CN102558282B - Ursolic acid derivative and preparation method thereof - Google Patents
Ursolic acid derivative and preparation method thereof Download PDFInfo
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- CN102558282B CN102558282B CN 201210012556 CN201210012556A CN102558282B CN 102558282 B CN102558282 B CN 102558282B CN 201210012556 CN201210012556 CN 201210012556 CN 201210012556 A CN201210012556 A CN 201210012556A CN 102558282 B CN102558282 B CN 102558282B
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Abstract
The invention relates to an ursolic acid derivative and a preparation method thereof. The ursolic acid derivative is 3-beta-acetoxy-ursolic alkyl-12-alkene-28-acyl (8'-aminobutyric acid) or 3-beta-acetoxyl-ursolic alkyl-12-alkene-28-acyl (4'-aminobutanol). The preparation method comprises the following steps of: converting ursolic acid into coarse 3-O-acetyl ursolic alkyl-28-acyl chloride intermediates via two steps, and making the coarse products as one of reactants react with 8-amino octanoic acid or 4-amino butanol, thereby obtaining the ursolic acid derivative. The ursolic acid derivative has good effects on inhibition of human leukemia U937 cell proliferation, which cannot be realized by the prior art. The synthesis reaction steps in the technical scheme are reduced, the purification method is simple, the cost can be reduced, and the product purity is high.
Description
Technical field
The present invention relates to the preparation method of derivative and the ursolic acid derivative of ursolic acid.
Background technology
(ursolic acid UA) has another name called urson to ursolic acid, belongs to pentacyclic triterpenoid, and it extensively is present in the natural phant.Its structural formula is:
Ursolic acid has multiple pharmacologically active, anti-tumor activity especially, and antitumor spectrum is wide.Ursolic acid can suppress kinds of tumor cells growth, inducing tumor cell differentiation, the formation of antitumor tissue blood vessel and inducing apoptosis of tumour cell etc., and therefore, ursolic acid has wide development and application prospect at anti-tumor aspect.For anti-tumor activity and the bioavailability that improves ursolic acid, improve it and become the property of medicine, need by different chemical modification methods the chemical structure of ursolic acid to be modified.
At present to the ursolic acid structure modify more, it is modified on the carboxyl of the hydroxyl that mainly concentrates on the 3-position again and 28-position.For example, " biological organic and medical chemistry " ［ Meng, Y.Q., Liu, D., Cai, L.L., Chen, H., Cao, B., Y.
Bioorganic ﹠amp; Medicinal Chemistry, 2009,17:848 – 854. ］ just reported the acetyl ursolic acid 28-amide derivatives of the product that carries out this class modification.Its preparation method is that first hydroxyl to ursolic acid 3-position carries out the acetylize protection; and then generation 3-O-ethanoyl ursolic acid; then itself and oxalyl chloride are reacted; again with the amino acid ester hydrochloride in a kind of---glycine methyl ester hydrochloride reaction, prepare acetyl ursolic acid 28-amide derivatives by hydrolysis more at last.This ursolic acid derivative has the effect that suppresses cervical cancer cell propagation, and its effect is better than ursolic acid.But this preparation method is complicated, and it is higher to be applied to the industrial production cost, and this compound is not fully up to expectations aspect anti-other tumours, and for example, aspect the sick U937 cell proliferation of human white blood, its effect is suitable substantially with the effect of modified ursolic acid not.
Summary of the invention
First purpose of the present invention is to provide a kind of at the ursolic acid derivative that better effects is arranged aspect the sick U937 cell proliferation of inhibition human white blood.
Second purpose of the present invention is that a kind of short-cut method for preparing the ursolic acid derivative of realizing described first purpose is provided.
Realize the technical scheme of described first goal of the invention, it is a kind of like this ursolic acid derivative, aspect same as the prior art is, the 3-position of ursolic acid parent is 3 β-acetoxyl group in this derivant structure, its improvements are, be 28-acyl (8 '-aminocaprylic acid) in the 28-position of ursolic acid parent, this ursolic acid derivative is 3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl (8 '-aminocaprylic acid), and its structural formula I is:
Perhaps, be 28-acyl (4 '-amino butanol) in the 28-position of parent ursolic acid, this ursolic acid derivative is 3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl (4 '-amino butanol), its structural formula II is:
Realizing the technical scheme of described second goal of the invention, is a kind of like this preparation method of ursolic acid derivative, and what this method prepared is the ursolic acid derivative of realizing described first goal of the invention; This method has following preparation process:
(1) with ursolic acid and acetic anhydride, generates the 3-O-acetyl ursolic acid the hydroxyl on the ursolic acid 3-position is carried out the acetylize protection;
(2) with 3-O-acetyl ursolic acid and oxalyl chloride reaction, generate 3-O-acetyl black bearberry alkane-28-acyl chlorides intermediate to modify in the 28-position;
(3) 3-O-acetyl black bearberry alkane-28-acyl chlorides intermediate is generated the ursolic acid derivative as one of reactant;
Its improvements are, the described 3-O-acetyl of step (3) black bearberry alkane-28-acyl chlorides intermediate is not have purified crude product, and another reactant in this step (3) is 8-aminocaprylic acid or 4-amino butanol, and its concrete steps are as follows:
(3-1) with methylene dichloride 3-O-acetyl black bearberry alkane-28-acyl chlorides intermediate crude product is fully dissolved;
(3-2) in gained solution, add catalyst of triethylamine and fully mixing, add 8-aminocaprylic acid or the 4-amino butanol of required reacting weight then; At 20～30 ℃ of following stirring reactions; Wherein, the molar weight of catalyst of triethylamine is no less than the molar weight of 3-O-acetyl black bearberry alkane-28-acyl chlorides;
Reaction is washed, afterwards separatory after finishing again;
(3-3) with gained organic phase behind the separatory with the anhydrous sodium sulfate drying of capacity, then concentrating under reduced pressure and 3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl (8 '-aminocaprylic acid) crude product or 3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl (4 '-amino butanol) crude product;
(3-4) described crude product is crossed post with 300～400 order silica gel, pulverous 3 β that must the be white in color-acetoxyl group-black bearberry alkane-12-alkene-pure product of 28-acyl (8 '-aminocaprylic acid), the pulverous 3 β-acetoxyl group-black bearberry alkane-12-alkene-pure product of 28-acyl (4 '-amino butanol) that must be white in color maybe; Wherein, crossing post, to separate 3 β-acetoxyl group-black bearberry alkane-12-alkene-used eluent of 28-acyl (8 '-aminocaprylic acid) be the mixed solution of methylene dichloride and methyl alcohol, its volume ratio is, methylene dichloride: methyl alcohol=50: 1, crossing post, to separate 3 β-acetoxyl group-black bearberry alkane-12-alkene-used eluent of 28-acyl (4 '-amino butanol) be the mixed solution of ethyl acetate and sherwood oil, its volume ratio is ethyl acetate: sherwood oil=2: 1.
From the scheme that realizes first goal of the invention as can be seen, ursolic acid derivative of the present invention---3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl (8 '-aminocaprylic acid), or 3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl (4 '-amino butanol), the derivative of locating in ursolic acid parent 28-position to connect with prior art is different, also be that ursolic acid derivative of the present invention and prior art have diverse structure in itself, checking shows, the present invention has the not available better effects of prior art aspect the sick U937 cell proliferation of inhibition human white blood.
From the scheme that realizes second goal of the invention as can be seen, the present invention is when modifying the carboxyl of ursolic acid parent 28-position, adopted synthetic route unlike the prior art, the present invention directly comes the runic of 3-O-acetyl black bearberry alkane-28-acyl chlorides intermediate and 8-aminocaprylic acid (in the amino acid a kind of) or 4-amino butanol (in the amino alcohol a kind of) reaction, and makes the ursolic acid derivative.So, not only saved the step of purifying 3-O-acetyl black bearberry alkane-28-acyl chlorides intermediate, but also saved prior art because adopting glycine methyl ester hydrochloride (or other amino acid ester hydrochlorides), and need hydrolysis could be worth the step of ursolic acid derivative, so, compared with prior art, the present invention not only can prepare and suppress the ursolic acid derivative that the sick U937 cell proliferation of human white blood has better effects, and under the situation that guarantees purity, also because having saved preparation process or having simplified synthetic route and reduced preparation cost.
The invention will be further described below in conjunction with embodiment.
Embodiment
One, a kind of ursolic acid derivative, the 3-position of ursolic acid parent is 3 β-acetoxyl group in this derivant structure, among the present invention, be 28-acyl (8 '-aminocaprylic acid) in the 28-position of ursolic acid parent, this ursolic acid derivative is 3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl (8 '-aminocaprylic acid), and its structural formula I is:
Perhaps, be 28-acyl (4 '-amino butanol) in the 28-position of parent ursolic acid, this ursolic acid derivative is 3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl (4 '-amino butanol), its structural formula II is:
Two, a kind of preparation method of ursolic acid derivative, what this method prepared is this embodiment one described ursolic acid derivative; This method has following preparation process:
(1) with ursolic acid and acetic anhydride, generates the 3-O-acetyl ursolic acid the hydroxyl on the ursolic acid 3-position is carried out the acetylize protection;
(2) with 3-O-acetyl ursolic acid and oxalyl chloride reaction, generate 3-O-acetyl black bearberry alkane-28-acyl chlorides intermediate to modify in the 28-position;
(3) 3-O-acetyl black bearberry alkane-28-acyl chlorides intermediate is generated the ursolic acid derivative as one of reactant;
In the present invention, the described 3-O-acetyl of step (3) black bearberry alkane-28-acyl chlorides intermediate is not have purified crude product, and another reactant in this step (3) is 8-aminocaprylic acid (H
2NCH
2CH
2CH
2CH
2CH
2CH
2CH
2COOH) or 4-amino butanol (NH
2CH
2CH
2CH
2CH
2OH), its concrete steps are as follows:
(3-1) with methylene dichloride (CH
2Cl
2) 3-O-acetyl black bearberry alkane-28-acyl chlorides intermediate crude product is fully dissolved;
(3-2) in gained solution, add catalyst of triethylamine ［ N (CH
2CH
3)
3And fully mix, add 8-aminocaprylic acid or the 4-amino butanol of required reacting weight then; At 20～30 ℃ of following stirring reactions; Wherein, the molar weight of catalyst of triethylamine is no less than the molar weight of 3-O-acetyl black bearberry alkane-28-acyl chlorides (catalyst consumption is can appropriateness excessive, to improve speed of reaction; But to be no more than the twice degree of being of 3-O-acetyl black bearberry alkane-28-acyl chlorides molar weight, too much consumption will cause unnecessary waste.In this catalyst levels scope, its reaction times is generally 12～24 hours);
Reaction is washed, afterwards separatory after finishing again;
(3-3) with anhydrous sodium sulphate (Sodium sulfate anhydrous.min(99), the Na of gained organic phase behind the separatory with capacity
2SO
4) drying, then concentrating under reduced pressure and 3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl (8 '-aminocaprylic acid) crude product or 3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl (4 '-amino butanol) crude product (obviously, the actual amount of anhydrous sodium sulphate, with can guarantee described " drying " can be relatively good and carry out degree of being soon);
(3-4) described crude product is crossed post with 300～400 order silica gel, pulverous 3 β that must the be white in color-acetoxyl group-black bearberry alkane-12-alkene-pure product of 28-acyl (8 '-aminocaprylic acid), the pulverous 3 β-acetoxyl group-black bearberry alkane-12-alkene-pure product of 28-acyl (4 '-amino butanol) that must be white in color maybe; Wherein, crossing post, to separate 3 β-acetoxyl group-black bearberry alkane-12-alkene-used eluent of 28-acyl (8 '-aminocaprylic acid) be the mixed solution of methylene dichloride and methyl alcohol, its volume ratio is, methylene dichloride: methyl alcohol=50: 1, crossing post, to separate 3 β-acetoxyl group-black bearberry alkane-12-alkene-used eluent of 28-acyl (4 '-amino butanol) be the mixed solution of ethyl acetate and sherwood oil, its volume ratio is, ethyl acetate: sherwood oil=2: as can be known, sherwood oil is only got getting final product of 30～60 ℃ of boiling range specifications to 1(those skilled in the art from above-mentioned steps).
Further, for obtaining better effect, in this embodiment, the described 3-O-acetyl ursolic acid of step (1) is made by following method:
Pyridine (Pyridine, C with ursolic acid and capacity
5H
5N) mix, stir and be warmed up to 100 ℃ to allow ursolic acid be dissolved in the pyridine fully; Drip excessive acetic anhydride via again, and remain on and allow ursolic acid and acetic anhydride under 100 ℃ of states;
It will be apparent to those skilled in the art that ursolic acid is dissolved in purpose in the pyridine, is for guaranteeing that the reaction between ursolic acid and the diacetyl oxide can normally carry out; With the purpose of excessive acetic acid acid anhydride, it is the product that obtains for whole ursolic acid can both be participated in reacting as much as possible.Therefore, the excessive degree of the consumption of pyridine, diacetyl oxide all should be can achieve the above object to degree---in this case, its reaction times is generally 4～5 hours.
After reaction finishes, with (consumption of frozen water mixed solution is can make fully degree of being cooled to of reaction solution, and its amount can suitably increase) in the reaction solution impouring frozen water mixed solution, filter, and water is washed till the non-pyridine flavor repeatedly, dry the 3-O-ethanoyl ursolic acid of white powder.
Specify, by above-mentioned filter repeatedly, wash after, unnecessary diacetyl oxide also has been removed already, namely in this step products 3-O-ethanoyl ursolic acid, does not contain the diacetyl oxide that does not participate in reaction in addition.
In this embodiment, the described 3-O-acetyl of step (2) black bearberry alkane-28-acyl chlorides intermediate is made by following method:
3-O-ethanoyl ursolic acid is dissolved in the methylene dichloride of capacity fully, add again excessive oxalyl chloride oxalyl chloride, (COCl)
2, under room temperature, stir, so that 3-O-ethanoyl ursolic acid and oxalyl chloride reaction;
It will be apparent to those skilled in the art that 3-O-ethanoyl ursolic acid is dissolved in purpose in the methylene dichloride, equally also is can normally carry out in order to ensure the reaction between 3-O-ethanoyl ursolic acid and the oxalyl chloride; With the purpose of excessive oxalul chloride, also be the product that obtains for whole 3-O-ethanoyl ursolic acid all participate in reacting as much as possible certainly.Therefore, the excessive degree of the consumption of methylene dichloride, oxalyl chloride all should be can achieve the above object to degree---in this case, its reaction times is generally 12～24 hours;
Reaction is removed methylene dichloride and unnecessary oxalyl chloride after finishing, and gets 3-O-acetyl black bearberry alkane-28-acyl chlorides intermediate crude product;
At last, or 3-O-acetyl black bearberry alkane-28-acyl chlorides intermediate crude product purified with standby, or be that raw material removes to prepare the ursolic acid derivative with described crude product directly.
For those skilled in the art can be expressly understood the present invention more, again according to step (1), (2), (3) in proper order, that the reaction formula disclosure of each step is as follows.
Step (1):
Step (2):
Step (3):
Perhaps:
The present invention has passed through the verification experimental verification in laboratory.Method and the step of two kinds of ursolic acid derivatives of preparation are identical with the step of this embodiment.During checking, at first two kinds of ursolic acid derivatives have been tested respectively with nuclear magnetic resonance analyser
1HNMR and
13The CNMR spectrogram.
3 β-acetoxyl group-black bearberry alkane-12 alkene-28-acyl (8 '-aminocaprylic acid)
1HNMR and
13CNMR is as follows:
1HNMR(400MHz,CDCl
3)：δ0.77(3H,?s);?0.87(9H,?s)?;?0.95(6H,?s);?1.06(3H,?s);?(7×CH
3);?2.05(3H,?s,?CH
3CO);?2.33(2H,t,?J=7.2Hz?H-7’);?2.99(1H,?m,?Ha-1’);?3.33(1H,?m,?Hb-1’);?4.50(1H,t,H-3);?5.30(1H,?H-12);?5.92(1H,?t-like,?NH)。
13CNMR(100MHz,CDCl
3)：
δ178.2(C-28),?171.0(-COOH),?140.0(C-13),?125.4(C-12),?80.8(C-3)。
3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl (4 '-amino butanol)
1HNMR and
13CNMR is as follows:
1HNMR(400MHz,CDCl
3)：δ0.78(3H,?s);?0.85(9H,?s)?;?0.95(6H,?s);?1.07(3H,?s);?(7×CH
3);?2.01(3H,?s,?CH
3CO);?3.01(1H,?m,?Ha-1’);?3.41(1H,?m,?Hb-1’);?3.67(2H,t,?H-3’);?4.49(1H,t,H-3);?5.31(1H,?H-12);?6.02(1H,?NH)。
13CNMR(100MHz,CDCl
3)：
δ178.2(C-28),?171.0(CH
3 CO),?139.9(C-13),?125.4(C-12),?80.8(C-3),?62.2(-CH
2OH)。
From above-mentioned
1HNMR and
13Among the CNMR as can be known the structure of two compounds be our required target compound structure.
Then, adopt MTT ［ 3-(4,5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole bromine salt, trade(brand)name: tetrazolium bromide ］ staining, at the inhibition result of the sick U937 cell proliferation of human white blood, carried out contrast verification with two kinds of ursolic acid derivatives that make and ursolic acid.Checking the results are shown in following table:
Inhibiting rate from proof list as can be seen, two kinds of ursolic acid derivatives of the present invention are suppressing aspect the sick U937 cell proliferation of human white blood, the effect of several concentration all is better than ursolic acid; Especially from concentration be 3 β-acetoxyl group-black bearberry alkane-12 alkene-28-acyl (8 '-aminocaprylic acid) specific concentration of 10 μ mol be 20 μ mol ursolic acid inhibiting rate also high this contrast as can be seen,, can obtain than faster, the better inhibition of ursolic acid with ursolic acid derivative of the present invention than under the serious situation in the sick U937 cell proliferation of human white blood; Not really under the serious situation, the actual amount of ursolic acid derivative of the present invention can obtain than ursolic acid still less, and then can save the treatment cost again in the sick U937 cell proliferation of human white blood.
Claims (4)
1. ursolic acid derivative, the 3-position of ursolic acid parent is 3 β-acetoxyl group in this derivant structure, it is characterized in that, be 28-acyl (8 '-aminocaprylic acid) in the 28-position of described ursolic acid parent, its structural formula is formula I:
Perhaps, be 28-acyl (4 '-amino butanol) in the 28-position of described parent ursolic acid, its structural formula is formula II:
2. the preparation method of a ursolic acid derivative as claimed in claim 1, this method has following preparation process:
(1) with ursolic acid and acetic anhydride, generates the 3-O-acetyl ursolic acid the hydroxyl on the ursolic acid 3-position is carried out the acetylize protection;
(2) with 3-O-acetyl ursolic acid and oxalyl chloride reaction, generate 3-O-acetyl black bearberry alkane-28-acyl chlorides intermediate to modify in the 28-position;
(3) 3-O-acetyl black bearberry alkane-28-acyl chlorides intermediate is generated described ursolic acid derivative as one of reactant;
It is characterized in that the described 3-O-acetyl of step (3) black bearberry alkane-28-acyl chlorides intermediate is not have purified crude product, another reactant in this step (3) is 8-aminocaprylic acid or 4-amino butanol, and its concrete steps are as follows:
(3-1) with methylene dichloride described 3-O-acetyl black bearberry alkane-28-acyl chlorides intermediate crude product is fully dissolved;
(3-2) in gained solution, add catalyst of triethylamine and fully mixing, add 8-aminocaprylic acid or the 4-amino butanol of required reacting weight then; At 20～30 ℃ of following stirring reactions; Wherein, the molar weight of described catalyst of triethylamine is no less than the molar weight of 3-O-acetyl black bearberry alkane-28-acyl chlorides;
Reaction is washed, afterwards separatory after finishing again;
(3-3) with gained organic phase behind the separatory with the anhydrous sodium sulfate drying of capacity, then concentrating under reduced pressure and the ursolic acid derivative crude product of the described formula I of claim 1 or formula II;
(3-4) described crude product is crossed post with 300～400 order silica gel, get the pure product of ursolic acid derivative of all the be white in color described formula I of pulverous claim 1 or formula II; Wherein, the used eluent of ursolic acid derivative of crossing the described formula I of post separation claim 1 is the mixed solution of methylene dichloride and methyl alcohol, its volume ratio is, methylene dichloride: methyl alcohol=50: 1, the used eluent of ursolic acid derivative of crossing the described formula II of post separation claim 1 is the mixed solution of ethyl acetate and sherwood oil, its volume ratio is ethyl acetate: sherwood oil=2: 1.
3. according to the preparation method of the described ursolic acid derivative of claim 2, it is characterized in that the described 3-O-acetyl ursolic acid of step (1) is made by following method:
Ursolic acid is mixed with the pyridine of capacity, stir and be warmed up to 100 ℃ to allow ursolic acid be dissolved in the pyridine fully; Drip excessive acetic anhydride via again, and remain on and allow described ursolic acid and acetic anhydride under 100 ℃ of states;
After reaction finishes, in reaction solution impouring frozen water mixed solution, filter, and water is washed till the non-pyridine flavor repeatedly, dry the 3-O-ethanoyl ursolic acid of white powder.
4. according to the preparation method of claim 2 or 3 described ursolic acid derivatives, it is characterized in that the described 3-O-acetyl of step (2) black bearberry alkane-28-acyl chlorides intermediate is made by following method:
3-O-ethanoyl ursolic acid is dissolved in the methylene dichloride of capacity fully, adds excessive oxalyl chloride again, under room temperature, stir, so that described 3-O-ethanoyl ursolic acid and oxalyl chloride reaction;
Reaction is removed methylene dichloride and unnecessary oxalyl chloride after finishing, and gets 3-O-acetyl black bearberry alkane-28-acyl chlorides intermediate crude product;
At last, or 3-O-acetyl black bearberry alkane-28-acyl chlorides intermediate crude product purified with standby, or be that raw material removes to prepare described ursolic acid derivative with described crude product directly.
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| CN104045678B (en) * | 2014-04-01 | 2016-03-02 | 广东工业大学 | Urson chemical modification object and its preparation method and application |
| CN107522766B (en) * | 2017-08-21 | 2020-03-27 | 南京林业大学 | Ursolic acid quinolyl hydrazide derivatives with anti-tumor activity and preparation method and application thereof |
| CN107698650A (en) * | 2017-10-26 | 2018-02-16 | 海南大学 | The extraction process of ursolic acid in a kind of old leaves of Kudingcha |
| CN113185567A (en) * | 2021-05-12 | 2021-07-30 | 张洪胜 | Ursolic acid derivative for treating rheumatoid arthritis and preparation method thereof |
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| WO2007002411A1 (en) * | 2005-06-22 | 2007-01-04 | Myriad Genetics, Inc. | Antiviral compounds |
| CN101157715A (en) * | 2007-11-20 | 2008-04-09 | 沈阳化工学院 | Ursolic acid chemical modified compound amino alcohol having antitumor activity |
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| CN101157715A (en) * | 2007-11-20 | 2008-04-09 | 沈阳化工学院 | Ursolic acid chemical modified compound amino alcohol having antitumor activity |
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