CN103864880B - Oleanolic Acid-miazines conjugate and its preparation method and application - Google Patents

Oleanolic Acid-miazines conjugate and its preparation method and application Download PDF

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CN103864880B
CN103864880B CN201410094110.9A CN201410094110A CN103864880B CN 103864880 B CN103864880 B CN 103864880B CN 201410094110 A CN201410094110 A CN 201410094110A CN 103864880 B CN103864880 B CN 103864880B
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alkene
acid
volatile oil
beta
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CN103864880A (en
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程克光
梁宏
苏春华
陈振锋
王恒山
莫伟彬
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Guangxi Normal University
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Abstract

The invention discloses a kind of Oleanolic Acid-miazines conjugate and preparation method thereof, and the above-mentioned Oleanolic Acid-application of miazines conjugate in pharmacy field.Applicant finds that the anti-tumor activity that above-mentioned Oleanolic Acid-miazines conjugate has is much higher than its parent Oleanolic Acid, provides lead compound for developing new antitumor drug.Described conjugate has the structure shown in following general formula (III).

Description

Oleanolic Acid-miazines conjugate and its preparation method and application
The application is the divisional application of " Oleanolic Acid-miazines conjugate and its preparation method and application ", the applying date of original application is: on March 31st, 2012, application number is: 201210092658.0, and denomination of invention is: Oleanolic Acid-miazines conjugate and its preparation method and application.
Technical field
The present invention relates to medical art, be specifically related to a kind of Oleanolic Acid-miazines conjugate and its preparation method and application.
Background technology
Tumour especially malignant tumour remains the great disease of human life's Health hazard.International cancer research institution (IARC) points out according to global pathogenesis of cancer information database, and pathogenesis of cancer spreads from developed country to developing country, and the death that all kinds of tumor disease causes is the second largest cause of the death being only second to cardiovascular disorder.In recent years, chemotherapy of tumors achieves sizable progress, the survival time of tumour patient obviously extends, particularly to leukemia, the treatment of malignant lymphoma etc. has had breakthrough, but to harm humans life and health the most serious, the treatment of the solid tumor that accounts for malignant tumour more than 90% also fails to reach satisfied effect, the expert of China's medicine is constantly studying new drug and is finding new way for this reason.
Oleanolic Acid is a kind of Triterpenoids sapogenins compounds, be distributed widely in nature, and have protect liver, separate malicious, antitumor, the AntiHIV1 RT activity of liver, the multiple biological activity (Sun Hongbin such as hypoglycemic, reducing blood-fat, the progress of pentacyclic triterpene natural product, pharmaceutical chemistry is in progress, 2006,4:253-279).Oleanolic Acid significantly can reduce the activity of gpt and glutamic-oxal(o)acetic transaminase; protect the emptying of liver gsh; alleviate hepatocellular sex change and reduce inflammatory reaction (Jeong; H.G.InhibitionofcytochromeP4502E1expressionbyoleanolicac id:hepatoprotectiveeffectsagainstcarbontetrachloride-ind ucedhepaticinjury.ToxicolLett; 1999,105 (3): 215-222).Oleanolic Acid has good broad-spectrum anti-tumor activity while having liver protecting activity, tumorigenic different steps can be acted on, comprise the formation of Tumor suppression, hinder tumor promotion and inducing tumor cell to break up and Tumor suppression new vessel generation effectively, stop infringement and the transfer (Ovesna of tumour cell, Z., Vachalkova, A.etal.Pentacyclictriterpenoicacids:Newchemoprotectiveco mpounds.Neoplasma, 2004,51 (5): 327-333); Although Oleanolic Acid can act on tumorigenic different steps, its anti-tumor activity relatively weak (Huang Minshan, Huang Wei, Wu Qinian etc. Oleanolic Acid induction cell apoptosis in human breast cancer and with Ca in cell 2+the research of level, contemporary Chinese medical journal, 2004,14 (16): 58-60).
Pyrimidines is the very important material of a class in vital movement, extensively be present in occurring in nature, 3 kinds are just had in modal 5 kinds of nitrogenous basic components containing pyrimidine structure (uridylic, cytosine(Cyt) and thymus pyrimidine), also containing pyrimidine ring in VITMAIN B1 in nucleic acid needed for life.Therefore, pyrimidine ring causes the concern (Bai Suzhen of people already as the basic building block of new drug molecular designing and synthesis, Lou Xinhua, Yin Guiling. the applied research progress of pyrimidine compound, Shanxi chemical industry, 2009,29 (1): 17-19), point of application based on pyridine derivatives antimetabolic is different, cross resistance is relatively less, and this compounds is mainly used in research (the molecular modification progress of Wang Weidong .5-fluorouracil cancer therapy drug, the pharmacy progress of antitumor drug, 2008,32 (12): 536-542).At present, the extensive concern that the problem strengthening pharmaceutical activity causes pharmaceutical chemists is modified and transformed to the structure of natural product, miazines small molecules has been become the important channel of antitumor drug research as the basic building block of new drug molecular designing and synthesis.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of new Oleanolic Acid-miazines conjugate and preparation method thereof, and the above-mentioned Oleanolic Acid-application of miazines conjugate in pharmacy field.
For solving the problems of the technologies described above, the present invention by the following technical solutions:
There is following general formula (I), the Oleanolic Acid-miazines conjugate of structure shown in (II) or (III) or its pharmacy acceptable salt or ester:
Wherein:
In general formula (I) and (II), n=1 ~ 30, R 1represent hydrogen or methyl;
In general formula (III), R 2represent straight or branched alkane, alkene, alkynes, phenyl, benzyl, the naphthyl of the non-substituted of 1 ~ 30 carbon or X replacement;
X represents F, Cl, Br, I, CN, NO 2, NH 2, CF 3, SH, OH, SO 3h, COOH, OR 3, COR 4or COOR 5;
R 3represent F, Cl, Br, I, CN, NO 2, NH 2, CF 3, the straight or branched alkane of 1 ~ 30 carbon, alkene, alkynes, phenyl or replacement phenyl;
R 4represent NH 2, CF 3, the straight or branched alkane of 1 ~ 30 carbon, alkene, alkynes, phenyl or replacement phenyl;
R 5represent CF 3, the straight or branched alkane of 1 ~ 30 carbon, alkene, alkynes, phenyl or replacement phenyl.
Stating in general formula (I) and (II), preferred n=2 ~ 12; In general formula (III), R 2be preferably methyl, ethyl, propyl group, butyl, pentyl, hexyl, heptane base, undecyl or pentadecyl.
Wherein preferred general formula (I) compound is:
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-ethyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-ethyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-propyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-propyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-normal-butyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-normal-butyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-pentyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-pentyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-hexyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-hexyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-heptyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-heptyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-octyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-octyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-nonyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-nonyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-positive decyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-positive decyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-undecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-undecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-dodecyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-dodecyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-tridecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-tridecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-tetradecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-tetradecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-Pentadecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-Pentadecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-hexadecyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-hexadecyl] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-heptadecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-heptadecane base] ester;
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-Octadecane base] ester; Or
3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-Octadecane base] ester;
Preferred general formula (II) compound is:
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyloxyethyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyloxyethyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-monomethacryloxypropyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-monomethacryloxypropyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen butyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen butyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen amyl group)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen amyl group)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octyl group)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octyl group)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen nonyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen nonyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen decyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen decyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen undecyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen undecyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen dodecyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen dodecyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tridecyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tridecyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tetradecyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tetradecyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen pentadecyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen pentadecyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexadecyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexadecyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptadecyl)-2,4 (1H, 3H)-pyrimidine dione;
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptadecyl)-2,4 (1H, 3H)-pyrimidine dione;
1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octadecyl)-2,4 (1H, 3H)-pyrimidine dione; Or
5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octadecyl)-2,4 (1H, 3H)-pyrimidine dione;
Preferred general formula (III) compound is:
3 β-acetoxyl group-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-propionyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-butyryl acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-penta acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-hexylyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-heptan acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-Xin acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides;
3 β-dodecanoyl oxygen base-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides; Or
3 β-palm acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides.
The synthetic route of the Oleanolic Acid shown in said structure general formula (I) and (II)-miazines conjugate is as follows:
Wherein, Y represents halogen atom; N=1 ~ 30, R 1represent hydrogen or methyl.
Concrete preparation method comprises the following steps:
A) Oleanolic Acid, dihalo hydrocarbon and alkali is taken by the mol ratio of 1:1.2 ~ 1.3:2 ~ 5, be placed in organic solvent reaction 0.5 ~ 24h, revolve and desolventize, residue with ethyl acetate dissolves, washing, anhydrous magnesium sulfate drying, filters, and filtrate concentrates, silica gel column chromatography on gained residue, to be the mixed solvent wash-out that the sherwood oil of 4 ~ 8:1 and ethyl acetate form by volume ratio, elutriant solvent evaporated, obtains halogenated alkane olea acid esters;
B) take halogenated alkane olea acid esters, uridylic or thymus pyrimidine and alkali by the mol ratio of 1:2 ~ 3.5:2 ~ 5 and be placed in organic solvent reaction 0.5 ~ 72h, decompression is revolved and is desolventized, residue with ethyl acetate dissolves, washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, silica gel column chromatography on gained residue, by volume ratio to be the mixed solvent wash-out that the sherwood oil of 3 ~ 5:1 and ethyl acetate form, elutriant solvent evaporated, obtains the Oleanolic Acid shown in general formula (II)-miazines conjugate; Then to be the mixed solvent wash-out that the sherwood oil of 3 ~ 1:1 and ethyl acetate form by volume ratio, elutriant solvent evaporated, obtains the Oleanolic Acid shown in general formula (I)-miazines conjugate.
The step of aforesaid method a) in, described dihalo hydrocarbon is difluoro alkane, dichloro alkanes, two bromoalkanes or diiodo-alkane, is preferably dichloro alkanes or two bromoalkanes.The temperature of described reaction is 0 ~ 60 DEG C, preferably at room temperature carries out; The time preferably 8 ~ 12h of reaction.
The step of aforesaid method a) and b) in, described alkali is pyridine, triethylamine, ammoniacal liquor, DMAP (DMAP), salt of wormwood, sodium carbonate, calcium carbonate, sodium bicarbonate or saleratus; Described organic solvent is for being selected from a kind of or two or more arbitrarily combination in tetrahydrofuran (THF) (THF), pyridine, methylene dichloride, ethyl acetate, ethyl formate, chloroform, toluene, dioxane and DMF (DMF); The consumption of described organic solvent is conventional amount used, as long as namely reactant all can be dissolved.
The synthetic route of the Oleanolic Acid shown in said structure general formula (III)-miazines conjugate is as follows:
Wherein, R 2definition as previously mentioned.
Concrete preparation method comprises the following steps:
1) oxygen acyl group oleanolic acid derivate is prepared;
2) take oxygen acyl group oleanolic acid derivate and acyl halide reagent by the mol ratio of 1:3 ~ 20, stirring reaction 0.5 ~ 72h, decompression is revolved and is desolventized, and obtains oxygen acyl group Oleanolic Acid chloride compounds;
3) gained oxygen acyl group Oleanolic Acid chloride compounds organic solvent dissolution, then add and be equivalent to the uridylic of oxygen acyl group oleanolic acid derivate molar weight 2 ~ 8 times and the alkali of 5 ~ 35 times, or else add or add the catalyzer being equivalent to oxygen acyl group oleanolic acid derivate molar weight 0.1 ~ 0.5 times, 0.5 ~ 72h is reacted under nitrogen protection, decompression is revolved and is desolventized, residue from dichloromethane dissolves, washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, silica gel column chromatography on gained residue, by volume ratio to be the mixed solvent wash-out that the sherwood oil of 5 ~ 1:1 and ethyl acetate form, elutriant solvent evaporated, obtain the Oleanolic Acid shown in general formula (III)-uridylic conjugate.
In the preparation method of the conjugate shown in said structure general formula (III):
Step 1) in, the preparation method of described oxygen acyl group oleanolic acid derivate is the preparation method of existing routine, can be specifically: Oleanolic Acid, alkali and esterifying reagent are placed in organic solvent, add or do not add catalyst reaction 0.5 ~ 24h, revolve and desolventize, resistates diluted hydrochloric acid dissolution, be extracted with ethyl acetate 1 ~ 3 time again, merge organic layer, washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, and gained residue, with being the mixed solvent recrystallization that the ethanol of 5 ~ 6:4 ~ 5 and sherwood oil form by volume ratio, to obtain final product; Or by silica gel column chromatography on residue, to be the mixed solvent wash-out that the sherwood oil of 10 ~ 20:1 and ethyl acetate form by volume ratio, elutriant solvent evaporated, to obtain final product.Described esterifying reagent can be acyl chlorides or acid anhydrides etc., and when oxygen acyl group oleanolic acid derivate is obtained by reacting in machine solvent by Oleanolic Acid, acyl chlorides and alkali, their mol ratio is 1:3 ~ 4:5 ~ 35; When oxygen acyl group oleanolic acid derivate is obtained by reacting in machine solvent by Oleanolic Acid, acid anhydrides and alkali, their mol ratio is 1:1.5 ~ 2.0:5 ~ 35.In this step, the temperature of reaction is 0 ~ 60 DEG C, preferably at room temperature carries out; The time preferably 8 ~ 12h of reaction; The temperature of recrystallization is preferably 70 ~ 90 DEG C, and described alkali and the selection of organic solvent are as previously mentioned.Described catalyzer is DMAP, and its add-on is 0.1 ~ 0.5 times of Oleanolic Acid molar weight, and the object adding catalyzer improves the yield of this step; In this step, when directly using using DMAP as alkali, then the DMAP adding catalyst levels more in addition is not needed.
Step 2) in, described acyl halide reagent is thionyl chloride or oxalyl chloride; The mol ratio of described oxygen acyl group oleanolic acid derivate and thionyl chloride or oxalyl chloride is 1:10 ~ 20, is preferably 1:15.
Step 3) in, described alkali is pyridine, triethylamine, ammoniacal liquor, DMAP (DMAP), salt of wormwood, sodium carbonate, calcium carbonate, sodium bicarbonate or saleratus; Described organic solvent is for being selected from a kind of or two or more arbitrarily combination in tetrahydrofuran (THF) (THF), pyridine, methylene dichloride, ethyl acetate, ethyl formate, chloroform, toluene, dioxane and DMF (DMF); The consumption of described organic solvent is conventional amount used, as long as namely reactant all can be dissolved.Described catalyzer is DMAP, its add-on is 0.1 ~ 0.5 times of Oleanolic Acid molar weight, the object adding catalyzer improves the yield of this step, usually when not adding catalyzer, the yield of this step is lower, about 5 ~ 30%, and when adding catalyzer, the yield of this step is 50 ~ 90%; In this step, when directly using using DMAP as alkali, then the DMAP adding catalyst levels more in addition is not needed.
The present invention also comprises the above-mentioned application of Oleanolic Acid-miazines conjugate in preparation prevention or treatment antitumor drug with structure shown in general formula (I), (II) or (III).
Compared with prior art, the invention provides a kind of new Oleanolic Acid-miazines conjugate and preparation method thereof and they application in pharmacy field, applicant finds that the anti-tumor activity that above-mentioned Oleanolic Acid-miazines conjugate has is much higher than its parent Oleanolic Acid, provides lead compound for developing new antitumor drug.
Embodiment
With specific embodiment, the invention will be further described below, but the present invention is not limited to these embodiments.
Embodiment 1:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-ethyl] ester (I 1) and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyloxyethyl)-2,4 (1H, 3H)-pyrimidine dione (II 1) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mLDMF, add 24.95mmol (3.44g) salt of wormwood and 6.49mmol (0.56mL) 1, 2-ethylene dibromide, 60 DEG C of stirring reactions 0.5 hour, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, use the HCl of 1N successively, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue is through purification by silica gel column chromatography, with sherwood oil: the mixed solvent wash-out of ethyl acetate=8:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(2-bromotrifluoromethane) ester 1.60g(white solid, yield 57%), 1hNMR (500MHz, CDCl 3) 0.74,0.78,0.93,0.99and1.14 (5s, each3H), 0.90 (s, 6H), 0.71-1.98 (m, 23H), 2.87 (dd, 1H), 3.20 (dd, 1H), 3.49 (t, 2H), 4.23-4.42 (m, 2H), 5.30 (s, 1H) .APCI-MSm/z:545.36 [M-OH] -.
B) getting 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(2-bromotrifluoromethane) ester 0.71mmol (0.40g) is dissolved in 3mLDMF, add 3.55mmol (0.49g) salt of wormwood and 2.49mmol (0.28g) uridylic, stirring reaction 0.5 hour at 50 DEG C, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then the HCl of 1N is used successively, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue is through purification by silica gel column chromatography, with sherwood oil: the mixed solvent wash-out of ethyl acetate=5:1 (volume ratio), thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain 0.12g Compound II per 1(white solid, yield 31%), then with the mixed solvent wash-out that the sherwood oil that is 3:1 by volume ratio and ethyl acetate form, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains 0.27g Compound I 1(white solid, yield 64%).
Gained Compound I 1detect through mass spectrum and proton nmr spectra:
m.p.289-291℃.APCI-MSm/z:621.53[M+C 2H 3] +. 1HNMR(500MHz,CDCl 3)δ0.66,0.77,0.89,0.99and1.13(5s,each3H),0.91(s,6H)0.71-2.03(m,23H),2.80(d,1H),3.21(d,1H),3.39-4.05(m,2H),4.25(d,2H),5.24(s,1H),5.69(d,1H),7.18(d,1H,),8.38(brs,1H)。
Therefore, Compound I can be determined 1be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-ethyl] ester, its structural formula is as follows:
Gained Compound II per 1detect through mass spectrum and proton nmr spectra:
m.p.185-187℃.APCI-MSm/z:1077.76[M-CH 3] +. 1HNMR(500MHz,CDCl 3):δ0.63,0.64,0.895,0.899,0.90,1.08and1.10(7s,each3H),0.76and0.96(2s,each6H),0.87(s,9H),0.71-1.73(m,46H),2.73–2.85(m,2H),3.18(dd,2H),3.83–4.23(m,8H),5.21(dd,2H),5.70(d,1H),7.13(d,1H)。
Therefore, Compound II per can be determined 1be 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyloxyethyl)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
Embodiment 2:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-ethyl] ester (I 2) and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyloxyethyl)-2,4 (1H, 3H)-pyrimidine dione (II 2) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mLDMF, add 24.95mmol (3.44g) salt of wormwood and 6.49mmol (0.56mL) 1, 2-ethylene dibromide, 60 DEG C of stirring reactions 0.5 hour, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, use the HCl of 1N successively, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue is through purification by silica gel column chromatography, with sherwood oil: the mixed solvent wash-out of ethyl acetate=8:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(2-bromotrifluoromethane) ester 1.60g(white solid, yield 57%), 1hNMR (500MHz, CDCl 3) 0.74,0.78,0.93,0.99and1.14 (5s, each3H), 0.90 (s, 6H), 0.71-1.98 (m, 23H), 2.87 (dd, 1H), 3.20 (dd, 1H), 3.49 (t, 2H), 4.23-4.42 (m, 2H), 5.30 (s, 1H) .APCI-MSm/z:545.36 [M-OH] -.
B) getting 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(2-bromotrifluoromethane) ester 0.71mmol (0.40g) is dissolved in 3mLDMF, add 3.55mmol (0.49g) salt of wormwood and 2.49mmol (0.31g) thymus pyrimidine, stirring reaction 0.5 hour at 50 DEG C, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then the HCl of 1N is used successively, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue is through purification by silica gel column chromatography, with sherwood oil: the mixed solvent wash-out of ethyl acetate=5:1 (volume ratio), thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain 0.18g Compound II per 2(white solid, yield 47%).Then with the mixed solvent wash-out that the sherwood oil that is 3:1 by volume ratio and ethyl acetate form, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains 0.13g Compound I 2(white solid, yield 31%).
Gained Compound I 2detect through mass spectrum and proton nmr spectra:
m.p.162-165℃. 1HNMR(500MHz,CDCl 3)δ0.73,0.77,0.88,0.90,0.91,0.97and1.11(7s,each3H),1.19(s,3H),0.63-2.03(m,23H),2.79(d,1H),3.20(dd,1H),3.95(m,2H),4.17-4.28(m,2H),5.22(s,1H),7.00(s,1H),8.61(s,1H)。
Therefore, Compound I can be determined 2be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-ethyl] ester, its structural formula is as follows:
Gained Compound II per 2detect through mass spectrum and proton nmr spectra:
m.p.172-175℃.APCI-MSm/z:1113.88[M+Na] +. 1HNMR(500MHz,CDCl 3):δ0.65,0.77,0.88,0.90,0.91,0.97and1.11(7s,each6H),1.91(s,3H),0.64-2.06(m,46H),2.79(d,2H),3.20(dd,2H),3.95(m,2H),4.16-4.33(m,6H),5.19(s,1H),5.22(s,1H),6.98(s,1H)。
Therefore, Compound II per can be determined 2for 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyloxyethyl)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
Embodiment 3:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-normal-butyl] ester; (I 3) and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen butyl)-2,4 (1H, 3H)-pyrimidine dione (II 3) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mLDMF, add 14.97mmol (2.07g) salt of wormwood and 0.72mL (5.99mmol) 1, 4-dibromobutane, 0 DEG C of stirring reaction 72 hours, revolve and desolventize, resistates 50mL acetic acid ethyl dissolution, use the HCl of 1N successively, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue is through purification by silica gel column chromatography, with sherwood oil: the mixed solvent wash-out of ethyl acetate=4:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(4-brombutyl) ester 1.78g (white solid, yield 61%), 1hNMR (500MHz, CDCl 3) 0.72,0.77,0.89,0.90,0.92,0.98and1.12 (7s, each3H), 0.71-1.98 (m, 27H), 2.85 (dd, 1H), 3.20 (dd, 1H), 3.42 (t, 2H), 4.04 (t, 2H), 5.27 (s, 1H) .APCI-MSm/z:575.40 [M-OH] -.
B) getting 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(4-brombutyl) ester 0.10mmol (0.59g) is dissolved in 3mLDMF, add 4.00mmol (0.55g) salt of wormwood and 2.50mmol (0.61g) uridylic, stirring reaction 24 hours at 50 DEG C, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then the HCl of 1N is used successively, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue is through purification by silica gel column chromatography, with sherwood oil: the mixed solvent wash-out of ethyl acetate=4:1 (volume ratio), thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain 0.17g Compound II per 3(white solid, yield 30%), then with the mixed solvent wash-out that the sherwood oil that is 2:1 by volume ratio and ethyl acetate form, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains 0.400g Compound I 3(white solid, yield 64%).
Gained Compound I 3detect through mass spectrum and proton nmr spectra:
m.p.131-134℃.APCI-MSm/z:623.54[M+H] +. 1HNMR(500MHz,CDCl 3)δ0.71,0.78,0.89,0.90,0.92,0.99and1.13(7s,each3H),0.71-2.03(m,27H),2.80(d,1H),3.21(d,1H),3.75(t,2H),4.06(t,2H),5.27(s,1H),5.69(d,1H),7.18(d,1H),9.56(s,1H)。
Therefore, Compound I can be determined 3be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-normal-butyl] ester, its structural formula is as follows:
Gained Compound II per 3detect through mass spectrum and proton nmr spectra:
m.p.149-151℃.APCI-MSm/z:1133.80[M-C 2H 5] +. 1HNMR(500MHz,CDCl 3):δ0.72,0.80,0.88,0.98and1.13(5s,each6H),0.90(s,12H),0.72-2.06(m,50H),2.86(dd,2H),3.21(dd,2H),3.75(m,2H),3.96(m,2H),4.00(dd,4H),5.27(s,2H),5.71(d,1H),7.08(d,1H)。
Therefore, Compound II per can be determined 3be 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen butyl)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
Embodiment 4:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-normal-butyl] ester (I 4) and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen butyl)-2,4 (1H, 3H)-pyrimidine dione (II 4) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mLDMF, add 14.97mmol (2.07g) salt of wormwood and 0.72mL (5.99mmol) 1, 4-dibromobutane, 0 DEG C of stirring reaction 72 hours, revolve and desolventize, resistates 50mL acetic acid ethyl dissolution, use the HCl of 1N successively, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue is through purification by silica gel column chromatography, with sherwood oil: the mixed solvent wash-out of ethyl acetate=4:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(4-brombutyl) ester 1.78g (white solid, yield 61%), 1hNMR (500MHz, CDCl 3) 0.72,0.77,0.89,0.90,0.92,0.98and1.12 (7s, each3H), 0.71-1.98 (m, 27H), 2.85 (dd, 1H), 3.20 (dd, 1H), 3.42 (t, 2H), 4.04 (t, 2H), 5.27 (s, 1H) .APCI-MSm/z:575.40 [M-OH] -.
B) getting 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(4-brombutyl) ester 0.676mmol (0.40g) is dissolved in 3mLDMF, add 2.70mmol (0.37g) salt of wormwood and 1.69mmol (0.41g) thymus pyrimidine, stirring reaction 24 hours at 50 DEG C, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then the HCl of 1N is used successively, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue is through purification by silica gel column chromatography, with sherwood oil: the mixed solvent wash-out of ethyl acetate=4:1 (volume ratio), thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain 0.25g Compound II per 4(white solid, yield 65%), then with the mixed solvent wash-out that the sherwood oil that is 2:1 by volume ratio and ethyl acetate form, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains 0.04g Compound I 4(white solid, yield 8%).
Gained Compound I 4detect through mass spectrum and proton nmr spectra:
m.p.133-136℃.APCI-MSm/z:637.44[M+H] +. 1HNMR(500MHz,CDCl 3)δ0.72,0.77,0.88,0.89,0.91,0.98and1.12(7s,each3H),1.19(s,3H),0.73-2.10(m,27H),2.85(dd,1H),3.20(dd,1H),3.72(t,2H),4.05(t,2H),5.26(s,1H),7.98(s,1H),8.84(s,1H)。
Therefore, Compound I can be determined 4be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-normal-butyl] ester, its structural formula is as follows:
Gained Compound II per 4detect through mass spectrum and proton nmr spectra:
m.p.157-160℃.APCI-MSm/z:1148.96[M-C 2H 5] +. 1HNMR(500MHz,CDCl3):δ0.73,0.86,0.90,0.96and1.13(5s,each6H),0.88(s,12H),1.90(s,3H),0.69-2.06(m,50H),2.83(d,2H),3.19(d,2H),3.71(t,2H),3.95(t,2H),4.02(m,4H),5.24(s,2H),6.94(s,1H)。
Therefore, Compound II per can be determined 4for 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen butyl)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
Embodiment 5:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-hexyl] ester (I 5) and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexyl)-2,4 (1H, 3H)-pyrimidine dione (II 5) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mLDMF, add 19.96mmol (2.76g) salt of wormwood and 6.24mmol (0.96mL) 1, 6-dibromo-hexane, 40 DEG C of stirring reactions 12 hours, revolve and desolventize, resistates 50mL acetic acid ethyl dissolution, use the HCl of 1N successively, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue is through purification by silica gel column chromatography, with sherwood oil: the mixed solvent wash-out of ethyl acetate=6:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(6-bromine hexyl) ester 1.80g (white solid, yield 58%), 1hNMR (500MHz, CDCl 3) 0.73,0.77,0.92,0.98and1.13 (5s, each3H), 0.89 (s, 6H), 0.71-1.98 (m, 31H), 2.86 (d, 1H), 3.21 (d, 1H), 3.40 (t, 2H), 4.02 (m, 2H), 5.27 (s, 1H) .APCI-MSm/z:601.45 [M-OH] -.
B) acid-(6-bromine hexyl) ester 0.83mmol (0.51g) is dissolved in 3mLDMF to get 3 beta-hydroxies-volatile oil-12-alkene-28-, add 1.66mmol (0.23g) salt of wormwood and 1.66mmol (0.41g) uridylic, stirring reaction 72 hours at 50 DEG C, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then the HCl of 1N, water, saturated sodium bicarbonate, water and saturated common salt water washing is used successively
Anhydrous magnesium sulfate drying, filters, and filtrate concentrates, and gained residue is through purification by silica gel column chromatography, and with sherwood oil: the mixed solvent wash-out of ethyl acetate=3:1 (volume ratio), elutriant solvent evaporated, obtains 0.22g Compound II per 5(white solid, yield 44%); Then with the mixed solvent wash-out that the sherwood oil that is 1:1 by volume ratio and ethyl acetate form, elutriant solvent evaporated, obtains 0.239g Compound I 5(white solid, yield 44%).
Gained Compound I 5detect through mass spectrum and proton nmr spectra:
m.p.126-128℃.APCI-MSm/z:651.56[M+H] +. 1HNMR(500MHz,CDCl 3)0.71,0.76,0.90,0.97and1.12(5s,each3H),0.88(s,6H),0.71-2.03(m,31H),2.84(d,1H),3.20(d,1H),3.70(t,2H),3.99(t,2H),5.25(s,1H),5.68(d,1H),7.13(d,1H),9.34(brs,1H)。
Therefore, Compound I can be determined 5be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-hexyl] ester, its structural formula is as follows:
Gained Compound II per 5detect through mass spectrum and proton nmr spectra:
m.p.140-142℃.APCI-MSm/z:1189.87[M+H] +. 1HNMR(500MHz,CDCl 3)0.73,0.78,0.89,0.90,0.93,0.98and1.13(7s,each6H),0.72-2.06(m,62H),2.86(dd,2H),3.21(dd,2H),3.70-3.73(m,2H),3.91-3.94(m,2H),4.01(dd,4H),5.21(s,2H),5.71(d,1H),7.08(d,1H)。
Therefore, Compound II per can be determined 5be 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexyl)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
Embodiment 6:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-hexyl] ester (I 6) and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexyl)-2,4 (1H, 3H)-pyrimidine dione (II 6) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mLDMF, add 19.96mmol (2.76g) salt of wormwood and 6.24mmol (0.96mL) 1, 6-dibromo-hexane, 40 DEG C of stirring reactions 12 hours, revolve and desolventize, resistates 50mL acetic acid ethyl dissolution, use the HCl of 1N successively, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue is through purification by silica gel column chromatography, with sherwood oil: the mixed solvent wash-out of ethyl acetate=6:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(6-bromine hexyl) ester 1.80g (white solid, yield 58%), 1hNMR (500MHz, CDCl 3) 0.73,0.77,0.92,0.98and1.13 (5s, each3H), 0.89 (s, 6H), 0.71-1.98 (m, 31H), 2.86 (d, 1H), 3.21 (d, 1H), 3.40 (t, 2H), 4.02 (m, 2H), 5.27 (s, 1H) .APCI-MSm/z:601.45 [M-OH] -.
B) acid-(6-bromine hexyl) ester 0.81mmol (0.50g) is dissolved in 3mLDMF to get 3 beta-hydroxies-volatile oil-12-alkene-28-, add 1.62mmol (0.22g) salt of wormwood and 1.62mmol (0.20g) thymus pyrimidine, stirring reaction 72 hours at 50 DEG C, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then the HCl of 1N is used successively, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue is through purification by silica gel column chromatography, with sherwood oil: the mixed solvent wash-out of ethyl acetate=3:1 (volume ratio), thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain 0.20g Compound II per 6(white solid, yield 42%), then with the mixed solvent wash-out that the sherwood oil that is 1:1 by volume ratio and ethyl acetate form, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains 0.122g Compound I 6(white solid, yield 23%).
Gained Compound I 6detect through mass spectrum and proton nmr spectra:
m.p.115-119℃.APCI-MSm/z:663.40[M-H] -. 1HNMR(500MHz,CDCl 3)0.73,0.77,0.91,0.98and1.12(5s,each3H),0.89(s,6H),1.19(s,3H),0.73-2.10(m,31H),2.85(d,1H),3.20(dd,1H),3.68(t,2H),4.00(t,2H),5.26(s,1H),6.96(s,1H),8.90(s,1H)。
Therefore, Compound I can be determined 6be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-hexyl] ester, its structural formula is as follows:
Gained Compound II per 6detect through mass spectrum and proton nmr spectra:
m.p.135-139℃.APCI-MSm/z:1226.04[M+Na] +. 1HNMR(500MHz,CDCl 3)0.71,0.76,0.90,0.95and1.11(5s,each6H),0.88(s,12H),1.91(s,3H),0.69-2.06(m,62H),2.85(dd,2H),3.19(dd,2H),3.67(t,2H),3.95(t,2H),3.98(dd,4H),5.25(s,2H),6.93(s,1H)。
Therefore, Compound II per can be determined 6for 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexyl)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
Embodiment 7:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-octyl] ester (I 7) and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octyl group)-2,4 (1H, 3H)-pyrimidine dione (II 7) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mLDMF, add 9.98mmol (1.38g) salt of wormwood and 6.49mmol (1.08mL) 1, 8-bis-bromooctane, stirring at room temperature reacts 18 hours, steaming desolventizes, resistates 50mL acetic acid ethyl dissolution, use the HCl of 1N successively, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue is through purification by silica gel column chromatography, with sherwood oil: the mixed solvent wash-out of ethyl acetate=5:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(8-bromine octyl group) ester 2.03g (white solid, yield 63%), 1hNMR (500MHz, CDCl 3) 0.72,0.77,0.89,0.90,0.93,0.98and1.13 (7s, each3H), 0.71-2.03 (m, 35H), 2.86 (dd, 1H), 3.20 (dd, 1H), 3.39 (t, 2H), 3.97-4.02 (m, 2H), 5.27 (s, 1H) .APCI-MSm/z:631.50 [M-CH 3] -.
B) acid-(8-bromine octyl group) ester 0.23mmol (0.15g) is dissolved in 3mLDMF to get 3 beta-hydroxies-volatile oil-12-alkene-28-, add 0.69mmol (0.09g) salt of wormwood and 0.69mmol (0.17g) uridylic, stirring reaction 48 hours at 50 DEG C, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then the HCl of 1N is used successively, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue is through purification by silica gel column chromatography, with sherwood oil: the mixed solvent wash-out of ethyl acetate=3.5:1 (volume ratio), thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain 0.103g Compound II per 7(white solid, yield 72%), then with the mixed solvent wash-out that the sherwood oil that is 1.5:1 by volume ratio and ethyl acetate form, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains 0.016g Compound I 7(white solid, yield 11%).
Gained Compound I 7detect through mass spectrum and proton nmr spectra:
m.p.101-105℃.APCI-MSm/z:679.60[M+H] +. 1HNMR(500MHz,CDCl 3)0.73,0.78,0.92,0.98and1.13(5s,each3H),0.90(s,6H),0.71-2.03(m,35H),2.86(dd,1H),3.21(dd,1H),3.71(t,2H),4.00(t,2H),5.27(s,1H),5.68(d,1H),7.13(d,1H),8.61(brs,1H)。
Therefore, Compound I can be determined 7be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-octyl] ester, its structural formula is as follows:
Gained Compound II per 7detect through mass spectrum and proton nmr spectra:
m.p.125-128℃.APCI-MSm/z:1245.90[M+H] +. 1HNMR(500MHz,CDCl 3)0.72,0.77,0.92,0.98and1.12(5s,each6H),0.89(s,12H),0.71-2.06(m,70H),2.86(dd,2H),3.21(dd,2H),3.69-3.72(m,2H),3.89-3.92(m,2H),3.99(dd,4H),5.27(s,2H),5.70(d,1H),7.08(d,1H)。
Therefore, Compound II per can be determined 7be 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octyl group)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
Embodiment 8:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-octyl] ester (I 8) and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octyl group)-2,4 (1H, 3H)-pyrimidine dione (II 8) preparation
A) 4.99mmol (2.28g) Oleanolic Acid is dissolved in 10mLDMF, add 9.98mmol (1.38g) salt of wormwood and 6.49mmol (1.08mL) 1, 8-bis-bromooctane, stirring at room temperature reacts 18 hours, steaming desolventizes, resistates 50mL acetic acid ethyl dissolution, use the HCl of 1N successively, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue is through purification by silica gel column chromatography, with sherwood oil: the mixed solvent wash-out of ethyl acetate=5:1 (volume ratio), elutriant solvent evaporated, obtain 3 beta-hydroxies-volatile oil-12-alkene-28-acid-(8-bromine octyl group) ester 2.03g (white solid, yield 63%), 1hNMR (500MHz, CDCl 3) 0.72,0.77,0.89,0.90,0.93,0.98and1.13 (7s, each3H), 0.71-2.03 (m, 35H), 2.86 (dd, 1H), 3.20 (dd, 1H), 3.39 (t, 2H), 3.97-4.02 (m, 2H), 5.27 (s, 1H) .APCI-MSm/z:631.50 [M-CH 3] -.
B) acid-(8-bromine octyl group) ester 0.23mmol (0.15g) is dissolved in 3mLDMF to get 3 beta-hydroxies-volatile oil-12-alkene-28-, add 0.69mmol (0.09g) salt of wormwood and 0.69mmol (0.09g) thymus pyrimidine, stirring reaction 48 hours at 50 DEG C, decompression is revolved and is desolventized, resistates 50mL acetic acid ethyl dissolution, then the HCl of 1N is used successively, water, saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue is through purification by silica gel column chromatography, with sherwood oil: the mixed solvent wash-out of ethyl acetate=3.5:1 (volume ratio), thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain 0.026g Compound II per 8(white solid, yield 18%), then with the mixed solvent wash-out that the sherwood oil that is 1.5:1 by volume ratio and ethyl acetate form, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains 0.100g Compound I 8(white solid, yield 62%).
Gained Compound I 8detect through mass spectrum and proton nmr spectra:
m.p.101-104℃.APCI-MSm/z:693.48[M+H] +. 1HNMR(500MHz,CDCl 3)0.72,0.76,0.91,0.97and1.12(5s,each3H),0.89(s,6H),1.31(s,3H),0.73-2.10(m,35H),2.85(d,1H),3.20(dd,1H),3.68(t,2H),3.92（d，1H）,4.00(t,2H),5.26(s,1H),6.95(s,1H)。
Therefore, Compound I can be determined 8be 3 beta-hydroxies-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-octyl] ester, its structural formula is as follows:
Gained Compound II per 8detect through mass spectrum and proton nmr spectra:
m.p.116-119℃.APCI-MSm/z:1282.15[M+Na] +. 1HNMR(500MHz,CDCl 3)0.71,0.76,0.91,0.97and1.12(5s,each6H),0.88(s,12H),1.91(s,3H),0.69-2.06(m,70H),2.85(d,2H),3.20(d,2H),3.67(t,2H),3.95(t,2H),3.98(d,4H),5.26(s,2H),6.93(s,1H)。
Therefore, Compound II per can be determined 8for 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octyl group)-2,4 (1H, 3H)-pyrimidine dione, its structural formula is as follows:
The preparation of embodiment 9:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-propyl] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-monomethacryloxypropyl)-2,4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,3-dibromopropane.
Embodiment 10:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-propyl] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-monomethacryloxypropyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,3-dibromopropane.
The preparation of embodiment 11:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-pentyl] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen amyl group)-2,4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with pentamethylene bromide.
Embodiment 12:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-pentyl] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen amyl group)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with pentamethylene bromide.
The preparation of embodiment 13:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-heptyl] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptyl)-2,4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,7-dibromo-heptane.
Embodiment 14:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-heptyl] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,7-dibromo-heptane.
The preparation of embodiment 15:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-nonyl] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen nonyl)-2,4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,9-bis-bromononane.
Embodiment 16:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-nonyl] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen nonyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,9-bis-bromononane.
The preparation of embodiment 17:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-positive decyl] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen decyl)-2,4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,10-dibromo-decane.
Embodiment 18:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-positive decyl] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen decyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,10-dibromo-decane.
Embodiment 19:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-undecane base] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen undecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,11-bis-bromo-n-11.
Embodiment 20:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-undecane base] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen undecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,11-bis-bromo-n-11.
Embodiment 21:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-dodecyl] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen dodecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,12-dibromo-dodecane.
Embodiment 22:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-dodecyl] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen dodecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,12-dibromo-dodecane.
Embodiment 23:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-tridecane base] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tridecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,13-dibromo tridecane.
Embodiment 24:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-tridecane base] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tridecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,13-dibromo tridecane.
Embodiment 25:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-tetradecane base] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tetradecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,14-bis-bromo-tetradecane.
Embodiment 26:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-tetradecane base] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen tetradecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,14-bis-bromo-tetradecane.
Embodiment 27:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-Pentadecane base] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen pentadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,15-bis-bromopen tadecane.
Embodiment 28:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-Pentadecane base] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen pentadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,15-bis-bromopen tadecane.
Embodiment 29:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-hexadecyl] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,16-dibromo n-Hexadecane.
Embodiment 30:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-hexadecyl] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen hexadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,16-dibromo n-Hexadecane.
Embodiment 31:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-n-heptadecane base] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,17-dibromo heptadecane.
Embodiment 32:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-n-heptadecane base] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen heptadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,17-dibromo heptadecane.
Embodiment 33:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(uridylic-1)-Octadecane base] ester and 1,3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 1, just replace glycol dibromide with 1,18-bis-bromo-octadecane.
Embodiment 34:3 beta-hydroxy-volatile oil-12-alkene-28-acid-[(thymus pyrimidine-1)-Octadecane base] ester and 5-methyl isophthalic acid, 3-bis--(3 beta-hydroxies-volatile oil-12-alkene-28-acyl-oxygen octadecyl)-2, the preparation of 4 (1H, 3H)-pyrimidine dione
With reference to the preparation method of embodiment 2, just replace glycol dibromide with 1,18-bis-bromo-octadecane.
Embodiment 35:3 β-acetoxyl group-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides (III 1) preparation
1) get Oleanolic Acid 11mmol (5.00g) and be dissolved in anhydrous pyridine/methylene dichloride (8mL, 7/1, v/v) in, add DMAP1.10mmol (0.13g) and diacetyl oxide 16.5mmol (58.2mL), stirring at room temperature reacts 12 hours, concentration of reaction solution, and resistates 2NHCl dissolves, be extracted with ethyl acetate 2 times, merge organic layer; Organic layer is used successively water, saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue ethanol and sherwood oil mixed solvent (V ethanol: V sherwood oil=6:5) in 80 DEG C of recrystallizations, obtain 3 β-acetoxyl group-volatile oil-12-alkene-28-acid 4.90g (white solid, yield 89%); 1hNMR (500MHz, CDCl 3) 0.76,0.85,0.87,0.91,0.93,0.94and1.13 (7s, each3H), 2.04 (s, 3H), 0.63-2.10 (m, 22H), 2.82 (d, 1H), 3.52 (brs, 1H), 4.50 (t, 1H), 5.28 (s, 1H).
2) get 3 β-acetoxyl group-volatile oil-12-alkene-28-acid 2.00mmol (1.00g) and be dissolved in anhydrous methylene chloride 1mL, oxalyl chloride 30.0mmol (2.6mL) is dripped at 0 DEG C, stirring at room temperature reacts 7 hours, and concentration of reaction solution obtains resistates;
3) step 2) the anhydrous THF dissolving of gained resistates 1mL; then uridylic 4.00mmol (0.45g) and triethylamine 1.00mmol (0.14mL) is added; under nitrogen protection, stirring at room temperature reacts 48 hours; concentration of reaction solution; resistates 50mL methylene dichloride dissolves; use water, saturated common salt water washing more successively; anhydrous magnesium sulfate drying; filter; filtrate concentrates; gained residue through purification by silica gel column chromatography, with methylene dichloride and methyl alcohol composition mixed solvent (V sherwood oil: V ethyl acetate=3:1) wash-out, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains 0.349g compound III 1(white solid, yield 29%).
Above-claimed cpd detects through proton nmr spectra:
m.p.208-211℃. 1HNMR(500MHz,CDCl 3)0.69,0.85,0.86,0.99and1.13(5s,each3H),0.92(s,6H),1.17(s,3H),0.63-2.10(m,22H),2.99(d,1H),4.47-4.60(m,1H),5.28(s,1H),5.74(d,1H),7.51(d,1H),8.20(brs,1H)。
Therefore, compound III can be determined 1be 3 β-acetoxyl group-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides, its structural formula is as follows:
Embodiment 36:3 β-propionyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides (III 2) preparation
1) get Oleanolic Acid 2.2mmol (1.00g) and be dissolved in anhydrous pyridine/methylene dichloride (8mL, 7/1, v/v) in, add DMAP1.10mmol (0.13g) and propionic anhydride 4.4mmol (0.57mL), stirring at room temperature reacts 12 hours, concentration of reaction solution, resistates 2NHCl dissolves, be extracted with ethyl acetate 1 time, organic layer is used successively water, saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue ethanol and sherwood oil mixed solvent (V ethanol: V sherwood oil=5:5) in 70 DEG C of recrystallizations, obtain 3 β-propionyloxy-volatile oil-12-alkene-28-carboxylic acid 0.85g (white solid, yield 76%); 1hNMR (500MHz, CDCl 3) δ 0.74,0.90,0.92,0.93and1.12 (5s, each3H), 0.85 (s, 6H), 0.81-2.10 (m, 25H), (2.32 q, 2H), 2.81 (d, 1H), 4.40 – 4.57 (m, 1H), 5.27 (s, 1H).
2) get 3 β-propionyloxy-volatile oil-12-alkene-28-carboxylic acid 0.59mmol (0.30g) and be dissolved in anhydrous methylene chloride 1mL, oxalyl chloride 5.90mmol (0.51mL) is dripped at 0 DEG C, 0 DEG C of stirring reaction 12 hours, concentration of reaction solution, obtains resistates;
3) step 2) the anhydrous THF dissolving of gained resistates 1mL; then uridylic 1.77mmol (0.43g), DMAP0.118mmol (0.014g) and triethylamine 7.17mmol (1mL) is added; under nitrogen protection, stirring at room temperature reacts 24 hours; concentration of reaction solution; resistates 50mL methylene dichloride dissolves; use water, saturated common salt water washing more successively; anhydrous magnesium sulfate drying; filter; filtrate concentrates; gained residue through purification by silica gel column chromatography, with methylene dichloride and methyl alcohol composition mixed solvent (V sherwood oil: V ethyl acetate=5:1) wash-out, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains 0.21g compound III 2(white solid, yield 60%).
Above-claimed cpd detects through proton nmr spectra:
m.p.119-122℃. 1HNMR(500MHz,CDCl 3)0.69,0.846,0.85,0,98and1.13(5s,each3H),0.91(s,6H),0.63-2.10(m,25H),2.32(q,2H),2.99(d,1H),4.47-4.60(m,1H),5.28(s,1H),5.74(d,1H),7.50(d,1H),8.98(brs,1H)。
Therefore, compound III can be determined 2be 3 β-propionyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides, its structural formula is as follows:
Embodiment 37:3 β-butyryl acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides (III 3) preparation
1) get Oleanolic Acid 2.2mmol (1.00g) and be dissolved in anhydrous pyridine/methylene dichloride (8mL, 7/1, v/v) in, add DMAP1.10mmol (0.13g) and butyryl oxide 2.75mmol (0.45mL), stirring at room temperature reacts 10 hours, concentration of reaction solution, and resistates 2NHCl dissolves, be extracted with ethyl acetate 2 times, merge organic layer; Organic layer is used successively water, saturated common salt water washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, gained residue ethanol and sherwood oil mixed solvent (V ethanol: V sherwood oil=6:4) in 90 DEG C of recrystallizations, obtain 3 β-butyryl acyloxy-volatile oil-12-alkene-28-carboxylic acid 0.79g (white solid, yield 68%); 1hNMR (500MHz, CDCl 3) 0.74,0.90,0.92,0.93,1.12and1.25 (6s, each3H), 0.85 (s, 6H), 0.63-2.10 (m, 24H), 2.28 (t, 2H), 2.81 (d, 1H), (3.66 s, 1H), 4.50 (d, 1H), 5.27 (s, 1H).
2) get 3 β-butyryl acyloxy-volatile oil-12-alkene-28-carboxylic acid 0.38mmol (0.20g) and be dissolved in anhydrous methylene chloride 1mL, oxalyl chloride 6.93mmol (0.59mL) is dripped at 0 DEG C, 60 DEG C of stirring reactions 0.5 hour, concentration of reaction solution, obtains resistates;
3) step 2) the anhydrous THF dissolving of gained resistates 1mL; then uridylic 1.73mmol (0.19g), DMAP0.035mmol (0.004g) and triethylamine 12.1mmol (1.69mL) is added; under nitrogen protection, stirring at room temperature reacts 12 hours; concentration of reaction solution; resistates 50mL methylene dichloride dissolves; use water, saturated common salt water washing more successively; anhydrous magnesium sulfate drying; filter; filtrate concentrates; gained residue through purification by silica gel column chromatography, with sherwood oil and ethyl acetate composition mixed solvent (V sherwood oil: V acetic acid second ester=5:1) wash-out, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains 0.13g compound III 3(white solid, yield 56%).
Above-claimed cpd detects through mass spectrum and proton nmr spectra:
m.p.285-287℃.APCI-MSm/z:619.38[M-H] -. 1HNMR(500MHz,CDCl 3)0.69,0.85,0.86,0.92,0.96,0.99and1.18(7s,each3H)0.63-2.10(m,27H),2.28(t,2H),2.99(d,1H),4.49(dd,1H),5.28(s,1H),5.74(d,1H),7.50(d,1H),8.13(brs,1H)。
Therefore, compound III can be determined 3be 3 β-butyryl acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides, its structural formula is as follows:
Embodiment 38:3 β-dodecanoyl oxygen base-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides (III 4) preparation
1) getting Oleanolic Acid 2.2mmol (1.00g) is dissolved in 3mL tetrahydrofuran (THF), add lauroyl chloride 6.6mmol (1.57mL) and triethylamine 11mmol (1.53mL), stirring at room temperature reacts 20 hours, concentration of reaction solution, and resistates 50mL methylene dichloride dissolves, use water, saturated common salt water washing successively, anhydrous magnesium sulfate drying, filters, and filtrate concentrates, gained residue through purification by silica gel column chromatography, with mixed solvent wash-out (V ethyl acetate: V sherwood oil=1:20), elutriant solvent evaporated, obtains 3 β-dodecanoyl oxygen base-volatile oil-12-alkene-28-carboxylic acid 1.04g (white solid, yield 75%); 1hNMR (500MHz, CDCl 3) 0.76,0.85,0.89,0.90,0.92,0.93and1.13 (7s, each3H), 0.63-2.10 (m, 43H), 2.29 (t, 2H), 2.76 (dd, 1H), 4.48-4.61 (m, 1H), 5.27 (s, 1H).
2) get 3 β-dodecanoyl oxygen base-volatile oil-12-alkene-28-carboxylic acid 0.44mmol (0.28g) and be dissolved in anhydrous methylene chloride 1mL, thionyl chloride 4.39mmol (0.31mL) is dripped at 0 DEG C, 60 DEG C of stirring reactions 0.5 hour, concentration of reaction solution, obtains resistates;
3) step 2) the anhydrous THF dissolving of gained resistates 1mL; then uridylic 4.08mmol (0.34g) and triethylamine 7.48mmol (1.04mL) is added; under nitrogen protection, stirring at room temperature reacts 24 hours; concentration of reaction solution; resistates 50mL methylene dichloride dissolves; use water, saturated common salt water washing more successively; anhydrous magnesium sulfate drying; filter; filtrate concentrates; gained residue through purification by silica gel column chromatography, with sherwood oil and ethyl acetate composition mixed solvent (V sherwood oil: V ethyl acetate=4:1) wash-out, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains 0.072g compound III 4(white solid, yield 22%).
Above-claimed cpd detects through proton nmr spectra:
1HNMR(500MHz,CDCl 3)0.70,1.00and1.19(3s,each3H),0.87and0.93(2s,each6H),0.63-2.10(m,43H),2.30(s,2H),3.01(d,1H),4.50(s,1H),5.30(s,1H),5.74(d,1H),7.52(d,1H),8.72(brs,1H)。
Therefore, compound III can be determined 4be 3 β-dodecanoyl oxygen base-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides, its structural formula is as follows:
Embodiment 39:3 β-palm acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides (III 5) preparation
1) getting Oleanolic Acid 2.2mmol (1.00g) is dissolved in 3mL tetrahydrofuran (THF), add palmityl chloride 8.8mmol (2.69mL) and triethylamine 77mmol (10.2mL), stirring at room temperature reacts 12 hours, concentration of reaction solution, and resistates 50mL methylene dichloride dissolves, use water, saturated common salt water washing successively, anhydrous magnesium sulfate drying, filters, and filtrate concentrates, gained residue through purification by silica gel column chromatography, with mixed solvent wash-out (V ethyl acetate: V sherwood oil=1:15), thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains 3 β-palm acyloxy-volatile oil-12-alkene-28-carboxylic acid 1.35g (white solid, yield 89%); 1hNMR (500MHz, CDCl 3) 0.76,0.85,0.89,0.90,0.93,0.94and1.14 (7s, each3H), 2.29 (t, 2H), 0.63-2.10 (m, 51H), 2.82 (dd, 1H), 4.50 (dd, 1H), 5.27 (s, 1H).
2) get 3 β-palm acyloxy-volatile oil-12-alkene-28-carboxylic acid 0.50mmol (0.35g) and be dissolved in anhydrous methylene chloride 1mL, thionyl chloride 7.40mmol (0.52mL) is dripped at 0 DEG C, stirring at room temperature reacts 12 hours, and concentration of reaction solution obtains resistates;
3) step 2) the anhydrous THF dissolving of gained resistates 1mL; then uridylic 1.11mmol (0.124g) and triethylamine 6.17mmol (0.86mL) is added; under nitrogen protection, stirring at room temperature reacts 24 hours; concentration of reaction solution; resistates 50mL methylene dichloride dissolves; use water, saturated common salt water washing more successively; anhydrous magnesium sulfate drying; filter; filtrate concentrates; gained residue through purification by silica gel column chromatography, with sherwood oil and ethyl acetate composition mixed solvent (V sherwood oil: V ethyl acetate=4:1) wash-out, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains 0.04g compound III 5(white solid, yield 11%).
Above-claimed cpd detects through mass spectrum and proton nmr spectra:
m.p.89-91℃.APCI-MSm/z:787.71[M-H] -. 1HNMR(500MHz,CDCl 3)0.69,0.85,0.86,0.99and1.18(5s,each3H),0.92(s,6H),0.63-2.10(m,51H),2.29(t,2H),2.99(dd,1H),4.47-4.60(m,1H),5.28(s,1H),5.74(d,1H),7.50(d,1H),8.17(brs,1H)。
Therefore, compound III can be determined 5be 3 β-palm acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides, its structural formula is as follows:
The preparation of embodiment 40:3 β-penta acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides
With reference to the preparation method of embodiment 38, just replace lauroyl chloride with n-amyl chloride.
The preparation of embodiment 41:3 β-hexylyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides
With reference to the preparation method of embodiment 38, just replace lauroyl chloride with caproyl chloride.
The preparation of embodiment 42:3 β-heptan acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides
With reference to the preparation method of embodiment 38, just replace lauroyl chloride with oenanthyl chloro.
The preparation of embodiment 43:3 β-Xin acyloxy-volatile oil-12-alkene-28-carboxylic acid uridylic acid amides
With reference to the preparation method of embodiment 38, just replace lauroyl chloride with capryl(yl)chloride.
In order to absolutely prove the application of conjugate of the present invention in pharmacy, the compound that embodiment 1 ~ 8 and embodiment 35 ~ 39 obtain by applicant carries out extracorporeal anti-tumor cell-proliferation activity experiment (adopting the blue colorimetry of conventional tetramethyl-nitrogen azoles) to multiple mankind's tumor line:
1, cell strain and cell cultures
HepG-2 (human hepatoma cell strain), A549 (human lung carcinoma cell line), BGC-823 (stomach cancer cell line), MCF-7 (breast carcinoma cell strain), PC-3 (Prostatic cancer cell lines) are selected in this experiment.
All cells strain is all cultivated containing in 1640 substratum of 10% foetal calf serum, at 37 DEG C of 5%CO 2cell culture incubator in be cultured to cell and reach logarithmic phase.
2, primary dcreening operation
All compounds all >=95%, are mixed with 100 μm of ol/L, solubility promoter DMSO final concentration≤0.5% by the purity of compound used therefor, test the suppression degree of compound on tumor Growth of Cells under this concentration.When final compound concentration is 10 μm of ol/L, namely inhibiting rate >=50% is judged to be that primary dcreening operation is effective.
3, (MTT) is tested
By test-compound to be measured with after DMSO hydrotropy, be made into the working fluid concentration of 100 μm of ol/L, 50 μm of ol/L, 10 μm of ol/L, 5 μm of ol/L, 1 μm of ol/L and 0.1 μm ol/L, deposit in 4 DEG C of Refrigerator stores, for test test-compound to the IC of selected tumor cell line 50value uses.
Get and be in one bottle, cell in good condition exponential phase of growth, add 0.25% tryptic digestive juice, digestion makes attached cell come off, counting 2 ~ 4 × 10 4individual/mL, makes cell suspension; Obtained cell suspension is inoculated on 96 orifice plates, and 180 μ L/ holes, put constant temperature CO 2cultivate 24 hours in incubator; Change liquid, add test-compound, 20 μ L/ holes, cultivate 72 hours; MTT is added in 96 orifice plates, 20 μ L/ holes, react 4 hours in incubator; Suck supernatant liquor, add DMSO, 150 μ L/ holes, jolting 5 minutes on plate shaker; Be the light absorption value in the every hole of mensuration, 570nm place at wavelength with enzyme-linked immunosorbent assay instrument, and calculate cell inhibitory rate (cell inhibitory rate %=(negative control group OD value-tested material group OD value)/negative control group OD value × 100%).Record the data (IC of the extracorporeal anti-tumor cell-proliferation activity of each test-compound 50, μm ol/L or μM) as shown in the following Table 1:
Table 1:
IC 50value is the mean value of three experiments; NI represents do not have activity when 100 μm of ol/L concentration.
According to the literature, the parent compound Oleanolic Acid of conjugate of the present invention is to the IC of HepG-2 cell line and lung cancer A549 cell 50value is respectively 70 μMs and 39 μMs of (Zheng, M.S.; Lee, Y.K.; Li, Y.; Etal.InhibitionofDNAtopoisomerasesIandIIandcytotoxicityo fcompoundsfromUlmusdavidianavar.japonica.ArchivesofPharm acalResearch, 2010,33 (9), 1307-1315); To the IC of MCF-7 Breast Cancer Cell 50be worth 88.36 μMs (Huang Minshan, Huang Wei, Wu Qinian etc. Oleanolic Acid induction cell apoptosis in human breast cancer and with Ca in cell 2+the research of level, contemporary Chinese medical journal, 2004,14 (16): 58-60).And pharmacological experimental data display in table 1, in tested compound, Compound II per 5there is the highest anti-HepG-2 cell line proliferation activity (IC 50=0.99 μM), be parent compound Oleanolic Acid (IC 50=70 μMs) 70 times of corresponding activity; Compound I 6, II 4, II 6and II 8there is very good suppressing lung cancer A 549 cell proliferation activity (IC 50< 0.1 μM), be parent compound Oleanolic Acid (IC 50=39 μMs) more than 390 times of corresponding activity; Compound I 7, II 5and III 1there is very high anti-breast cancer MCF-7 cell-proliferation activity (IC 50< 0.1 μM), be at least parent compound Oleanolic Acid (IC 50=88.36 μMs) 880 times of corresponding activity.Compound III in addition 1, III 2and III 5show extraordinary anti-BGC-823 Cells proliferation activity (IC 50< 0.1 μm).
According to pharmacological experimental data display in table 1, general formula of the present invention (I), (II) or (III) compound have good anti-tumor activity, to the suppression IC of tested tumour cell 50value major part is all at micromolar levels; In institute's test compounds, the activity of outstanding compound or even more than 800 times of parent compound Oleanolic Acid activity; Therefore, the compound with structure shown in above-mentioned general formula (I), (II) or (III) of the present invention has good anti-tumor activity, can be used for the medicine preparing prevention or treatment tumor disease.Have pharmacy acceptable salt or the ester of structural compounds shown in above-mentioned general formula (I), (II) or (III), they prepare with general formula (I), (II) or (III) compound the same can be used for the medicine preventing or treat tumor disease.
The pharmaceutical preparation of the Oleanolic Acid described in the present invention-miazines conjugate can adopt common capsule, tablet, particle or other oral preparations; also administered parenterally can be carried out; any conventionally form can be taked, such as injection, ointment, percutaneous dosing, inhalation etc.

Claims (5)

1. there is Oleanolic Acid-miazines conjugate or its pharmacy acceptable salt of following shown structure:
2. the preparation method of Oleanolic Acid according to claim 1-miazines conjugate, is characterized in that: comprise the following steps:
1) oxygen acyl group oleanolic acid derivate is prepared; The preparation method of described oxygen acyl group oleanolic acid derivate is: Oleanolic Acid, alkali and esterifying reagent are placed in organic solvent, add or do not add catalyst reaction 0.5 ~ 24h, decompression is revolved and is desolventized, resistates diluted hydrochloric acid dissolution, be extracted with ethyl acetate 1 ~ 3 time again, merge organic layer, washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, and gained residue, with being the mixed solvent recrystallization that the ethanol of 5 ~ 6:4 ~ 5 and sherwood oil form by volume ratio, to obtain final product; Or by silica gel column chromatography on residue, to be the mixed solvent wash-out that the sherwood oil of 10 ~ 20:1 and ethyl acetate form by volume ratio, elutriant solvent evaporated, to obtain final product;
2) take oxygen acyl group oleanolic acid derivate and acyl halide reagent by the mol ratio of 1:3 ~ 20, stirring reaction 0.5 ~ 72h, decompression is revolved and is desolventized, and obtains oxygen acyl group Oleanolic Acid chloride compounds;
3) gained oxygen acyl group Oleanolic Acid chloride compounds organic solvent dissolution, then add and be equivalent to the uridylic of oxygen acyl group oleanolic acid derivate molar weight 2 ~ 8 times and the alkali of 5 ~ 35 times, or else add or add the catalyzer being equivalent to oxygen acyl group oleanolic acid derivate molar weight 0.1 ~ 0.5 times, 0.5 ~ 72h is reacted under nitrogen protection, decompression is revolved and is desolventized, residue from dichloromethane dissolves, washing, anhydrous magnesium sulfate drying, filter, filtrate concentrates, silica gel column chromatography on gained residue, by volume ratio to be the mixed solvent wash-out that the sherwood oil of 5 ~ 1:1 and ethyl acetate form, elutriant solvent evaporated, obtain described Oleanolic Acid-uridylic conjugate.
3. preparation method according to claim 2, is characterized in that: in step 2) in, described acyl halide reagent is thionyl chloride or oxalyl chloride, and the mol ratio of described oxygen acyl group oleanolic acid derivate and thionyl chloride or oxalyl chloride is 1:10 ~ 20.
4. preparation method according to claim 2, is characterized in that: described catalyzer is DMAP.
5. the application of Oleanolic Acid according to claim 1-miazines conjugate in preparation prevention or treatment antitumor drug.
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