CN102492014A - Preparation method of tanshinone IIA tocopheryl acid phenolic ester derivative - Google Patents
Preparation method of tanshinone IIA tocopheryl acid phenolic ester derivative Download PDFInfo
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- CN102492014A CN102492014A CN2011104328219A CN201110432821A CN102492014A CN 102492014 A CN102492014 A CN 102492014A CN 2011104328219 A CN2011104328219 A CN 2011104328219A CN 201110432821 A CN201110432821 A CN 201110432821A CN 102492014 A CN102492014 A CN 102492014A
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- tanshinone iia
- phenolic ester
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- tocopheryl acid
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Abstract
The invention provides a tanshinone IIA tocopheryl acid phenolic ester derivative and a preparation method thereof. The method comprises the following steps of: dissolving tanshinone IIA into an organic solvent; performing hydrogenation reduction; adding succinyl oxide; adding an alkaline catalyst of the tanshinone IIA; reacting and performing column chromatography separation and purification; and eluting with petroleum ether and ethyl acetate in the ratio of 9:1 to obtain a target product. In the method, a one-step reaction is undergone, so that an intermediate is not required to be separated or purified, and tocopheryl acid molecules are introduced into a matrix structure of the tanshinone IIA through an ester bond. According to the property that a terminal carboxyl group of the tocopheryl acid is salified with an alkali, an organic salt with high water solubility can be formed with the alkali, and a plurality of dosage forms such as injections and the like can be prepared conveniently, so that bioavailability is increased, and a drug effect is brought into play quickly in vivo. Compounds of the type can be transformed into tanshinone IIA in vivo, so that a treatment effect is achieved. The method has a reasonable design, a simple and convenient process and low cost, and is suitable for industrial production. The tanshinone IIA tocopheryl acid phenolic ester derivative can be used for preparing important prodrugs for treating tumors, cardiovascular and cerebrovascular diseases, and the like.
Description
Technical field
The invention belongs to pharmacy field, relate to a kind of preparation method of tanshinone IIA succsinic acid phenol ester derivative, this tanshinone IIA succsinic acid phenol ester derivative can be used as the prodrug of preparation treatment tumour, cardiovascular and cerebrovascular diseases.
Background technology
Tanshinone IIA is one of effective constituent main in the red sage root; In recent years it is furtherd investigate discovery; That tanshinone IIA has is more extensive, outstanding biological activity, as can suppress Ang II institute inductive cardiac cellular apoptosis and hypertrophy (Xie Hui, Zheng Zhi. tanshinone IIA is to myocardial cell's hypertrophy of hypertensin, the influence of apoptosis. the hypertension magazine; 2004; 12 (4): 359), significantly improve spontaneous hypertensive rat left ventricular hypertrophy (clock is strong for Liu Feng, Zheng Zhi. tanshinone IIA is to the influence of spontaneous hypertensive rat left ventricular hypertrophy apoptosis of cardiac muscle.The practical traditional Chinese and western medicine magazine of China; 2004; 17 (8): 1096), the restraining effect to lipid peroxidation due to the rats'liver stellate cell oxidative stress shows significant anti-hepatic fibrosis effect (Yang Wei peak on cell levels; Chen Houchang, Xia Bijun. tanshinone IIA is to the influence of HSCs propagation and secretory cell epimatrix.Practical medical journal; 2003; 19 (11): 1191) and through improving mitochondrial energy metabolism after brain, antioxygenation to cerebral ischemia re-pouring injured provide protection (Hu Xiamin; Careful younger sister, Hu Xianmin, Wang Jun. tanshinone IIA reaches the influence to energy metabolism to the provide protection of cerebral ischemia re-pouring rat brain damage.China's clinical pharmacy magazine, 2006,15 (3), 176-179).Experiment shows that it is to mammary cancer (Lu Q, Zhang P; Zhang X, Chen J. Experimental study of the anti-cancer mechanism of tanshinone IIA against human breast cancer. International Journal of Molecular Medicine. 2009,24 (6); 773-780), white blood disease (Zhou LL, Chan WK, Xu NH; Xiao K, Luo, HW; Luo K Q, Chang DC. Tanshinone IIA, an isolated compound from
Salvia miltiorrhizaBunge, induces apoptosis in HeLa cells through mitotic arrest. Life Sciences, 2008,83 (11-12) 394-403.) wait tumor disease also to demonstrate therapeutic value preferably.Deep expansion along with research is expected tanshinone IIA is developed to the new drug that cardiovascular and cerebrovascular diseases, tumour etc. is had good therapeutic action.The Tanshinone II A structural formula is:
Yet the critical defect of naturally occurring tanshinone IIA is that bioavailability is extremely low, trace it to its cause, and the one, because poorly water-soluble causes absorption difference, this is inseparable with its constructional feature.Tanshinone IIA is as a diterpene quinone; It is a planar molecule that hydrophobicity is very strong; Polarity is very little, and almost insoluble in water, solubleness is also little in methyl alcohol, ethanol; Only in some weakly polar organic solvents such as chloroform, ETHYLE ACETATE, ether etc., have solubleness preferably, these characteristics have greatly limited clinical application.Its two be since tanshinone IIA behind oral administration, have serious first pass effect of hepar; Plasma Concentration is extremely low after causing getting into blood circulation; Its bioavailability is less than 3.5% (Haiping Hao, Guangji Wang, Nan Cui; Et al. Pharmacokinetics, Absorption and Tissue Distribution of Tanshinone IIA Solid Dispersion [J]. Plant Med. 2006. 72:1311-1317.).Therefore have only through drug administration by injection and just can overcome this shortcoming.Have at present sodium tanshinone IIA sulfate salt is made in the Tanshinone II A sulfonation, administrated by injection can reduce MCO, dwindles myocardial infarction area, clinically various types of stenocardia is all had certain improvement effect.Yet its sulfonate sodium is an ionic compound, and difficult biofilm structure system through being the basis with lipid and protein component is unfavorable for bringing into play its wide range of therapeutic effect.
Summary of the invention
The objective of the invention is for overcoming above-mentioned technological deficiency; Utilization prodrug principle of design provides a kind of tanshinone IIA succsinic acid phenolic ester analog derivative and preparation method thereof, realizes through following scheme: tanshinone IIA is dissolved in organic solvent (according to weight (g)/volume (ml) than 1:10-1:100); Through behind the hydro-reduction; Add succinyl oxide according to mol ratio 1:1.1-1:1.5, add the basic catalyst of tanshinone IIA quality 10-300% again, after reaction is accomplished through column chromatographic isolation and purification; With sherwood oil: ETHYLE ACETATE 9:1 wash-out obtains the title product of tanshinone IIA succsinic acid phenolic ester.
Described organic solvent is selected from one or more in acetone, methylene dichloride, ETHYLE ACETATE, THF, the ether.
Described hydro-reduction method comprises palladium carbon/hydrogen reducing, Raney Ni and adding zinc powder reduction.The basic catalyst that adds comprises DMAP, triethylamine, pyridine, N, accelerine or N, N-diisopropylethylamine etc.
Technical scheme of the present invention is shown in following reaction formula:
The present invention is through single step reaction, and midbody need not separation and purification, through ester bond succinic acid molecules is introduced in the tanshinone IIA precursor structure.Utilize the salifiable character of succsinic acid terminal carboxyl(group) and alkali, can form water-soluble good organic salt, can process multiple formulations such as injection easily, thereby improve bioavailability, bring into play drug effect in vivo fast with alkali.This compounds can be converted into tanshinone IIA in vivo, the performance therapeutic action.This method is reasonable in design, and technology is easy, cost is low, is fit to suitability for industrialized production.Can be used as the important prodrug of preparation treatment tumour, cardiovascular and cerebrovascular diseases etc.
Embodiment
Further specify the present invention through embodiment below.The following embodiment of mandatory declaration is used for explaining better the present invention rather than limitation of the present invention.
Embodiment 1
Tanshinone IIA (1g) is dissolved in THF (10-30 ml), adds 0.9g DMAP, the 0.6g zinc powder; Add the 0.8g succinyl oxide simultaneously, the nitrogen protection refluxed is spent the night, and treats that solution becomes nearly colourless stopped reaction; Remove by filter zinc powder, concentrate to remove and desolvate, through silica gel column chromatography; With sherwood oil: ETHYLE ACETATE 9:1 wash-out obtains target compound.The spectral data of this compound is following:
Embodiment 2
Tanshinone IIA (0.3g) is dissolved in ETHYLE ACETATE (10-20 ml), adds the palladium carbon of 15mg10%, feed hydrogen, treat that solution becomes the nearly hydrogen that removes when colourless; Change nitrogen protection into, add 0.2g succinyl oxide, N simultaneously, the N-diisopropylethylamine continues back flow reaction; Treat that solution becomes nearly colourless stopped reaction, remove by filter palladium carbon, concentrate to remove and desolvate; Through silica gel column chromatography, with sherwood oil: ETHYLE ACETATE 9:1 wash-out obtains target compound.The spectral data of compound is seen embodiment 1.
Embodiment 3
Tanshinone IIA (3g) is dissolved in ether (50-100 ml), adds the palladium carbon of 150mg10%, feed hydrogen; Treating that solution becomes closely removes hydrogen when colourless, changes nitrogen protection into, adds the 2g succinyl oxide simultaneously, the 5ml triethylamine continues back flow reaction; Treat that solution becomes nearly colourless stopped reaction, remove by filter palladium carbon, concentrate to remove and desolvate; Through silica gel column chromatography, with sherwood oil: ETHYLE ACETATE 9:1 wash-out obtains target compound.The spectral data of compound is seen embodiment 1.
Embodiment 4
Tanshinone IIA (1g) is dissolved in acetone (30-50 ml), adds the 3ml pyridine, the 0.6g zinc powder; Add the 0.8g succinyl oxide simultaneously, the nitrogen protection refluxed is spent the night, and treats that solution becomes nearly colourless stopped reaction; Remove by filter zinc powder, concentrate to remove and desolvate, through silica gel column chromatography; With sherwood oil: ETHYLE ACETATE 9:1 wash-out obtains target compound.The spectral data of compound is seen embodiment 1.
Embodiment 5
Tanshinone IIA (3g) is dissolved in methylene dichloride (100-120 ml), adds 5ml N, accelerine; The 2g zinc powder adds 2.6 g succinyl oxides simultaneously, and the nitrogen protection refluxed is spent the night; Treat that solution becomes nearly colourless stopped reaction, remove by filter zinc powder, concentrate to remove and desolvate; Through silica gel column chromatography, with sherwood oil: ETHYLE ACETATE 9:1 wash-out obtains target compound.The spectral data of compound is seen embodiment 1.
Embodiment 6
Tanshinone IIA (1g) is dissolved in THF (30-60 ml), adds the 15mg Raney Ni, feed hydrogen; Treating that solution becomes closely removes hydrogen when colourless, changes nitrogen protection into, adds 0.5g succinyl oxide and 0.5g DMAP simultaneously and continues back flow reaction; Treat that solution becomes nearly colourless stopped reaction, remove by filter Raney Ni, concentrate to remove and desolvate; Through silica gel column chromatography, with sherwood oil: ETHYLE ACETATE 9:1 wash-out obtains target compound.The spectral data of compound is seen embodiment 1.
Claims (3)
1. tanshinone IIA succsinic acid phenolic ester analog derivative and preparation method thereof is characterized in that, realizes through following scheme: by weight/and volume ratio is 1:10-1:100; Tanshinone IIA is dissolved in the organic solvent; Through behind the hydro-reduction, add succinyl oxide according to mol ratio 1:1.1-1:1.5, add the basic catalyst of tanshinone IIA quality 10-300% again; After reaction is accomplished through column chromatographic isolation and purification; With sherwood oil: ETHYLE ACETATE 9:1 wash-out, obtain the title product of tanshinone IIA succsinic acid phenolic ester, reaction formula is:
2. a kind of tanshinone IIA succsinic acid phenolic ester analog derivative according to claim 1 and preparation method thereof is characterized in that organic solvent is selected from one or more in acetone, methylene dichloride, ETHYLE ACETATE, THF, the ether.
3. a kind of tanshinone IIA succsinic acid phenolic ester analog derivative according to claim 1 and preparation method thereof; It is characterized in that; Described hydro-reduction method is selected palladium carbon/hydrogen reducing for use, Raney Ni and adding zinc powder reduction, and the basic catalyst of adding is selected DMAP, triethylamine, pyridine, N for use; Accelerine or N, the N-diisopropylethylamine.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103382214A (en) * | 2013-07-29 | 2013-11-06 | 上海朗萨医药科技有限公司 | Tanshinone IIA phosphate phenolic ester derivative and preparation process thereof |
| CN103980341A (en) * | 2014-06-05 | 2014-08-13 | 上海朗萨医药科技有限公司 | Amino acid tanshinone phenolic ester derivatives and preparation method thereof |
| CN105884856A (en) * | 2014-11-05 | 2016-08-24 | 中国药科大学 | Application of tanshinone II A derivative in drugs |
| CN117487154A (en) * | 2023-10-31 | 2024-02-02 | 暨南大学 | Tanshinone derivative and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102079774A (en) * | 2010-12-13 | 2011-06-01 | 中山大学 | Niacin salvia miltiorrhiza phenolic ester derivative, preparation method and application thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102079774A (en) * | 2010-12-13 | 2011-06-01 | 中山大学 | Niacin salvia miltiorrhiza phenolic ester derivative, preparation method and application thereof |
Non-Patent Citations (3)
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| 孙存济，等: "丹参酮有关化合物的合成", 《药学学报》 * |
| 林峰: "《精细有机合成技术》", 31 August 2009 * |
| 沙鸥，等: "植物甾醇琥珀酸酐酯化产物的分析表征", 《中国油脂》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103382214A (en) * | 2013-07-29 | 2013-11-06 | 上海朗萨医药科技有限公司 | Tanshinone IIA phosphate phenolic ester derivative and preparation process thereof |
| CN103382214B (en) * | 2013-07-29 | 2016-03-02 | 上海朗萨医药科技有限公司 | A kind of Tanshinone II A phosphoric acid phenol ester derivative and preparation method thereof |
| CN103980341A (en) * | 2014-06-05 | 2014-08-13 | 上海朗萨医药科技有限公司 | Amino acid tanshinone phenolic ester derivatives and preparation method thereof |
| CN105884856A (en) * | 2014-11-05 | 2016-08-24 | 中国药科大学 | Application of tanshinone II A derivative in drugs |
| CN117487154A (en) * | 2023-10-31 | 2024-02-02 | 暨南大学 | Tanshinone derivative and preparation method and application thereof |
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Application publication date: 20120613 |