CN102070697A - Oleanolic acid derivative, and preparation method and purpose thereof - Google Patents
Oleanolic acid derivative, and preparation method and purpose thereof Download PDFInfo
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- UPDGHRIWCHZQAO-WAHUAFOISA-N CC(CC1)C(C)(C)[C@H](CC2)[C@@]1(C)[C@@H]1[C@]2(C)[C@](C)(CC[C@@]2([C@H]3CC(C)(C)CC2)C(OCc2ccccc2)=O)C3=CC1 Chemical compound CC(CC1)C(C)(C)[C@H](CC2)[C@@]1(C)[C@@H]1[C@]2(C)[C@](C)(CC[C@@]2([C@H]3CC(C)(C)CC2)C(OCc2ccccc2)=O)C3=CC1 UPDGHRIWCHZQAO-WAHUAFOISA-N 0.000 description 1
Abstract
The invention relates to the field of medicine, in particular to an oleanolic acid derivative shown as a formula I, and pharmaceutically acceptable salts, a preparation method and purpose thereof. The invention also discloses application of the compound shown by the formula I to the preparation of anti-tumor medicine of 2-cyano-3, 12-dioxo oleanane-1, 9(11)-diene-28-carboxylic acid (XI, CDDO), 2-cyano-3, 12-dioxo oleanane-1, 9(11)-diene-28-carboxylic imidazole (XIII, CDDO-Im) and 2-cyano-3, 12-dioxo oleanane-1, 9(11)-diene-28-carboxyl methylamine (XIV, CDDO-MA).
Description
Technical field
The present invention relates to pharmaceutical field, be specifically related to the oleanolic acid derivate shown in a kind of formula (I) or its pharmacy acceptable salt, its preparation method.The present invention also further relates to the compound shown in the formula (I) at preparation antitumor drug 2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-28-carboxylic acid (CDDO), 2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-28-carboxylic acyl imidazoles (CDDO-Im) and 2-cyano group-3, application in 12-dioxo volatile oil-1,9 (11)-diene-28-carboxylic acyl methylamine (CDDO-MA).
Background technology
With Oleanolic Acid (oleanolic acid, OA) for the oleanane type of representative (oleanane) pentacyclic triterpene compound at the nature ubiquity, and has a wide biological activity (Neoplasma, 2004,51,327-333), based on the optimization of these natural compound structures with to derive be one of focus of Natural Medicine Chemistry research.
2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-28-carboxylic acid (CDDO) are that Oleanolic Acid is carried out structure of modification and the volatile oil compounds with good anti-inflammatory and anti-tumor activity that obtains.CDDO has unique mechanism of action, and safe, the pharmacologically active of its methyl ester derivation (CDDO-Me) and CDDO suitable (Nature Reviews Cancer, 2007,7,357-69).At present, CDDO-Me is in the clinical development stage, is respectively applied for treatment carcinoma of the pancreas and chronic nephropathy (CKD).
With CDDO is guide's thing, its C28 position carboxyl is carried out the 2-cyano group-3 that derivatize obtains, 12-dioxo volatile oil-1,9 (11)-diene-28-carboxylic acyl imidazoles (CDDO-Im) and 2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-28-carboxylic acyl methylamine (CDDO-MA), both pharmacologically actives all are better than CDDO and CDDO-Me (Blood, 2004,103,3158-3366; PLoS One, 2009,4, e5757).
Studies show that the C28 bit substituent of this compounds is very big to the pharmacologically active influence, so C28 position carboxyl is the critical sites of structural modification.Yet (WO 9965478 for the synthetic method of at present relevant CDDO; Jouranl of Medicinal Chemistry, 2000,43,4233) there is certain defective.The people such as Honda of the former developer of CDDO U.S. Dartmouth College are also candid, and existing composition problem has badly influenced further research and development (the Bioorganic ﹠amp of CDDO derivative; Medicinal Chemistry Letters, 2002,12,1027-1030).
The CDDO synthetic method of people such as Honda report is to be raw material with the Oleanolic Acid, and its C28 position carboxyl is made CDDO through series reaction again after the esterification protection, and its synthetic route is as follows:
Reagents?and?conditions：(a)CH
2N
2；(b)Ac
2O，pyr；(c)H
2O
2，AcOH；(d)Br
2，HBr，AcOH；(e)KOH，aq?MeOH；(f)Jones；(g)HCO
2Et，NaOMe，PhH；(h)NH
2OH·HCl，aq?EtOH；(i)NaOMe，Et
2O，MeOH；(j)DDQ，PhH；(k)LiI
Mainly there is following shortcoming in above-mentioned CDDO synthetic route: 1. because the C28 position carboxyl in the Oleanolic Acid molecule is in the big steric hindrance of parent nucleus shadow zone, reactive behavior is low, therefore needs to use methyl iodide or diazomethane could carry out esterification reaction of organic acid smoothly in step a.Yet, these reagent exist cost an arm and a leg, inflammable and explosive, hypertoxic and be difficult to shortcoming such as preservation; 2. step k relates to the hydrolysis of the C28 position carboxylate methyl ester of CDDO-Me, and it can not carry out under the acid of routine or alkaline condition smoothly, need to use expensive anhydrous lithium iodide make reagent, and long-time backflow just can be finished in dry DMF.Simultaneously, the aftertreatment of this reaction is loaded down with trivial details, needs multistep operations such as column chromatography, recrystallization.Therefore, " protection and the deprotection " of C28 position carboxyl is that this synthetic route needs most improved place.
The present invention adopts benzyl reagent that the C28 position carboxyl of Oleanolic Acid is carried out benzyl esterification protection, compares with the Honda method, and the reagent that the present invention adopts is not only cheap and easy to get, reaction yield height, and the also relative raising greatly with environment friendly of reaction safety.
Summary of the invention
The present invention discloses a kind of oleanolic acid derivate (I) or its pharmacy acceptable salt, Preparation Method And The Use first.The preparation method of The compounds of this invention has the reaction yield height, production cost is low and characteristics such as reaction conditions gentleness.Compound of the present invention can be used for preparing antitumor drug CDDO, CDDO-Im and CDDO-MA.
One of purpose of the present invention is to provide oleanolic acid derivate or its pharmacy acceptable salt of formula (I):
Another purpose of the present invention is to provide the preparation method of formula of the present invention (I) compound, it is characterized in that, comprises the steps:
(1) is raw material with Oleanolic Acid (OA), under alkaline condition, makes the olea acid benzyl ester shown in the formula (II) with benzyl reagent generation esterification; Preparation formula (II) compound is characterised in that the alkaline reagents of employing is selected from salt of wormwood or yellow soda ash; The benzyl reagent that adopts is selected from Benzyl Chloride or cylite; The solvent that adopts is selected from acetonitrile, methylene dichloride, methyl alcohol, N, dinethylformamide or ethyl acetate; The reaction times of adopting is 1-24 hour;
(2) in pyridine, olea acid benzyl ester (II) makes the 3-acetoxyl group olea acid benzyl ester shown in the formula (III) with the aceticanhydride reaction down in 4-Dimethylamino pyridine (DMAP) effect;
(3) reaction of formula (III) compound and oxidising agent makes the 3-acetoxyl group shown in the formula (IV)-12-oxo oleanane-28-carboxylic benzyl ester; Preparation formula (IV) compound is characterised in that the oxidising agent of employing is selected from hydrogen peroxide or peroxidation phenylformic acid; The solvent that adopts is selected from acetate, formic acid, methylene dichloride, acetonitrile, N, dinethylformamide or water; The reaction times of adopting is 1-24 hour;
(4) formula (IV) compound and Br
2Replace-eliminate reaction with HBr and make the 3-acetoxyl group shown in the formula V-12-oxo volatile oil-9 (11)-alkene-28-benzyl carboxylate; Preparation formula V compound is characterised in that Br
2Charging capacity be the 2-4 equivalent of formula (IV) compound; The solvent that adopts is selected from acetate or formic acid; The temperature of reaction that adopts is 25～50 ℃; The reaction times of adopting is 1-24 hour;
(5) the formula V compound makes 3 beta-hydroxies shown in the formula (VI)-12-oxo volatile oil-9 (11)-alkene-28-benzyl carboxylate through basic hydrolysis; The basic cpd that adopts is selected from sodium hydroxide or potassium hydroxide; The reaction times of adopting is 1-12 hour.
(6) reaction of formula (VI) compound and oxidising agent makes 3 shown in the formula (VII), 12-dioxo volatile oil-9 (11)-alkene-28-benzyl carboxylate; Preparation formula (VII) compound is characterised in that the oxygenant of employing is selected from Sarrett reagent, Jones reagent, Collins reagent or Oppenauer oxidising agent; The solvent that adopts is selected from ether, acetonitrile, acetone, ethyl acetate, water or methylene dichloride; The reaction times of adopting was at 10-60 minute;
(7) formula (VII) compound makes the 2-hydroxyl methyne-3 shown in the formula (VIII) with ethyl formate generation nucleophilic addition under alkaline condition, 12-dioxo volatile oil-9 (11)-alkene-28-benzyl carboxylate; Preparation formula (VIII) compound is characterised in that the alkaline reagents of employing is selected from sodium methylate, sodium ethylate or sodium hydride; The solvent that adopts is selected from methylene dichloride, chloroform, tetrahydrofuran (THF), methyl alcohol, ether, N, dinethylformamide or acetonitrile; The reaction times of adopting is 1-12 hour;
(8) formula (VIII) compound and oxammonium hydrochloride back flow reaction in ethanol make 12-oxo isoxazole [4,5-b] volatile oil-9 (11)-alkene-28-benzyl carboxylate shown in the formula (IX);
(9) formula (IX) compound makes 12-oxo isoxazole [4,5-b] volatile oil-9 (11)-alkene-28-carboxylic acid shown in the formula (X) through the Pd-C catalytic hydrogenation; Preparation formula (X) compound is characterised in that the content of Pd is 1%-10% among the Pd-C of employing; The solvent that adopts is selected from tetrahydrofuran (THF), methyl alcohol, water, ethanol, N, dinethylformamide or acetonitrile; The reaction times of adopting is 1-48 hour;
(10) formula (X) compound is eliminated at alkalescence effect generation Kemp and is made the 2-cyano-3-hydroxy shown in the formula (I)-12-oxo volatile oil-2 (3), 9 (11)-diene-28-carboxylic acid; Preparation formula (I) compound is characterised in that the alkaline reagents of employing is selected from sodium methylate, potassium methylate, sodium ethylate or potassium ethylate; The solvent that adopts is selected from methyl alcohol, ethanol, ether, methylene dichloride, ethyl acetate; The reaction times of adopting was at 1-2 hour;
Its synthetic general line is as follows:
Preparation formula (II) compound is characterised in that, the preferred salt of wormwood of the alkaline reagents of employing; The preferred Benzyl Chloride of benzyl reagent that adopts; The preferred N of solvent that adopts, dinethylformamide; The reaction times of adopting is 4 hours.
Preparation formula (IV) compound is characterised in that, the preferred hydrogen peroxide of the oxidising agent of employing; The solvent preferable formic acid and the methylene dichloride mixed solvent that adopt; The reaction times of adopting is 24 hours.
Preparation formula V compound is characterised in that Br
2Charging capacity be 3 equivalents of formula (IV) compound; The preferred acetate of solvent that adopts; The temperature of reaction that adopts is 25～50 ℃; The reaction times of adopting is 24 hours.
Preparation formula (VI) compound is characterised in that, the preferred potassium hydroxide of the basic cpd of employing; The reaction times of adopting is 1 hour.
Preparation formula (VII) compound is characterised in that, the preferred Jones reagent of the oxygenant of employing; The preferred acetone of solvent that adopts; The reaction times of adopting is 20 minutes.
Preparation formula (VIII) compound is characterised in that, the alkaline reagents particular methanol sodium of employing; The preferred methylene dichloride of solvent that adopts; The reaction times of adopting is 12 hours.
Preparation formula (IX) compound is characterised in that the content of Pd is 10% among the Pd-C of employing; The preferred tetrahydrofuran (THF) of solvent that adopts; The reaction times of adopting is 5 hours.
Preparation formula (I) compound is characterised in that, the alkaline reagents particular methanol sodium of employing; The solvent particular methanol and the ether mixed solvent that adopt; The reaction times of adopting was at 1 hour.
Another object of the present invention is to provide formula (I) compound preparing antitumor drug: the 2-cyano group-3 shown in the formula (XI), 12-dioxo volatile oil-1,9 (11)-diene-28-carboxylic acid (CDDO), 2-cyano group-3 shown in the formula (XIII), 12-dioxo volatile oil-1,2-cyano group-3 shown in 9 (11)-diene-28-carboxylic acyl imidazoles (CDDO-Im) and the formula (XIV), 12-dioxo volatile oil-1, application in 9 (11)-diene-28-carboxylic acyl methylamine (CDDO-MA), it is characterized in that, formula (I) compound and oxidant reaction make formula (XI) compound, formula (XI) compound further makes formula (XII) compound with the chloride reagent reaction, formula (XII) compound is under alkaline condition, respectively with imidazoles, the methylamine hydrochloride reaction makes formula (XIII) and formula (XIV) compound, and its synthetic route is:
Wherein, preparation formula (XI) compound is characterised in that the oxygenant of employing is selected from 2,3-two chloro-5,6-dicyanobenzoquinone, tetrachlorobenzoquinone or tin anhydride; The solvent that adopts is selected from benzene,toluene,xylene, dioxane, acetonitrile, tetrahydrofuran (THF) or methylene dichloride; The reaction times of adopting is 1-48 hour; The temperature of reaction that adopts is 25-140 ℃.
Preparation formula (XII) compound is characterised in that, adopts chloride reagent to be selected from oxalyl chloride or thionyl chloride; The employing solvent is anhydrous methylene chloride, anhydrous chloroform, anhydrous tetrahydro furan, anhydrous acetonitrile or anhydrous propanone; The reaction times of adopting is 1-24 hour; The temperature of reaction that adopts is 0-50 ℃.
Preparation formula (XIII) and formula (XIV) compound are characterised in that the alkaline reagents of employing is selected from triethylamine, pyridine or 4-Dimethylamino pyridine; The employing solvent is anhydrous methylene chloride, anhydrous chloroform, anhydrous tetrahydro furan, anhydrous acetonitrile or anhydrous propanone; The reaction times of adopting is 1-24 hour; The temperature of reaction that adopts is 0-50 ℃.
Embodiment
In order further to illustrate the present invention, provide a series of embodiment below, these embodiment are illustrative fully, they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.The used Oleanolic Acid of the present invention is the chemical pure raw material that market is bought.
Embodiment 1
The preparation of 3 beta-hydroxies volatile oil-12-alkene-28-benzyl carboxylate (II)
With Oleanolic Acid (100g, 220mmol) and K
2CO
3(61g 440mmol) places DMF (800mL), and 50～55 ℃ drip benzyl chloride (33mL in following 20 minutes, 290mmol), drip and finish, continue reaction 3～4 hours, be cooled to room temperature, filter, filter cake washs with DMF (50mL * 3), in (3000mL), have a large amount of white solids to separate out in the filtrate impouring frozen water, leave standstill treat solid particulate become big after, suction filtration is collected solid, the water thorough washing, the dry white solid II (114g, 95.5%) that gets.Compound I I is a known compound, and its CAS number is 303114-51-4.
Embodiment 2
The preparation of 3 β-acetoxyl group volatile oil-12-alkene-28-benzyl carboxylate (III)
(5.46g 10mmol) is dissolved in the 20mL pyridine, and 0～5 ℃ slowly drips diacetyl oxide (10.2g with Compound I I, 100mmol), and adding DMAP after dropwising (0.12g, 1mmol), there is solid to separate out, continues reaction 1～2 hour under the room temperature, add an amount of methylene dichloride (50mL) dissolving, solution is used 5%HCl solution successively, saturated sodium bicarbonate solution, saturated aqueous common salt respectively wash 3 times, anhydrous sodium sulfate drying, decompression gets white solid III (5.4g, 91.3%) after removing solvent.Compound III is a known compound, and its CAS number is 357953-27-6.
Embodiment 3
The preparation of 3 β-acetoxyl group-12-oxo oleanane-28-carboxylic benzyl ester (IV)
(5.88g 10mmol) is dissolved in an amount of methylene dichloride (50mL), adds formic acid (10mL), H with compound III
2O
2(1.36g, 40mmol), room temperature reaction 24 hours, TLC monitoring reaction process, after treating that raw material point disappears, with saturated sodium bicarbonate solution reaction solution is washed till nearly neutrality, saturated common salt water washing 3 times, anhydrous sodium sulfate drying, decompression get light yellow solid, AcOH-H after removing solvent
2The O recrystallization gets white solid IV (4.7g, 78%).Compound IV is a known compound, and its CAS number is 357953-28-7.
Embodiment 4
The preparation of 3 β-acetoxyl group-12-oxo volatile oil-9 (11)-alkene-28-benzyl carboxylate (V)
(6.04g 10mmol) is dissolved in the acetate (300mL), and (40%, AcOH) solution is heated to 40～45 ℃, slowly drips Br to drip several HBr with compound IV
2(1.6g, acetic acid solution 10mmol) after dropwising, stir a moment, and other adds Br
2(reaction is 24 hours under the room temperature for 3.2g, acetic acid solution 20mmol).After reacting end, in solution impouring frozen water, collect and separate out solid, use saturated sodium sulfite solution respectively, water washing, oven dry gets faint yellow crude product, and recrystallizing methanol gets white solid V (4.39g, 79.8%).
m.p.216-218℃；
ESI-MS：603[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ7.34-7.26(m，5H)，5.7(s，1H)，5.16(d，J＝12.6Hz，1H)，5.11(d，J＝12.6Hz，1H)，4.46(m，1H)，3.03(m，1H)，2.93(d，J＝4.5Hz，1H)，2.05(s，3H)，2.01，1.57，1.16，1.00，0.95，0.92，0.89(s，each?3H)ppm.
Embodiment 5
The preparation of 3 beta-hydroxies-12-oxo volatile oil-9 (11)-alkene-28-benzyl carboxylate (VI)
With compound V (6.02g, 10mmol), KOH (33.6g, 600mmol) be dissolved in methyl alcohol (300mL), reflux 1 hour, solvent is removed in decompression, and remaining solid is washed till nearly neutrality with the HCl solution of 6mol/L, water layer extracts with methylene dichloride (100mL * 3), organic layer saturated sodium bicarbonate solution, saturated aqueous common salt respectively wash 3 times, anhydrous sodium sulfate drying, decompression gets white solid VI (5.32g, 95%) after removing solvent.
m.p.197-198℃；
ESI-MS?m/z：561[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ7.34-7.26(m，5H)，5.7(s，1H)，5.16(d，J＝12.6Hz，1H)，5.11(d，J＝12.6Hz，1H)，3.22-3.17(m，1H)，3.03(m，1H)，2.25(d，J＝4.5Hz，1H)，1.14，1.02，1.00，0.96，0.92，0.89，0.81(s，each?3H)ppm.
Embodiment 6
3, the preparation of 12-dioxo volatile oil-9 (11)-alkene-28-benzyl carboxylate (VII)
(5.6g 10mmol) is dissolved in the acetone (200mL), and 0 ℃ slowly drips Jones reagent (3.8mL) down, dropwised the back room temperature reaction 10～20 minutes, TLC monitoring reaction process with compound VI.After treating ℃ mistake of raw material point, solvent is removed in decompression, add water in the residue, extract with methylene dichloride (100mL * 3), organic layer saturated sodium bicarbonate solution, saturated aqueous common salt respectively wash 3 times, anhydrous sodium sulfate drying, decompression gets the light brown solid after removing solvent, and silica gel column chromatography makes white solid VII (4.9g, 88%) fast.
m.p.146-147℃；
ESI-MS?m/z：559[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ7.38-7.28(m，5H)，5.8(s，1H)，5.16(d，J＝12.6Hz，1H)，5.11(d，J＝12.6Hz，1H，)，3.06(m，1H)，2.78(d，J＝4.5Hz，1H)，2.66，2.49，2.17(m，each?1H)，1.26，1.11，1.07，1.00，0.97，0.95，0.89(s，each?3H)ppm.
Embodiment 7
2-hydroxyl methyne-3, the preparation of 12-dioxo volatile oil-9 (11)-alkene-28-benzyl carboxylate (VIII)
With compound VI I (5.58g, 10mmol) be dissolved in the exsiccant methylene dichloride, (3.24g 60mmol), forms suspension to 0 ℃ of adding new system sodium methylate, stir moments later, slow dropping ethyl formate (3.33g, 45mmol), room temperature reaction 12 hours, the TLC monitoring, after reaction finishes, regulate reacting liquid pH value down to neutral, the methylene dichloride dilution for 0 ℃, the organic layer saturated sodium bicarbonate solution, saturated aqueous common salt respectively washs 3 times, anhydrous sodium sulfate drying, and decompression gets faint yellow solid after removing solvent, make white solid VIII (5.3g, 90.2%) through quick silica gel column chromatography.
m.p.110-114℃；
ESI-MS：587[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ14.85(d，J＝2.4Hz，1H)，8.75(s，1H)，7.34-7.26(m，5H)，5.7(s，1H)，5.16(d，J＝12.6Hz，1H)，5.11(d，J＝12.6Hz，1H)，3.03(m，1H)，2.83(d，J＝4.5Hz，1H)，2.61(d，J＝14.4Hz，1H)，2.25(d，J＝14.4Hz，1H)，1.24，1.15，1.14，1.01，0.98，0.94，0.85(s，each?3H)ppm.
Embodiment 8
The preparation of 12-oxo isoxazole [4,5-b] volatile oil-9 (11)-alkene-28-benzyl carboxylate (IX)
With compound VIII (5.8g, 10mmol), oxammonium hydrochloride (6.95g 100mmol) is dissolved in ethanol (95%) 100mL, reflux 1 hour, reaction finishes.Be spin-dried for reaction solution, residue ethyl acetate (50mL) dissolving, organic layer saturated sodium bicarbonate solution, saturated aqueous common salt respectively wash 3 times, anhydrous sodium sulfate drying, decompression gets white solid IX (4.8g, 82.7%) after removing solvent.
m.p.120-122℃；
ESI-MS：584[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ8.05(s，1H)，7.34-7.26(m，5H)，5.8(s，1H)，5.16(d，J＝12.6Hz，1H)，5.11(d，J＝12.6Hz，1H)，3.10(m，1H)，2.80(d，J＝4.5Hz，1H)，2.75(d，J＝15Hz，1H)，3.38(d，J＝15Hz，1H)，1.37，1.26，1.12，1.01，0.99，0.95，0.90(s，each?3H)ppm.
Embodiment 9
The preparation of 12-oxo isoxazole [4,5-b] volatile oil-9 (11)-alkene-28-carboxylic acid (X)
With Compound I X (1.00g, 1.71mmol) be dissolved in tetrahydrofuran (THF) (15mL), add 5% palladium carbon (0.1g), normal pressure hydrogenation reacted about 5 hours, the TLC detection reaction, timely termination reaction after raw material disappears, filtering palladium carbon, washing leaching cake, merging filtrate, solvent is removed in decompression, and rapid column chromatography gets white solid X (0.7g, 87.3%).
m.p.224-226℃；
ESI-MS：492[M-H]
-；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ8.05(s，1H)，5.8(s，1H)，3.03(m，1H)，2.93(d，J＝4.5Hz，1H)，2.78(d，J＝15.3Hz，1H)，2.40(d，J＝15.3Hz，1H)，1.35，1.31，1.26，1.16，1.01，0.97，0.85(s，each?3H)ppm.
Embodiment 10
The preparation of 2-cyano-3-hydroxy-12-oxo volatile oil-2 (3), 9 (11)-diene-28-carboxylic acid (I)
(0.49g 1mmol), is dissolved in methyl alcohol 6mL, ether 12mL with compounds X, adding sodium methylate under 0 ℃ (1.62g, 30mmol), room temperature reaction 1 hour, methylene dichloride dilution, with 5% dilute hydrochloric acid acidifying, organic layer is washed 3 times with saturated sodium bicarbonate, saturated common salt washing 3 times, anhydrous sodium sulfate drying.Decompression gets faint yellow solid I (0.44g, 89%) after removing solvent.
m.p.198-200℃；
ESI-MS：492[M-H]
-；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ8.01(s，1H)，5.9(s，1H)，3.03(m，1H)，2.93(d，J＝4.5Hz，1H)，2.41(d，J＝9.0Hz，1H)，2.26(d，J＝9.0Hz，1H)，1.26，1.21，1.24，1.20，1.16，1.00，0.91(s，each?3H)ppm.
Embodiment 11
2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-28-carboxylic acid (XI, preparation CDDO)
With Compound I (0.25g, 0.51mmol) and dicyan dichloro quinone (DDQ) (0.25g, 0.51mmol) be dissolved in the 20mL dry-out benzene, reflux 20 minutes is after reaction finishes, filter, filtrate concentrates, and rapid column chromatography gets white solid XI (0.23g, 91.1%), compounds X I is a known compound, and its CAS number is 218600-44-3.
m.p.180-182℃；
ESI-MS?m/z：490M-H]
-，492[M+H]
+；
1HNMR(300M?Hz，CDCl
3，25℃，TMS)：δ8.05(1H，s)，5.99(1H，s)，3.03-2.98(2H，m)，1.55，1.38，1.34，1.22，1.00，0.91，0.85(each?3H，s，CH
3)ppm.
Embodiment 12
2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-28-carboxylic acyl imidazoles (XIII, preparation CDDO-Im)
With Compound I (0.25g 0.51mmol) is dissolved in the 20mL anhydrous methylene chloride, 0 ℃ drip down slowly oxalyl chloride (0.64g, 5.1mmol), room temperature reaction 12 hours, after reaction finishes, reaction solution concentrate yellow solid XII (0.23g, 89.5%).
With compounds X II (0.23g, 0.45mmol) be dissolved in the 10mL anhydrous methylene chloride, 0 ℃ slowly drips imidazoles (0.03g down, 0.45mmol) and triethylamine (0.09g, 0.9mmol) dichloromethane solution (5mL), room temperature reaction 1-4 hour, after reaction finishes, reaction solution dilutes with an amount of methylene dichloride, organic layer respectively with 5% dilute hydrochloric acid, saturated sodium bicarbonate wash, saturated aqueous common salt respectively washs 3 times, anhydrous sodium sulfate drying concentrates, rapid column chromatography gets white solid XIII (0.20g, 82.1%).Compounds X III is a known compound, and its CAS number is 443104-02-7.
Embodiment 13
2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-28-carboxylic acyl methylamine (XIV, preparation CDDO-MA)
The synthetic method of reference compound XIII (embodiment 12), by compounds X II (0.23g, 0.45mmol) with methylamine hydrochloride (0.03g, 0.45mmol), (0.13g, 1.35mmol) prepared in reaction gets white solid XIV (0.18g, 80.1%) to triethylamine.Compounds X IV is a known compound, and its CAS number is 443103-35-3.
Claims (10)
1. the oleanolic acid derivate shown in the formula (I) or its pharmacy acceptable salt:
2. a method for preparing the described formula of claim 1 (I) compound is characterized in that, comprises the steps:
(1) is raw material with Oleanolic Acid (OA), under alkaline condition, makes the olea acid benzyl ester shown in the formula (II) with benzyl reagent generation esterification; Preparation formula (II) compound is characterised in that the alkaline reagents of employing is selected from salt of wormwood or yellow soda ash; The benzyl reagent that adopts is selected from Benzyl Chloride or cylite; The solvent that adopts is selected from acetonitrile, methylene dichloride, methyl alcohol, N, dinethylformamide or ethyl acetate; The reaction times of adopting is 1-24 hour;
(2) in pyridine, olea acid benzyl ester (II) makes the 3-acetoxyl group olea acid benzyl ester shown in the formula (III) with the aceticanhydride reaction down in 4-Dimethylamino pyridine (DMAP) effect;
(3) reaction of formula (III) compound and oxidising agent makes the 3-acetoxyl group shown in the formula (IV)-12-oxo oleanane-28-carboxylic benzyl ester; Preparation formula (IV) compound is characterised in that the oxidising agent of employing is selected from hydrogen peroxide or peroxidation phenylformic acid; The solvent that adopts is selected from acetate, formic acid, methylene dichloride, acetonitrile, N, dinethylformamide or water; The reaction times of adopting is 1-24 hour;
(4) formula (IV) compound and Br
2Replace-eliminate reaction with HBr and make the 3-acetoxyl group shown in the formula V-12-oxo volatile oil-9 (11)-alkene-28-benzyl carboxylate; Preparation formula V compound is characterised in that Br
2Charging capacity be the 2-4 equivalent of formula (IV) compound; The solvent that adopts is selected from acetate or formic acid; The temperature of reaction that adopts is 25～50 ℃; The reaction times of adopting is 1-24 hour;
(5) the formula V compound makes 3 beta-hydroxies shown in the formula (VI)-12-oxo volatile oil-9 (11)-alkene-28-benzyl carboxylate through basic hydrolysis; The basic cpd that adopts is selected from sodium hydroxide or potassium hydroxide; The reaction times of adopting is 1-12 hour.
(6) reaction of formula (VI) compound and oxidising agent makes 3 shown in the formula (VII), 12-dioxo volatile oil-9 (11)-alkene-28-benzyl carboxylate; Preparation formula (VII) compound is characterised in that the oxygenant of employing is selected from Sarrett reagent, Jones reagent, Collins reagent or Oppenauer oxidising agent; The solvent that adopts is selected from ether, acetonitrile, acetone, ethyl acetate, water or methylene dichloride; The reaction times of adopting was at 10-60 minute;
(7) formula (VII) compound makes the 2-hydroxyl methyne-3 shown in the formula (VIII) with ethyl formate generation nucleophilic addition under alkaline condition, 12-dioxo volatile oil-9 (11)-alkene-28-benzyl carboxylate; Preparation formula (VIII) compound is characterised in that the alkaline reagents of employing is selected from sodium methylate, sodium ethylate or sodium hydride; The solvent that adopts is selected from methylene dichloride, chloroform, tetrahydrofuran (THF), methyl alcohol, ether, N, dinethylformamide or acetonitrile; The reaction times of adopting is 1-12 hour;
(8) formula (VIII) compound and oxammonium hydrochloride back flow reaction in ethanol make 12-oxo isoxazole [4,5-b] volatile oil-9 (11)-alkene-28-benzyl carboxylate shown in the formula (IX);
(9) formula (IX) compound makes 12-oxo isoxazole [4,5-b] volatile oil-9 (11)-alkene-28-carboxylic acid shown in the formula (X) through the Pd-C catalytic hydrogenation; Preparation formula (X) compound is characterised in that the content of Pd is 1%-10% among the Pd-C of employing; The solvent that adopts is selected from tetrahydrofuran (THF), methyl alcohol, water, ethanol, N, dinethylformamide or acetonitrile; The reaction times of adopting is 1-48 hour;
(10) formula (X) compound is eliminated at alkalescence effect generation Kemp and is made the 2-cyano-3-hydroxy shown in the formula (I)-12-oxo volatile oil-2 (3), 9 (11)-diene-28-carboxylic acid; Preparation formula (I) compound is characterised in that the alkaline reagents of employing is selected from sodium methylate, potassium methylate, sodium ethylate or potassium ethylate; The solvent that adopts is selected from methyl alcohol, ethanol, ether, methylene dichloride, ethyl acetate; The reaction times of adopting was at 1-2 hour;
Its synthetic general line is as follows:
3. method according to claim 2, preparation formula (II) compound is characterised in that, the preferred salt of wormwood of the alkaline reagents of employing; The preferred Benzyl Chloride of benzyl reagent that adopts; The preferred N of solvent that adopts, dinethylformamide; The reaction times of adopting is 4 hours.
4. method according to claim 2, preparation formula (IV) compound is characterised in that, the preferred hydrogen peroxide of the oxidising agent of employing; The solvent preferable formic acid and the methylene dichloride mixed solvent that adopt; The reaction times of adopting is 24 hours.
4, method according to claim 2, preparation formula V compound is characterised in that Br
2Charging capacity be 3 equivalents of formula (IV) compound; The preferred acetate of solvent that adopts; The temperature of reaction that adopts is 25～50 ℃; The reaction times of adopting is 24 hours.
5. method according to claim 2, preparation formula (VI) compound is characterised in that, the preferred potassium hydroxide of the basic cpd of employing; The reaction times of adopting is 1 hour.
6. method according to claim 2, preparation formula (VII) compound are characterised in that, the preferred Jones reagent of the oxygenant of employing; The preferred acetone of solvent that adopts; The reaction times of adopting is 20 minutes.
7. method according to claim 2, preparation formula (VIII) compound are characterised in that, the alkaline reagents particular methanol sodium of employing; The preferred methylene dichloride of solvent that adopts; The reaction times of adopting is 12 hours.
8. method according to claim 2, preparation formula (X) compound is characterised in that the content of Pd is 10% among the Pd-C of employing; The preferred tetrahydrofuran (THF) of solvent that adopts; The reaction times of adopting is 5 hours.
9. method according to claim 2, preparation formula (I) compound are characterised in that, the alkaline reagents particular methanol sodium of employing; The solvent particular methanol and the ether mixed solvent that adopt; The reaction times of adopting was at 1 hour.
10. the described formula of claim 1 (I) compound is preparing antitumor drug: the 2-cyano group-3 shown in the formula (XI), 12-dioxo volatile oil-1,9 (11)-diene-28-carboxylic acid (CDDO), 2-cyano group-3 shown in the formula (XIII), 12-dioxo volatile oil-1,2-cyano group-3 shown in 9 (11)-diene-28-carboxylic acyl imidazoles (CDDO-Im) and the formula (XIV), 12-dioxo volatile oil-1, application in 9 (11)-diene-28-carboxylic acyl methylamine (CDDO-MA), it is characterized in that, formula (I) compound and oxidant reaction make formula (XI, CDDO) compound, formula (XI) compound further makes formula (XII) compound with the chloride reagent reaction, formula (XII) compound is under alkaline condition, respectively with imidazoles, the methylamine hydrochloride reaction makes formula (XIII) and formula (XIV) compound, and its synthetic route is:
Wherein, preparation formula (XI) compound is characterised in that the oxygenant of employing is selected from 2,3-two chloro-5,6-dicyanobenzoquinone, tetrachlorobenzoquinone or tin anhydride; The solvent that adopts is selected from benzene,toluene,xylene, dioxane, acetonitrile, tetrahydrofuran (THF) or methylene dichloride; The reaction times of adopting is 1-48 hour; The temperature of reaction that adopts is 25-140 ℃;
Preparation formula (XII) compound is characterised in that the chloride reagent of employing is selected from oxalyl chloride or thionyl chloride; The employing solvent is anhydrous methylene chloride, anhydrous chloroform, anhydrous tetrahydro furan, anhydrous acetonitrile or anhydrous propanone; The reaction times of adopting is 1-24 hour; The temperature of reaction that adopts is 0-50 ℃;
Preparation formula (XIII) and formula (XIV) compound are characterised in that the alkaline reagents of employing is selected from triethylamine, pyridine or 4-Dimethylamino pyridine; The employing solvent is anhydrous methylene chloride, anhydrous chloroform, anhydrous tetrahydro furan, anhydrous acetonitrile or anhydrous propanone; The reaction times of adopting is 1-24 hour; The temperature of reaction that adopts is 0-50 ℃.
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