CN103626828A - Anti-tumor active ursolic acid chemical modifier and preparation method thereof - Google Patents

Anti-tumor active ursolic acid chemical modifier and preparation method thereof Download PDF

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CN103626828A
CN103626828A CN201310583080.3A CN201310583080A CN103626828A CN 103626828 A CN103626828 A CN 103626828A CN 201310583080 A CN201310583080 A CN 201310583080A CN 103626828 A CN103626828 A CN 103626828A
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ursolic acid
react
ursolic
compound
acid
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孟艳秋
白洁
白忠伟
聂慧慧
刘凤鑫
张良锋
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Shenyang University of Chemical Technology
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Shenyang University of Chemical Technology
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Abstract

The invention discloses an anti-tumor active ursolic acid chemical modifier and a preparation method thereof, relating to a structure transformation technology of a natural product ursolic acid. A series of structure analogues with biological activity are obtained through transformation and modification of the chemical structure of the natural product ursolic acid. The ursolic acid chemical modifier is mainly prepared by the steps of oxidizing hydroxyl at the C-3 site of ursolic acid into acetoxyimino group, carbonyl, alkacyloxy and the like; introducing hydroxyl into the C-2 site or oxidizing into carbonyl and aldehyde group or introducing hydroxymethylene group; performing a condensation reaction between carboxyl at the C-28 site and amine, alcohol, phenol, imidazole ring, hydrazine and the like to obtain compounds (I-XIV); or modifying the A ring of ursolic acid into six-membered cycloalkene; transforming the structure of ursolic acid to obtain a series of ursolic acid derivatives (XV-XIX). Study indicates that the compounds have perfect inhibitory activity on the Hela cells of human cervical cancer, SKOV3 cells of human ovarian cancer, HepG2 cells of human liver cancer and BGC-823 cells of stomach cancer.

Description

Acid as chemical modifier for ursolic of a kind of anti-tumor activity and preparation method thereof
Technical field
The structure of modification technology that the present invention relates to a kind of natural product ursolic acid, particularly relates to acid as chemical modifier for ursolic of a kind of anti-tumor activity and preparation method thereof.
Background technology
Ursolic acid (Ursolic acid, UA), has another name called ursonic acid, and urson is pentacyclic triterpenoid, chemistry 3 β-Hydroxy-urs-12-en-28-oic acid by name, and sterling is white, needle-shaped crystals (crystallization in ethanol), molecular formula is C 30h 48o 3, molecular weight is: 456.68.Fusing point 277 ~ 278 ℃ of (also having report is 285 ~ 288 ℃), [α] d=+65.3 ° (concentration C=0.45 g/mL of methyl alcohol), water insoluble and sherwood oil, is soluble in dioxane, pyridine, ethanol and methyl alcohol, dissolves in benzene, chloroform.Extensively be present in herbal medicine, food and other plant.Research in recent years finds, ursolic acid has biologic activity and development prospect widely, found ursolic acid have antitumor, protect the pharmacotoxicological effects such as liver, reducing blood-fat, anti-inflammatory, antimicrobial, parasiticide and promotion hemopoietic system functional rehabilitation.
The chemical structural formula of ursolic acid:
In recent years, ursolic acid comes into one's own day by day to the inhibition of tumour and lethal effect.Research shows, ursolic acid is active except suppressing DNA topological enzyme, suppresses outside the increment of cell, can also improve intracellular calcium level, activate the proteolysis cascade reaction of caspase, induction lung carcinoma cell A-549, the kinds of tumor cells apoptosis such as leukemia cell P-388.
Summary of the invention
The object of the present invention is to provide acid as chemical modifier for ursolic of a kind of anti-tumor activity and preparation method thereof, the method be take ursolic acid as lead compound, design the chemical modification object of a series of ursolic acid, it is active that this compounds has good inhibition to Human Cervical Hela cell, human ovarian cancer SKOV3 cell, human hepatoma HepG2 cell and BGC-823 Cells.
The object of the invention is to be achieved through the following technical solutions:
An acid as chemical modifier for ursolic for anti-tumor activity, described modifier is the structure of modification to A ring, and the modification to C-28 position, obtains ursolic acid ester compounds; Described acid as chemical modifier for ursolic comprises following two classes:
Figure 898312DEST_PATH_IMAGE001
(1) on the basis of ursolic acid structure, modify, in C-3 position, introduce alkyloyloxyethyl imino-, carbonyl, alkanoyloxy, hydrogen, hydrogen, aldehyde radical, hydroxyl or hydroxyl methene base, carbonyl are introduced in C-2 position, C-28 position is alkoxyl group, hydroxyl, amino, diazanyl, alkyl, alkoxy acyl replacement for R3, obtains series compound; Compound structure is as shown in the table:
Compound R 1 R 2 R 3
I CH 3COON= H -OCH 2C 6H 5
II CH 3COON= H -OH
III CH 3COON= H
IV CH 3COON= H
Figure 657506DEST_PATH_IMAGE003
V CH 3CH 2ON= H
VI O -CHO CH 3CH 2-
VII ClCH 2COO- H -OC 2H 5
VIII C 3H 3N 2 CH 2COO- H -OC 2H 5
IX ClCH 2COON= H -OCH 2COOC 2H 5
X OH OH -C 6H 4(2-CH 2OH)
XI OH OH -NHC 6H 5
XII O HOCH 2= -NHCH 2CH 2CH 2OH
XIII OH H
Figure 991722DEST_PATH_IMAGE005
XIV H O -N(CH 2CH 3) 2
(2) on the basis of ursolic acid structure, A ring is modified to tetrahydrobenzene, in C-3 position, introduce halogen (as chlorine), ester group is introduced in C-28 position, obtains ursolic acid ester compounds; Structure is as shown in the table:
Compound R 4 R 5
XV Cl -OCH 2CH 3
XVI H -OC 2H 5
XVII H -OCH 2COOC 2H 5
XVIII H -OCH(CH 3) 2
XIX H -O(CH 2) 3CH 3
An acid as chemical modifier for ursolic preparation method for anti-tumor activity, said method comprising the steps of:
(1) ursolic acid and Jones reagent react obtain 3-oxo ursolic acid;
(2) 3-oxo ursolic acid is dissolved in appropriate pyridine, adds oxammonium hydrochloride, react to obtain 3-oximido-Ursane-12-alkene-28-carboxylic acid (UA-1);
(3) UA-1 reacts with diacetyl oxide or butyryl oxide again, then with after oxalyl chloride activation, reacts generate ester class and hydrazides class target Compound I ~ V with benzylalcohol, p-NP, aniline, phenylhydrazine etc.;
(4) take 3-oxo ursolic acid is raw material, reacts and obtains 3-oxo black bearberry carboxylicesters, then add Vilsmeier reagent with haloalkane, obtains compound VI; In chloroformic solution, add phosphorus pentachloride, obtain compounds X V;
(5) ursolic acid C-3 position is selected to introduce oximido after being oxidized to carbonyl, and C-28 position becomes after different types of ester, and C-3 position oximido is reacted with chloroacetyl chloride and obtains compound VI I ~ VIII;
(6) the C-28 position of UA-1 is become after different types of ester, generate 3-oximido-Ursane-12-alkene-28 carboxylic acid ester compound, under again C-3 position oximido on A ring being refluxed with chloroacetyl chloride 56 C under acetone solvent, react, generate the chloro-acetoxyl group of 3-[] imino--Ursane-12-alkene-28-carboxylic acid ester compound IX;
(7) on the basis of the original C-3 of ursolic acid position hydroxyl, after hydroxyl is introduced in C-2 position, C-28 position carboxyl reacts and obtains target product X ~ XI with amino alcohol, aminated compounds again, in C-2 position, introduce hydroxy methylene, C-28 position carboxyl reacts to obtain target product X II with 3-amino-1-propyl alcohol;
(8) take ursolic acid or 3-oxo ursolic acid is raw material, react with ClCH2COOC2H5 and make after ursolic acid ethoxycarbonyl methyl esters, react with hydrazine hydrate and form hydrazides, and then react with carbonyl reagent and obtain acylhydrazone analog derivative, finally in diacetyl oxide, cyclization obtains target product X III;
(9) take 3-oxo ursolic acid is starting raw material, react with excessive potassium tert.-butoxide, generate α, beta-unsaturated ketone compound, react again reduction with sodium borohydride and obtain dibastic alcohol compound, in pyridine solution, react with Tosyl chloride, product reacts with diethylamine react activation with oxalyl chloride after again, generates compounds X IV;
(10) ursolic acid and halohydrocarbon carry out esterification and generate 3 beta-hydroxies-Ursane-12-alkene-28-carboxylicesters, under ice bath 0 C condition, generate 3 Beta-methyl sulfonyloxy-Ursanes-12-alkene-28-carboxylicesters with Methanesulfonyl chloride, the DMAC of further take generates Ursane-2-, 12 diene-28-carboxylicesters XVI ~ XIX as solvent reacts with Quilonum Retard under 168 ℃ of reflux conditionss.
Embodiment
Below in conjunction with embodiment, the invention will be further described.
1. the extraction using alcohol medicinal extract of Loquat Leaf is with sherwood oil, and 1% sodium hydroxide and water are colourless to elutant, dehydrated alcohol heating for dissolving, and activated carbon decolorizing, filtrate placement is separated out white crystals, with recrystallization from hot methanol, obtains ursolic acid.
2. the 3-oxo ursolic acid of take is starting raw material, in pyridine solution, reflux, add oxammonium hydrochloride, reaction obtains 3-oximido-Ursane-12-alkene-28-carboxylic acid (UA-1), at (UA-1) N-[3-oximido-Ursane-12-alkene-28-acyl] on the basis of-amine (ester) compounds synthetic route by C-28 position carboxyl after the oximido acetylize of C-3 position again with amino alcohol, aminated compounds reaction or C-28 position carboxyl directly react with haloalkane, or react with diacetyl oxide or butyryl oxide, again with after oxalyl chloride activation, with benzylalcohol, p-NP, aniline, the reaction such as phenylhydrazine generates ester class and hydrazides class target Compound I ~ V.
Figure 998205DEST_PATH_IMAGE006
wherein: R 3for-OCH 2c 6h 5;-OH;
Under ice bath stirs, to dripping phosphorus oxychloride in DMF, prepare Vilsmeier reagent, the 3-oxo ursolic acid of take is raw material, with haloalkane at K 2cO 3under alkaline condition, in DMF, reaction obtains 3-oxo black bearberry carboxylicesters, then adds Vilsmeier reagent to react in methylene dichloride, obtains compound VI.
Figure 202921DEST_PATH_IMAGE007
Ursolic acid C-3 position is selected to introduce oximido after being oxidized to carbonyl, and C-28 position becomes after different types of ester, and C-3 position oximido is reacted with chloroacetyl chloride and obtains compound VI I ~ VIII.
Figure 588772DEST_PATH_IMAGE008
Wherein: R is-Cl ,-C 3h 3n 2.
The C-28 position of UA-1 is become after different types of ester, generate 3-oximido-Ursane-12-alkene-28 carboxylic acid ester compound, under again C-3 position oximido on A ring being refluxed with chloroacetyl chloride 56 C under acetone solvent, react, generate the chloro-acetoxyl group of 3-[] imino--Ursane-12-alkene-28-carboxylic acid ester compound IX.
Figure 257651DEST_PATH_IMAGE009
On the basis of the original C-3 of ursolic acid position hydroxyl, after hydroxyl is introduced in C-2 position, C-28 position carboxyl reacts and obtains target product X ~ XI with amino alcohol, aminated compounds again.
Figure 188698DEST_PATH_IMAGE010
Wherein: R is-C 6h 4(2-CH 2oH) ,-C 6h 5.
Ursolic acid C-3 position hydroxyl oxygen is changed into after carbonyl, introduce hydroxy methylene in C-2 position, C-28 position carboxyl reacts to obtain target product X II with 3-amino-1-propyl alcohol.
 
Wherein: R 1for carbonyl, R 2for hydroxyl methene base, R 3for-CH 2cH 2cH 2oH.
Take ursolic acid or 3-oxo ursolic acid is raw material, with ClCH 2cOOC 2h 5reaction makes after ursolic acid ethoxycarbonyl methyl esters, react formation hydrazides, and then react with carbonyl reagent and obtain acylhydrazone analog derivative with hydrazine hydrate, and finally in diacetyl oxide, cyclization obtains target product X III.
Figure 129978DEST_PATH_IMAGE011
The 3-oxo ursolic acid of take is starting raw material, react with excessive potassium tert.-butoxide, generate α, beta-unsaturated ketone compound, react again reduction with sodium borohydride and obtain dibastic alcohol compound, in pyridine solution, react with Tosyl chloride, product reacts with diethylamine react activation with oxalyl chloride after again, generates compounds X IV.
The 3-oxo ursolic acid of take is raw material, and haloalkane is at K 2cO 3under alkaline condition, in DMF, reaction obtains 3-oxo ursolic acid ester, adds phosphorus pentachloride in chloroformic solution, obtains compounds X V.
Figure 515009DEST_PATH_IMAGE013
Ursolic acid and halohydrocarbon carry out esterification and generate 3 beta-hydroxies-Ursane-12-alkene-28-carboxylicesters, under ice bath 0 C condition, generate 3 Beta-methyl sulfonyloxy-Ursanes-12-alkene-28-carboxylicesters with Methanesulfonyl chloride, the DMAC of further take generates Ursane-2-, 12 diene-28-carboxylicesters XVI ~ XIX as solvent reacts with Quilonum Retard under 168 ℃ of reflux conditionss.
Figure 882536DEST_PATH_IMAGE014
Wherein: R is-C 2h 5;-CH 2cOOC 2h 5;-CH (CH 3) 2;-(CH 2) 3cH 3.
With Gefitinib and the positive contrast of VP-16, take mtt assay to carry out preliminary anti tumor activity in vitro to the compound of ursolic acid and synthesized thereof and detect.The compound that research shows synthesized is to Human Cervical (Hela) cell, human ovarian cancer (SKOV3) cell, human liver cancer cell (HepG2) and cancer of the stomach (BGC-823) cell have certain restraining effect, and compound structure and experiment in vitro result are as following table.
Figure 314042DEST_PATH_IMAGE016
 
Note; A. compound concentration is at 10- 5the inhibiting rate recording during mol/L, b.IC 50represent half effective inhibition concentration.
Below in conjunction with embodiment, the present invention will be further described:
Embodiment 1
N-[3-oximido-Ursane-12-alkene-28-acyl] preparation of-hexahydroaniline
By compound UA-1 (50mg, 0.1066mmol) be dissolved in 4mL methylene dichloride, add oxalyl chloride (0.4264m mol), stirring at room 20 hours, generate 3-oximido-Ursane-12-alkene-28-acyl chlorides, steam except reaction solvent and unreacted oxalyl chloride, resistates adds 2mL hexanaphthene, remove hexanaphthene under reduced pressure, repeatable operation 2 times.After adding 2mL methylene dichloride to make it to dissolve completely in acyl chlorides, adding triethylamine tune pH is 9～10, stirs after 5 minutes, adds hexahydroaniline (42.21mg, 0.4264mmol), under room temperature, reacts, and TLC monitors reaction end.After reaction finishes, remove methylene dichloride under reduced pressure, in reaction solution, add 2mL water, with 2mol/L hydrochloric acid, adjust pH to 3～4, separate out white solid, decompress filter, washing filter cake is to neutral.Drying at room temperature obtains white solid UA-2.Crude product silica gel chromatography, eluent is petrol ether/ethyl acetate=5/1 (V/V), obtains white powder solid 19.4mg, productive rate is 33.05%.mp?96.6~98.9℃；IR?(KBr):?3357,?2927,?2853,?1732,?1634,?1454?cm -1;? 1H-NMR?(300MHz,?CDCl 3):?δ?7.73(s,?1H,?CON H),?5.37(s,?1H,?H-12),?3.37~3.39?(m,?1H,?NC H),?2.58(d,?1H,?H-18),?2.29(s,?1H,?O H),?1.645~1.665(m,?10H,?C H 2 ×5),?1.33~1.38?(m,?2H,?H-2),?1.11?(s,?6H,?CH 3×2),?1.07?(s,?3H,?CH 3),?1.05?(s,3H,?CH 3),?0.98(s,3H,CH 3),?0.89?(d,?3H,?CH 3),?0.85(s,?3H,?CH 3);?ESI-MS:?587.5(M+Cl) +。
Embodiment 2
N-[3-acetyl oxyimino group-Ursane-12-alkene-28-acyl] preparation of-2-aminobenzyl alcohol
By Compound I I (50mg, 0.0978mmol) be dissolved in 4mL methylene dichloride, add oxalyl chloride (0.3914m mol), stirring at room 20 hours, generate 3-acetyl oxyimino group-Ursane-12-alkene-28-acyl chlorides, steam except reaction solvent and unreacted oxalyl chloride, resistates adds 2mL hexanaphthene, remove hexanaphthene under reduced pressure, repeatable operation 2 times.After adding 2mL methylene dichloride to make it to dissolve completely in acyl chlorides, adding triethylamine tune pH is 9～10, stirs after 5 minutes, adds 2-aminobenzyl alcohol (48.14mg, 0.3914mmol), under room temperature, reacts, and TLC monitors reaction end.After reaction finishes, remove methylene dichloride under reduced pressure, in reaction solution, add 2mL water, with 2mol/L hydrochloric acid, adjust pH to 3～4, separate out white solid, decompress filter, washing filter cake is to neutral.Drying at room temperature obtains white solid I.Crude product silica gel chromatography, eluent is petrol ether/ethyl acetate=8/1 (V/V), obtains white powder solid 23.4mg, productive rate is 38.78%.mp?78.4~84.6℃；IR?(KBr):?2921,?2851,?1746,?1460,?1250?cm-1;?ESI-MS:?618.4(M+H)+。
Embodiment 3
N-[2,3-dihydroxyl-Ursane-12-alkene-28-acyl] preparation of-2-aminobenzyl alcohol
By compound 2,3-dihydroxyl-Ursane-12-alkene-28-carboxylic acid (50mg, 0.1059mmol) be dissolved in 4mL methylene dichloride, add oxalyl chloride (0.4237m mol), stirring at room 20 hours, generate 2,3-dihydroxyl-Ursane-12-alkene-28-acyl chlorides, steams except reaction solvent and unreacted oxalyl chloride, and resistates adds 2mL hexanaphthene, remove hexanaphthene under reduced pressure, repeatable operation 2 times.After adding 2mL methylene dichloride to make it to dissolve completely in acyl chlorides, adding triethylamine tune pH is 9～10, stirs after 5 minutes, adds 2-aminobenzyl alcohol (52.12mg, 0.4237mmol), under room temperature, reacts, and TLC monitors reaction end.After reaction finishes, remove methylene dichloride under reduced pressure, in reaction solution, add 2mL water, with 2mol/L hydrochloric acid, adjust pH to 3～4, separate out white solid, decompress filter, washing filter cake is to neutral.Drying at room temperature obtains white solid X.Crude product silica gel chromatography, eluent is petrol ether/ethyl acetate=5/1 (V/V), obtains white powder solid 19.4mg, productive rate is 31.75%.mp?125.2~129.6℃；IR?(KBr):?3330,?2922,?2852,?1650,?1591,?1537,?1456,?1287,?1181,755?cm -1;?ESI-MS:?599.3(M+Na) +。
Embodiment 4
3-oxo ursolic acid-3-ethanoyl-2-[dimethyl]-2,3-dihydro-1,3,4-oxadiazole-5-methyl esters
By 3-oxo ursolic acid (200mg, 0.44 mmol) be dissolved in 4mL acetone, reflux is fully dissolved it, after solution clarification, stop heating, add salt of wormwood (83 mg), stirring at room solution becomes after oyster white, (20mg) potassiumiodide and 4mL triethylamine are joined in this solution, slowly drip 1.6mL ethyl chloroacetate, room temperature reaction, TLC monitors reaction end, after reaction finishes, filter, a small amount of acetone rinsing, after concentrating under reduced pressure, add saturated aqueous common salt, ethyl acetate extraction 3 times, merge organic phase, be washed to neutral rear with anhydrous sodium sulfate drying, filter, concentrated, obtain white solid.The heating reflux reaction in 4mL dehydrated alcohol by this white solid 110mg (0.2 mmol) and 0.8mL 80% hydrazine hydrate, TLC monitors reaction end.After reaction finishes, be cooled to room temperature, adularescent solid is separated out, suction filtration, and filter cake seasoning, obtains white solid.This white solid 66mg (0.12 mmol) is dissolved in and in 3mL dehydrated alcohol, adds acetone (1.04 mmol) (glacial acetic acid that suitably adds catalytic amount), stir, heating reflux reaction, TLC monitors reaction end, after reaction finishes, cooling, suction filtration after standing 2 hours, filter cake seasoning, obtains white solid.Get this white solid (45 mg, 0.074 mmol) and join in the reaction flask of 25mL, add 3.0mL diacetyl oxide, reflux 1 hour, after cooling, pour in frozen water, vigorous stirring is completely curing to oily matter, filters, washing, be dried to obtain target product (XIII), crude product silica gel chromatography, eluent is petrol ether/ethyl acetate=20/1 (V/V), obtain white powder solid 18.7mg, productive rate is 6.99%.mp?132.6~134.7℃；IR?(KBr):?3416,?2962,?2926,?1732,?1379,?1116?cm -1;?ESI-MS:?579.0?(M-2CH 3+H) +。
Embodiment 5
N-[2-hydroxy methylene-3-oxo-Ursane-12-alkene-28-acyl]-3-amino-1-propyl alcohol
3-oxo ursolic acid (100mg, 0.22 mmol) is dissolved in 4mL methylene dichloride, adds under freshly prepd sodium methylate (1.05mL) and ethyl formate (1.05mL) room temperature and react, TLC monitors reaction end.React complete, remove under reduced pressure after methylene dichloride, add appropriate saturated aqueous common salt, be extracted with ethyl acetate 3 times, merge organic phase, water-based is to neutral, and anhydrous sodium sulfate drying spends the night, and concentrates to obtain white solid.By this white solid (50mg, 0.1037mmol) be dissolved in 4mL methylene dichloride, add oxalyl chloride (0.4148mmol), stirring at room 20 hours, generate 2-hydroxy methylene-3-oxo-Ursane-12-alkene-28-acyl chlorides, steam except reaction solvent and unreacted oxalyl chloride, resistates adds 2mL hexanaphthene, remove hexanaphthene under reduced pressure, repeatable operation 2 times.After adding 2mL methylene dichloride to make it to dissolve completely in acyl chlorides, adding triethylamine tune pH is 9～10, stirs after 5 minutes, adds 3-amino-1-propyl alcohol (31.11mg, 0.4148mmol), under room temperature, reacts, and TLC monitors reaction end.After reaction finishes, remove methylene dichloride under reduced pressure, in reaction solution, add 2mL water, with 2mol/L hydrochloric acid, adjust pH to 3～4, separate out white solid, decompress filter, washing filter cake is to neutral.Drying at room temperature obtains white solid (XII).Crude product silica gel chromatography, eluent is petrol ether/ethyl acetate=7/1 (V/V), obtains white powder solid 13.6mg, productive rate is 11.47%.mp?167.7~169.2℃；IR?(KBr):?3434,?2961,?2928,?1729,?1600,?1581,?1468,?1286,?1123,?744
cm -1;? 1H-NMR?(300MHz,?CDCl 3):?δ?15.0(d,?1H,?=CH-O H),?7.7(s,?1H,?CON H),?6.15?(d,?1H,?=C H-OH),
5.27~5.31?(s,?1H,?H-12),?3.20~3.53(m,?6H,?(C H 2 ) 3),?2.22?(d,?1H,?H-18),?2.0(t,?1H,?O H),?1.11?(s,?6H,
CH 3×2),?1.07?(s,?3H,?CH 3),?1.05?(s,?3H,?CH 3),?0.98?(s,?3H,?CH 3),?0.89?(d,?3H,?CH 3),?0.85?(s,?3H,?CH 3);?ESI-MS:?562.2(M+Na) +。

Claims (1)

1. an acid as chemical modifier for ursolic for anti-tumor activity, is characterized in that, described modifier is the structure of modification to A ring, and the modification to C-28 position, obtains ursolic acid ester compounds; Described acid as chemical modifier for ursolic comprises following two classes:
(1) on the basis of ursolic acid structure, modify, in C-3 position, introduce alkyloyloxyethyl imino-, carbonyl, alkanoyloxy, hydrogen, hydrogen, aldehyde radical, hydroxyl or hydroxyl methene base, carbonyl are introduced in C-2 position, C-28 position is alkoxyl group, hydroxyl, amino, diazanyl, alkyl, alkoxy acyl replacement for R3, obtains series compound; Compound structure is as shown in the table:
Figure DEST_PATH_IMAGE003AAAA
(2) on the basis of ursolic acid structure, A ring is modified to tetrahydrobenzene, in C-3 position, introduce halogen (as chlorine), ester group is introduced in C-28 position, obtains ursolic acid ester compounds; Structure is as shown in the table:
Figure 2013105830803100001DEST_PATH_IMAGE005
An acid as chemical modifier for ursolic preparation method for anti-tumor activity, is characterized in that, said method comprising the steps of:
(1) ursolic acid and Jones reagent react obtain 3-oxo ursolic acid;
(2) 3-oxo ursolic acid is dissolved in appropriate pyridine, adds oxammonium hydrochloride, react to obtain 3-oximido-Ursane-12-alkene-28-carboxylic acid (UA-1);
(3) UA-1 reacts with diacetyl oxide or butyryl oxide again, then with after oxalyl chloride activation, reacts generate ester class and hydrazides class target Compound I ~ V with benzylalcohol, p-NP, aniline, phenylhydrazine etc.;
(4) take 3-oxo ursolic acid is raw material, reacts and obtains 3-oxo black bearberry carboxylicesters, then add Vilsmeier reagent with haloalkane, obtains compound VI; In chloroformic solution, add phosphorus pentachloride, obtain compounds X V;
(5) ursolic acid C-3 position is selected to introduce oximido after being oxidized to carbonyl, and C-28 position becomes after different types of ester, and C-3 position oximido is reacted with chloroacetyl chloride and obtains compound VI I ~ VIII;
(6) the C-28 position of UA-1 is become after different types of ester, generate 3-oximido-Ursane-12-alkene-28 carboxylic acid ester compound, under again C-3 position oximido on A ring being refluxed with chloroacetyl chloride 56 C under acetone solvent, react, generate the chloro-acetoxyl group of 3-[] imino--Ursane-12-alkene-28-carboxylic acid ester compound IX;
(7) on the basis of the original C-3 of ursolic acid position hydroxyl, after hydroxyl is introduced in C-2 position, C-28 position carboxyl reacts and obtains target product X ~ XI with amino alcohol, aminated compounds again, in C-2 position, introduce hydroxy methylene, C-28 position carboxyl reacts to obtain target product X II with 3-amino-1-propyl alcohol;
(8) take ursolic acid or 3-oxo ursolic acid is raw material, react with ClCH2COOC2H5 and make after ursolic acid ethoxycarbonyl methyl esters, react with hydrazine hydrate and form hydrazides, and then react with carbonyl reagent and obtain acylhydrazone analog derivative, finally in diacetyl oxide, cyclization obtains target product X III;
(9) take 3-oxo ursolic acid is starting raw material, react with excessive potassium tert.-butoxide, generate α, beta-unsaturated ketone compound, react again reduction with sodium borohydride and obtain dibastic alcohol compound, in pyridine solution, react with Tosyl chloride, product reacts with diethylamine react activation with oxalyl chloride after again, generates compounds X IV;
(10) ursolic acid and halohydrocarbon carry out esterification and generate 3 beta-hydroxies-Ursane-12-alkene-28-carboxylicesters, under ice bath 0 C condition, generate 3 Beta-methyl sulfonyloxy-Ursanes-12-alkene-28-carboxylicesters with Methanesulfonyl chloride, the DMAC of further take generates Ursane-2-, 12 diene-28-carboxylicesters XVI ~ XIX as solvent reacts with Quilonum Retard under 168 ℃ of reflux conditionss.
CN201310583080.3A 2013-11-20 2013-11-20 Anti-tumor active ursolic acid chemical modifier and preparation method thereof Pending CN103626828A (en)

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Publication number Priority date Publication date Assignee Title
CN106831929A (en) * 2016-12-21 2017-06-13 沈阳化工大学 Oleanane type antitumoral compounds and preparation method thereof
CN111764165A (en) * 2020-07-06 2020-10-13 温州大学 Preparation method of antibacterial drug-loaded gauze and foot cover for diabetic foot patient
CN111764165B (en) * 2020-07-06 2022-11-18 温州大学 Preparation method of antibacterial drug-loaded gauze and foot cover for diabetic foot patient
CN112250728A (en) * 2020-10-28 2021-01-22 籍建亚 Antiviral ursolic acid derivative and preparation method thereof
CN114409721A (en) * 2022-01-24 2022-04-29 大连理工大学 Pentacyclic triterpene derivatives containing electrophilic warheads, and preparation method and application thereof

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