CN105418721A - Oleanolic acid chemical modifier with antitumor activity and preparation method thereof - Google Patents

Oleanolic acid chemical modifier with antitumor activity and preparation method thereof Download PDF

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CN105418721A
CN105418721A CN201510744325.5A CN201510744325A CN105418721A CN 105418721 A CN105418721 A CN 105418721A CN 201510744325 A CN201510744325 A CN 201510744325A CN 105418721 A CN105418721 A CN 105418721A
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oleanolic acid
acid
compound
oleanane type
carboxylic acid
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CN105418721B (en
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孟艳秋
刘立伟
刘冬莹
李丹
关赛
王晓晨
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Shenyang University of Chemical Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom

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Abstract

The invention relates to a structural transformation method of a natural product oleanolic acid, in particular to an oleanolic acid chemical modifier with antitumor activity and a preparation method thereof. In the method, a series of structural analogues with bioactivity are obtained by chemical structural transformation and modification of the natural product oleanolic acid. Pharmacological experiments prove that the oleanolic acid chemical modifier is well inhibitory of human cervical cancer Hela cells, human liver cancer HepG2 cells and gastric cancer BGC-823 cells and is better than the parent compound oleanolic acid. The oleanolic acid chemical modifier includes following three types.

Description

A kind of Oleanolic Acid chemical modification object with anti-tumor activity and preparation method thereof
Technical field
The present invention relates to a kind of structure of modification method of natural product Oleanolic Acid, particularly relate to a kind of Oleanolic Acid chemical modification object with anti-tumor activity and preparation method thereof.
Background technology
Oleanolic Acid (OleanolicAcid, OA), has another name called (3BETA)-3-Hydroxyolean-12-en-28-oic acid, is pentacyclic triterpenoid, is extensively present in the plants such as Spreading Hedyotis Herb, hawthorn, cloves, date, Glossy Privet Fruit, Loquat Leaf, wood and Spica Prunellae with form that is free or that be combined into glycosides.Chemistry (3 β)-3-Hydroxyolean-12-en-28-oicacid by name, sterling is white crystalline powder, odorless, tasteless.Molecular formula is: C 30h 48o 3, molecular weight: 456.71.Fusing point: 308 DEG C ~ 310 DEG C, [α] 20D+68 ° ~+78 ° (C=0.15, chloroform).Water insoluble, dissolve in ethanol, chloroform, acetone.Recent study finds, Oleanolic Acid has biological activity widely, comprises hypoglycemic lipid-lowering effect, antitumor, antiviral and microorganism, anti-ageing, antiulcer agent, anti-inflammatory, on immune impact, and liver protecting etc.
The chemical structural formula of Oleanolic Acid:
In recent years, Oleanolic Acid comes into one's own day by day to the suppression of tumour and lethal effect.Oleanolic Acid can the formation of Tumor suppression, hinders tumor promotion and inducing tumor cell differentiation, and effectively can suppress infringement and the transfer of blood vessel generation tumour cell.Stronger cytotoxicity is shown to tumour cell, as people's lung fibroblast WI-38, HepG2 cell lines, colorectal carcinoma HCTl5 cell strain, ovarian cancer HO-8910 cell strain, breast cancer cell line MCF-7 etc.To Hematological Malignant Cell K562, HI, 60, the proliferation activity of Jurkat etc. is inhibited too.
Summary of the invention
The object of the present invention is to provide a kind of Oleanolic Acid chemical modification object with anti-tumor activity and preparation method thereof, the method take Oleanolic Acid as lead compound, design a series of Oleanolic Acid chemical modification object, this compounds is to Human Cervical Hela cell, and human hepatoma HepG2 cell and BGC-823 Cells have good inhibit activities.
The object of the invention is to be achieved through the following technical solutions:
Have an Oleanolic Acid chemical modification object for anti-tumor activity, mainly to Oleanolic Acid A ring, the structure of modification of C ring, and the chemically modified to C-3 position and C-28 position, obtain olea esters of gallic acid or amides.Described Oleanolic Acid chemical modification object comprises following three classes:
(1) modify on the basis of Oleanolic Acid structure, introduce hydrogen, alkoxyl group, C-12 in C-3 position, introduce two hydroxyl or alkoxyl group, C-28 position alkoxyl group, hydroxyl for 13, amido replaces, and obtains a series of compound.Compound structure is as shown in the table:
(2) modify on the basis of Oleanolic Acid structure, A ring C-3 position is modified to 3-oximido or 3-cinnyl oxyimino group, introduce ester group or amide group in C-28 position, obtain a series of compound, compound structure is as shown in the table simultaneously:
(3) modify on the basis of Oleanolic Acid structure, be seven membered lactams rings by A ring ring expansion, C-28 position carboxyl introduces different alkoxyl groups.Obtain a series of compound, compound structure is as shown in the table:
There is an Oleanolic Acid chemical modification object preparation method for anti-tumor activity, said method comprising the steps of:
(1) Oleanolic Acid C-12 position double bond is oxidized by metachloroperbenzoic acid, and generate epoxy compounds, open loop obtains dihydroxy compound in acid condition.Final obtained 3 β, 12 α, 13 β-trihydroxy--oleanane type-28-carboxylic acid (OA-1).
(2) OA-1 is dissolved in DMF with corresponding haloalkane and salt of wormwood again, reaction generation 3 β, 12 α, 13 β-trihydroxy--oleanane type-28-carboxylic acid ester compound I 1~ I 2.
(3) OA-1 and diacetyl oxide are under pyridine catalysis, and 3,12 hydroxyls are acetylation, and generate 3 β, 12 α-diacetoxy-13 beta-hydroxies-oleanane type-28-carboxylic acid (OA-2).
(4) after OA-2 and oxalyl chloride react, generation 3 β is reacted with corresponding amine, 12 α-diacetoxy-13 beta-hydroxies-oleanane type-28-amides target compound I 3~ I 4.
(5) Oleanolic Acid and Jones reagent react to obtain 3-oxo Oleanolic Acid (OA-3).
(6) OA-3 is dissolved in appropriate pyridine, with hydrochloric acid hydroxyl by being obtained by reacting 3-oximido-oleanane type-12-alkene-28-carboxylic acid (OA-4).
(7) OA-4 and corresponding haloalkane are according to step (2), obtain 3-oximido-oleanane type-12-alkene-28-carboxylic acid esters target compound II 1~ II 2.
(8) styracin and oxalyl chloride react to obtain cinnamyl chloride.
(9) OA-4 and cinnamyl chloride are dissolved in benzene, add a small amount of DMAP, are obtained by reacting 3-cinnyl oxyimino group-oleanane type-12-alkene-28-carboxylic acid (OA-5).3-cinnyl oxyimino group-bromo-1-of oleanane type-12-alkene-28-(2-is obtained by reacting again according to (2) step and glycol dibromide) second fat II 3.
(10) OA-5 and corresponding amine obtain 3-cinnyl oxyimino group-oleanane type-12-alkene-28-amides target compound II according to (4) step reaction 4~ II 7.
(11) OA-4 reacts with thionyl chloride in dioxane, becomes the same ring of seven membered lactams derivative A--4-azepine-3-oxo oleanane type-12-alkene-28-carboxylic acid III through Beckmann rearrangement 1.
(12) III 1with corresponding haloalkane according to step (2), obtain the same ring of A--4-azepine-3-oxo oleanane type-12-alkene-28-carboxylic acid esters target compound III 2~ III 3.
Advantage of the present invention and effect are:
The present invention carries out chemically modified to natural product Oleanolic Acid, obtain the analog of a series of Oleanolic Acid, prove through pharmacological evaluation, they are to Human Cervical Hela cell, human hepatoma HepG2 cell and BGC-823 Cells have good restraining effect, and are better than parent compound Oleanolic Acid.
Embodiment
Below in conjunction with example, the present invention is further described.
1. the extraction using alcohol medicinal extract of Glossy Privet Fruit is with sherwood oil, 1% sodium hydroxide with to be washed to elutant colourless, and dehydrated alcohol heating for dissolving, activated carbon decolorizing, obtains white crystal Oleanolic Acid (OA) through condensation separation, purification refine.
2. the C-12 position double bond of Oleanolic Acid is oxidized by metachloroperbenzoic acid, generate epoxy compounds, in acid condition open loop, finally obtain 3 β, 12 α, 13 β-trihydroxy--oleanane type-28-carboxylic acid (OA-1), on the basis of OA-1 synthetic line, C-28 carboxylic acid and corresponding haloalkane are under potassium alkaline condition, be dissolved in DMF, obtain 3 β, 12 α, 13 β-trihydroxy--oleanane type-28-carboxylic acid ester compound I 1~ I 2.
Wherein: R 2for-OCH (CH 3) 2with-OCH 2cH (CH 3) 2.
OA-1 and diacetyl oxide are under pyridine catalysis, and 3,12 hydroxyls are acetylation; obtain 3 β; 12 α-diacetoxy-13 beta-hydroxies-oleanane type-28-carboxylic acid (OA-2), after the basis of OA-2 synthetic line is obtained by reacting acyl chlorides with oxalyl chloride, then is obtained by reacting target compound I with corresponding amine 3~ I 4.
Wherein: R 2for-OC 2h 5with .
Styracin and oxalyl chloride react, obtained cinnamyl chloride.OA-4 and cinnamyl chloride are dissolved in benzene, add a small amount of DMAP, are obtained by reacting 3-cinnyl oxyimino group-oleanane type-12-alkene-28-carboxylic acid (OA-5).Again with glycol dibromide under potassium alkaline condition, be dissolved in DMF, be obtained by reacting target compound II 3.
After OA-5 and oxalyl chloride are obtained by reacting acyl chlorides, then be obtained by reacting target compound II with corresponding amine 4~ II 7.
Wherein: R 5for-N (C 2h 5) 2, .
OA-4 reacts with thionyl chloride in dioxane, becomes the same ring of seven membered lactams derivative A--4-azepine-3-oxo oleanane type-12-alkene-28-carboxylic acid III through Beckmann rearrangement 1.III 1with corresponding haloalkane under potassium alkaline condition, be dissolved in DMF, be obtained by reacting target compound III 2~ III 3.
Wherein: R 6for-OH ,-OC 2h 5with .
With Gefitinib and VP-16 for positive control, mtt assay is taked to carry out preliminary anti tumor activity in vitro test to Oleanolic Acid and synthesized compound thereof.Research shows that part of compounds is to Human Cervical Hela cell, and human hepatoma HepG2 cell and BGC-823 Cells have good inhibit activities, and are better than Oleanolic Acid.Compound structure and vitro test result as shown in the table.
Note; A. compound concentration is 10 -5the inhibiting rate recorded during mol/L, b.IC 50represent half effective inhibition concentration.
Below in conjunction with embodiment, the present invention will be further described:
Embodiment 1
3 β, 12 α, 13 β-trihydroxy--oleanane type-28-carboxylic acid isopropyl (I 1) preparation:
By starting raw material OA(l.9mmol, 0.87g) be dissolved in 10mL methylene dichloride with metachloroperbenzoic acid (3.8mmol, 0.65g).The mixed stirred at ambient temperature of reaction spends the night.Add 10mL water, after layering, water layer is with dichloromethane extraction (10mL × 2).Merge organic phase, be washed till slight alkalinity with saturated sodium bicarbonate solution, then be washed to neutrality.Anhydrous magnesium sulfate drying, filters, concentrates, obtain epoxide.Then epoxide (0.4mmol) is dissolved in 10mL chloroform, adds appropriate concentrated hydrochloric acid and adjust PH to neutral.The mixed stirred at ambient temperature of reaction 6 hours.Add 10mL water, after layering, water layer is with chloroform extraction (10mL × 3).Merge organic phase, saturated sodium bicarbonate solution washing to slight alkalinity, then is washed to neutrality.Anhydrous magnesium sulfate drying, filters, and concentrated, vacuum-drying obtains white, amorphous solid OA-1.
Compound OA-1(0.100g, 0.20mmol is added in the eggplant-shape bottle of 25mL), Anhydrous potassium carbonate 0.06g, DMF 4mL, slowly drip isobutane bromide 3 (0.88mmol), room temperature reaction, TLC detection reaction terminal.After reaction terminates, decompression steams remaining haloalkane, adds appropriate saturated NaCl solution 2mL, extraction into ethyl acetate (4mL × 3), merges organic phase, anhydrous magnesium sulfate drying, filters, and concentrated, vacuum-drying obtains white solid.Through silica gel chromatography, eluent is petrol ether/ethyl acetate=7/1 (V/V), obtains white crystalline solid I 155.8mg, productive rate 50.1%.mp207.2~212.4℃。IR(KBr):3559,2955,1712,1577,1386cm -1。 1H-NMR(CDCl 3,300MHz)δ：5.21(brs,1H,12-OH),4.93(brs,1H,13-OH),4.65(brs,1H,3-OH),4.20(m,1H,OC H(CH 3) 2),3.89~3.96(m,1H,H-12),3.12~3.24(m,1H,H-3),1.32(d, J=8.0Hz,3H,COOCH(C H 3a ) 2),1.27(d, J=8.0Hz,3H,COOCH(C H 3b ) 2),1.20,1.15,1.07,0.98,0.90,0.84,0.77(7s,21H,CH 3×7)。ESI-MS:533.4(M+H) +。
Embodiment 2
3 β, 12 α-diacetoxy-13 beta-hydroxies-oleanane type-28-hexahydroaniline (I 3) preparation:
OA-1(200mg is added in 50mL single port bottle, 0.41mmol), tetrahydrofuran (THF) 20mL, OA-1 adds pyridine 1mL, diacetyl oxide (1.35g after dissolving under room temperature, 13.2mmol) with a small amount of DMAP, stirred at ambient temperature, with TLC detection reaction terminal (developping agent: petrol ether/ethyl acetate=3/1, developer is 10% ethanol solution of sulfuric acid), react complete, remove reaction solvent under reduced pressure, with water dispersible solid, 2mol/L hydrochloric acid adjusts pH to 3 ~ 4, separate out white solid, suction filtration, filter cake is washed to neutrality, natural drying at room temperature, obtains 3 β, 12 α-diacetoxy-13 β-hydroxyl-oleanane type-28-carboxylic acid, crude product, through silica gel column chromatogram separating purification, obtains white solid (OA-2) 189.7mg, productive rate 84.5%.
By compound OA-2(100mg, 0.18mmol) be dissolved in 3mL methylene dichloride, add oxalyl chloride (0.8mmol), stirring at room temperature 20 hours, generate 3 β, 12 α-diacetoxy-13 β-hydroxyl-oleanane type-28-acyl chlorides, steam except reaction solvent and unreacted oxalyl chloride, resistates adds 2mL hexanaphthene, removes hexanaphthene under reduced pressure, repeatable operation 2 times.Add 2mL methylene dichloride in acyl chlorides, add triethylamine and adjust pH to be 9 ~ 10, stir after 5 minutes, add hexahydroaniline (0.6mmol), react under room temperature, with TLC detection reaction terminal.After reaction terminates, remove methylene dichloride under reduced pressure, in reaction solution, add the saturated NaCl solution of 3mL, adjust pH to 3 ~ 4 with 2mol/L hydrochloric acid, separate out white solid, suction filtration, washing filter cake is extremely neutral, drying at room temperature, and crude product is through silica gel column chromatogram separating purification, eluent is petrol ether/ethyl acetate=8/1 (V/V), obtains white crystal I 342.5mg, productive rate 35.6%.mp219.7~225.1℃。IR(KBr):3382,2932,1734,1662,1243cm -1。 1H-NMR(CDCl 3,300MHz)δ：5.62(brs,1H,NH),4.80(brs,1H,13-OH),3.71(m,1H,NHC H),3.32~3.50(m,1H,H-12),3.19~3.24(m,1H,H-3),2.09（s,3H,CH 3CO）,2.03（s,3H,CH 3CO）,1.99~1.94(m,4H,CHC H 2 ×2),1.80~1.75(m,4H,CHCH 2C H 2 ×2),1.66~1.60(m,2H,CH 2),1.25,1.16,1.07,0.98,0.89,0.93,0.77(21H,7s,CH 3×7)。ESI-MS:691.1(M+Cl) +。
Embodiment 3
3-oximido-oleanane type-12-alkene-28-ethyl ester (II 1) preparation:
By compound OA-3(50mg, 0.11mmol) be dissolved in 5ml anhydrous pyridine, add oxammonium hydrochloride 100mg, 120 DEG C of back flow reaction 1 hour, cooling, dilute with water, decompress filter, filter cake washes with water, dry, obtain white powder 3-oximido-oleanane type-12-alkene-28-carboxylic acid (OA-4) 45.8mg, yield is 81.5%.IR(KBr)：3244，2944，1685，1648，1460，1386，1365，1278，1179cm -1。
By compound OA-4 (100mg, 0.20mmol), monobromethane (0.06ml) and salt of wormwood (121mg, 0.8774mmol) are dissolved in the DMF solution of 6ml, at room temperature stir and spend the night.TLC tracing detection.After reaction terminates, decompression steams remaining haloalkane, adds appropriate saturated NaCl solution 2mL, extraction into ethyl acetate (4mL × 3), merges organic phase, anhydrous magnesium sulfate drying, filters, and concentrated, vacuum-drying obtains white solid.Crude product is through silica gel column chromatogram separating purification, and eluent is petrol ether/ethyl acetate=4/1 (V/V), obtains white crystal II 166.8mg, productive rate 65.2%.mp189.6~193.5℃；IR(KBr)：3263，2943，1723，1633，1462，1385，1363，1263，1181cm -1； 1H-NMR(CDCl 3,300MHz)δ：5.20(t, J=3.5Hz,1H,H-12),4.08~4.05(m,2H,COOC H 2 CH 3),2.56(d, J=7.5Hz,1H,H-18),1.53(t, J=7.5Hz,1H,H-9),1.25(t, J=8.7Hz,3H,COOCH 2C H 3 ),1.10,0.98,0.88,0.86,0.83,0.75,0.68(7s,21H,CH 3×7)。ESI-MSm/z：497.5M +。
Embodiment 4
N-[3-cinnyl oxyimino group-oleanane type-12-alkene-28-acyl group]-methylpiperazine (II 5) preparation:
By compound OA-5(100mg, 0.20mmol) be dissolved in 4mL methylene dichloride, add oxalyl chloride (0.44mmol), stirring at room temperature 20 hours, generate 3-cinnyl oxyimino group-oleanane type-12-alkene-28-acyl chlorides, steam except reaction solvent and unreacted oxalyl chloride, resistates adds hexanaphthene, removes hexanaphthene (2mL × 3) under reduced pressure.After add after 2mL methylene dichloride makes it to dissolve completely, add triethylamine and adjust pH to be 9 ~ 10, stirs after 5 minutes, add N methyl piperazine (20mmol), reaction 6 hours under room temperature, with TLC detection reaction terminal.After reaction terminates, decompression desolventizes, water dispersible solid, and adjust pH to 3 ~ 4 with 2mol/L hydrochloric acid, suction filtration, obtains brown solid.Crude product silica gel chromatography, eluent is petrol ether/ethyl acetate=8/1(V/V), obtain white powder II 521mg, productive rate 14%.mp192.8~194.1℃,IR(KBr):1742,1656,1454,1210,721cm -1; 1H-NMR(CDCl 3,300MHz)δ：7.74(d,2H,Ph-H×2, J=12.0Hz),7.70(d,1H,Ph-CH, J=15.0Hz),7.40(t,2H,Ph-H, J=15.0Hz),6.50(d,1H,CHCOON, J=16.5Hz),5.18(t, J=3.5Hz,1H,H-12),3.40(t, J=7.5Hz,4H,C H 2a NHC H 2a ),3.32(t,J=8.0Hz,4H,C H 2b NHC H 2b ),2.43(d, J=8.0Hz,1H,H-18),2.28(s,3H,NCH 3),1.48(t, J=7.5Hz,1H,H-9),1.20,1.16,1.10,0.99,0.94,0.87,0.76(7s,21H,CH 3×7).ESI-MS:682.5(M+H) +。
Embodiment 5
The same ring of A--4-azepine-3-oxo-oleanane type-12-alkene-28-ethyl ester (III 2) preparation:
By compound OA-4(50mg, 0.20mmol) be dissolved in 10ml anhydrous dioxane, at 10 DEG C, drip the thionyl chloride solution 0.2ml of brand-new, stir 10min, with the potassium hydroxide solution dilution of 10%, decompress filter, filter cake washes with water, dry, obtains white solid (III 1) 32.8mg, productive rate 75.6%.
Compound III is added by the eggplant-shape bottle of 50mL 1(100mg, 0.20mmol), Anhydrous potassium carbonate 0.06g, DMF 4mL, slowly drip monobromethane (0.8mmol, 0.06ml), room temperature reaction, TLC detection reaction terminal.After reaction terminates, decompression steams remaining haloalkane, adds appropriate saturated NaCl solution 2mL, then adds extraction into ethyl acetate (4mL × 3), merges organic phase, anhydrous magnesium sulfate drying, filters, and concentrated, vacuum-drying obtains white solid.Through silica gel chromatography, eluent is petrol ether/ethyl acetate=4.5/1 (V/V), obtains white crystal III 267.7mg, productive rate 68.2%.mp120.2~122.6℃；IR(KBr)：3200,2924,1728,1458,1384,1262,1180,1159,1042cm -1; 1H-NMR(CDCl 3,300MHz)δ：5.69(1H,s,N-H,lactam),5.30(t, J=3.5Hz,1H,H-12),4.08~4.05(m,2H,COOC H 2 CH 3),2.67(1H,d, J=8.0Hz,H-18),1.25(t, J=8.7Hz,3H,COOCH 2C H 3 ),1.20,1.17,1.13,1.10,0.93,0.90,0.77(21H,7s,CH 3×7).ESI-MS:498.4(M+H) +。

Claims (1)

1. have an Oleanolic Acid chemical modification object for anti-tumor activity, it is characterized in that, described modifier is to A ring, the structure of modification of C ring, and the modification to C-3 position and C-28 position, obtains olea esters of gallic acid or amides; Described Oleanolic Acid chemical modification object comprises following three classes:
(1) modify on the basis of Oleanolic Acid structure, C-3 position is hydrogen, alkoxyl group, C-12, and introduce two hydroxyl or alkoxyl group, C-28 position alkoxyl group, hydroxyl for 13, amido replaces, and obtains a series of compound; Compound structure is as shown in the table:
(2) on the basis of Oleanolic Acid structure, A ring C-3 position is modified to 3-oximido or 3-cinnyl oxyimino group, introduce ester group or amido in C-28 position, obtain a series of compound, structure is as shown in the table simultaneously:
(3) on the basis of Oleanolic Acid structure, be seven membered lactams rings by A ring ring expansion, C-28 position carboxyl introduces different alkoxyl groups;
An Oleanolic Acid chemical modification object preparation method for anti-tumor activity, is characterized in that, said method comprising the steps of:
(1) Oleanolic Acid C-12 position double bond is oxidized by metachloroperbenzoic acid, and generate epoxy compounds, open loop obtains dihydroxy compound in acid condition; Final obtained 3 β, 12 α, 13 β-trihydroxy--oleanane type-28-carboxylic acid (OA-1);
(2) OA-1 is dissolved in DMF with corresponding haloalkane and salt of wormwood again, and final reaction generates 3 β, 12 α, 13 β-trihydroxy--oleanane type-28-carboxylic acid ester compound I 1~ I 2;
(3) OA-1 and diacetyl oxide are under pyridine catalysis, and 3,12 hydroxyls are acetylation, final generation 3 β, 12 α-diacetoxy-13 beta-hydroxies-oleanane type-28-carboxylic acid (OA-2);
(4) after OA-2 and oxalyl chloride react, then react with corresponding amine and generate amides target compound I 3~ I 4;
(5) Oleanolic Acid and Jones reagent are obtained by reacting 3-oxo Oleanolic Acid (OA-3);
(6) OA-3 is dissolved in appropriate pyridine, with hydrochloric acid hydroxyl by being obtained by reacting 3-oximido-oleanane type-12-alkene-28-carboxylic acid (OA-4);
(7) OA-4 and corresponding haloalkane are according to step (2), obtain target compound II 1~ II 2;
(8) styracin and oxalyl chloride react, obtained cinnamyl chloride;
(9) OA-4 and cinnamyl chloride are dissolved in benzene, add a small amount of DMAP, are obtained by reacting 3-cinnyl oxyimino group-oleanane type-12-alkene-28-carboxylic acid (OA-5); 3-cinnyl oxyimino group-bromo-1-of oleanane type-12-alkene-28-(2-is obtained by reacting again according to step (2) and glycol dibromide) second fat II 3;
(10) OA-5 and corresponding amine are obtained by reacting target compound II according to step (4) 4~ II 7;
(11) OA-4 reacts with thionyl chloride in dioxane, becomes the same ring of seven membered lactams derivative A--4-azepine-3-oxo oleanane type-12-alkene-28-carboxylic acid III through Beckmann rearrangement 1;
(12) III 1with corresponding haloalkane according to step (2), obtain target compound III 2~ III 3.
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CN106008650A (en) * 2016-05-13 2016-10-12 中国药科大学 Oleanane derivative
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CN109485688A (en) * 2017-09-13 2019-03-19 陈重 Tetraterpene derivatives and its pharmaceutical composition and application
CN111574581A (en) * 2020-06-09 2020-08-25 烟台大学 Low-toxicity and anti-inflammatory ursolic acid derivative and preparation method and application thereof
CN113817017A (en) * 2021-11-19 2021-12-21 华南理工大学 Oleanolic acid oxime ester derivative and preparation method and application thereof
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CN109485688A (en) * 2017-09-13 2019-03-19 陈重 Tetraterpene derivatives and its pharmaceutical composition and application
CN109485688B (en) * 2017-09-13 2021-04-23 陈重 Triterpene derivative, and pharmaceutical composition and application thereof
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CN109206473B (en) * 2018-10-23 2021-01-29 福州大学 C12 and C13 substituted oleanolic acid derivatives, and preparation and application thereof
CN111574581A (en) * 2020-06-09 2020-08-25 烟台大学 Low-toxicity and anti-inflammatory ursolic acid derivative and preparation method and application thereof
CN111574581B (en) * 2020-06-09 2022-03-04 烟台大学 Low-toxicity and anti-inflammatory ursolic acid derivative and preparation method and application thereof
CN115806580A (en) * 2021-09-14 2023-03-17 中国医学科学院药物研究所 12-O-fatty acid ester oleanolic acid compound and preparation method and application thereof
CN113817017A (en) * 2021-11-19 2021-12-21 华南理工大学 Oleanolic acid oxime ester derivative and preparation method and application thereof

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