides a kind of
The effective ways of anti-oxidation medicine.Potentiality with exploitation treatment atherosclerosis relevant disease drug.
Above-mentioned detailed description is illustrating for one of them possible embodiments of the present invention, the embodiment not to
The scope of the claims of the present invention is limited, all equivalence enforcements or change without departing from carried out by the present invention are intended to be limited solely by the technology of the present invention
In the range of scheme.
Claims (10)
1. one kind having the beta-elemene dimer derivate or its pharmaceutically acceptable salt of logical formula (II), (III) or (IV)：
Wherein Y is selected from-OC (O)-,-O- or-S-；R2Selected from C1-10Straight chained alkyl, C3-10Branched alkyl, C2-10Straight-chain alkenyl or
C3-10Branched-chain alkenyl；
R3Selected from C1-10Straight chained alkyl, C3-10Branched alkyl, C1-10Straight chain acyl, C3-10Branched chain acyl, C6-12Cycloalkanoyl or virtue
Acyl group, C2-10Straight-chain alkenyl, C3-10Branched-chain alkenyl, C3-10Straight chain enoyl- or C4-10Branch alkenoyl；
R4Selected from H, C1-5Straight chained alkyl or C3-5Branched alkyl；
R5Selected from (CH2)n, n=0-10 or C3-10Branched alkyl；
R6Selected from C1-10Straight chained alkyl, C3-10Branched alkyl, C2-10Straight-chain alkenyl or C3-10Branched-chain alkenyl.
2. the derivative of claim 1 or its pharmaceutically acceptable salt, wherein Y is-OC (O)-or-O-；R2For (CH2)2、
(CH2)3、(CH2)4、(CH2)5Or (CH2)6；
R3For (CH2)2、(CH2)3、(CH2)4、(CH2)2CO、(CH2)3CO、CH2(CH3)2CH2CO, CH=CHCO or C6H4CO；
R4For H, CH2Or CH3；
R5For (CH2)n, n=0-5；
R6For (CH2)2、(CH2)3、(CH2)4、(CH2)5Or (CH2)6。
3. the derivative of claim 1 or its pharmaceutically acceptable salt, wherein Y is-OC (O)-；R2For (CH2)2、(CH2)3Or
(CH2)4；
R3For (CH2)2、(CH2)3、(CH2)2CO or (CH2)3CO；
R4For CH2Or CH3；
R5For (CH2)n, n=0-1；
R6For (CH2)4、(CH2)5Or (CH2)6。
4. the derivative of claim 1 or its pharmaceutically acceptable salt, are following any compounds or its is pharmaceutically acceptable
Salt：
1,2- bis- (N- methyl-N-13- beta-elemenes) ethylenediamine；
Isosorbide-5-Nitrae-two (N-13- beta-elemenes) piperazine；
1,2- bis- (N- methyl-N-3- propionic acid -13- β-elemi alcohol ester) ethylenediamine；
1,2- bis- (N- methyl-N-4- butyric acid -13- β-elemi alcohol ester) ethylenediamine；
Isosorbide-5-Nitrae-two (N-3- propionic acid -13- β-elemi alcohol ester) piperazine；
Isosorbide-5-Nitrae-two (N-4- butyric acid -13- β-elemi alcohol ester) piperazine；
Isosorbide-5-Nitrae-two (N-4- butyric acid -13- β-elemol monoesters) piperazine diamides.
5. the preparation method of the beta-elemene dimer derivate of any one of claim 1-4, formula of (II), (III) and
(IV) preparation of compound shown in is respectively required for by 13- β-elemi alcohol intermediate.
6. the preparation method of claim 5, including following steps：Beta-elemene is with sodium hypochlorite in dichloromethane and ice vinegar
It is reacted in sour mixed solution, under condition of ice bath and 13- chloros-beta-elemene is made；Then 13- chloros-beta-elemene is with anhydrous DMF
It is reacted in a heated condition with anhydrous sodium acetate for solvent and generates 13- β-elemi alcohol acetic ester, then made through potassium hydroxide hydrolysis
Obtain intermediate 13- β-elemol.
7. the preparation method of claim 5, part of compounds can be prepared according to reaction five in formula of (II), 13- β-elemi
Alcohol and acrylic acid are reacted using dichloromethane as solvent under EDCI and DMAP catalysis, and 13- β-elemol acrylate is made,
Then back flow reaction can be prepared by corresponding product in tetrahydrofuran from different diamines；
Reaction five：
Part of compounds can be prepared according to reaction six in logical formula (II), and 13- β-elemol is molten with dichloromethane with bromo carboxylic acid
Agent is reacted under DCC and DMAP catalysis, and gained intermediate is then from different diamines with Et3N is acid binding agent in anhydrous DMF
Middle heating reaction can be prepared by corresponding product；
Reaction six：
Part of compounds can be prepared according to reaction seven in logical formula (II), and 13- β-elemol is molten with dichloromethane with ring dicarboxylic anhydride
Agent is in DMAP and Et3It is reacted under N catalysis, gained intermediate is generated using dichloromethane as solvent under the action of thionyl chloride
Acid chloride intermediate, then from different diamines with Et3N, which reacts for acid binding agent in anhydrous methylene chloride, can be prepared by accordingly producing
Object；
Reaction seven：
Logical formula (III) can be prepared with compound in (IV) according to reaction eight, and 13- β-elemol be with dichloromethane with bromo carboxylic acid
Solvent is reacted under DCC and DMAP catalysis, and gained intermediate reacts in anhydrous DMF under 80 DEG C of heating with sodium azide again
Intermediate 1 is made；13- β-elemol and different acetylenic acids using dichloromethane as solvent under DCC and DMAP catalysis or with different bromines
Substituted alkyl alkynes is reacted as solvent under the effect of sodium hydrogen using anhydrous DMF is made intermediate 2 and intermediate 3 respectively；Then 2 He of intermediate
Intermediate 3 is respectively with intermediate 1 or with two nitrine alkane in dichloromethane and water mixed solution, in cupric sulfate pentahydrate and anti-bad
Corresponding product is made in the lower reaction of hematic acid sodium effect.
Reaction eight：
8. a kind of oxidation resistant pharmaceutical composition, wherein the logical formula (II), (III) containing any one of claim 1-4 or (IV)
Beta-elemene dimer derivate or its pharmaceutically acceptable salt.
9. the oxidation resistant pharmaceutical composition of claim 8, wherein containing pharmaceutically acceptable carrier.
10. the beta-elemene dimer derivate or its pharmacy of the logical formula (II) of any one of claim 1-4, (III) or (IV)
Upper acceptable salt is used to prepare the purposes of anti-oxidation medicine.
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