CN104926764A - Method for preparing dimethyl lithospermate B - Google Patents
Method for preparing dimethyl lithospermate B Download PDFInfo
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- CN104926764A CN104926764A CN201510408043.8A CN201510408043A CN104926764A CN 104926764 A CN104926764 A CN 104926764A CN 201510408043 A CN201510408043 A CN 201510408043A CN 104926764 A CN104926764 A CN 104926764A
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- salvianolic acid
- dimethyl ester
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- alkali
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing dimethyl lithospermate B. The method for preparing the dimethyl lithospermate B aims at being simple in operation process, good in product purity and high in productivity. According to the technical scheme, the method comprises the steps that 1, danshinolic acid B, iodomethane and alkali are weighed out according to the mole ratio of 1:1-5:1-5; 2, the danshinolic acid B, iodomethane and alkali weighed out in the step 1 are dissolved in solvents, the reaction time is one hour to 20 hours at the temperature of 25 DEG C to 50 DEG C, and a crude product of the dimethyl lithospermate B is obtained; 3, the crude product of the dimethyl lithospermate B prepared in the step 2 is cooled, water is added, then organic solvents are used for extraction, organic phases are combined, a saturated salt solution is used for washing, the solvents are steamed to be removed, then washing and petroleum ether washing are carried out in sequence, liquid is removed, little educt is dissolved through ethyl acetate, vacuum concentration is carried out, and a finished product of the dimethyl lithospermate B is obtained. The method belongs to the technical field of organic synthesis.
Description
Technical field
The present invention relates to a kind of preparation method of salvianolic acid B derivative, specifically, relate to a kind of preparation method of salvianolic acid B dimethyl ester, belong to technical field of organic synthesis.
Background technology
Salvianolic acid B is the soluble salvianolic acid active component extracted from salviamiltiorrhizabung, to tumour, chronic disease, cancer, cardiovascular disorder, anti-virus, neural liver cell increment, shock etc. has prevention, result for the treatment of, but " the salvianolic acid B stability study in aqueous " of the people such as Zhang Wenxin (Beijing University of Chinese Medicine's journal, 2009 years the 32nd volume the 12nd phases); " stability of salvianolic acid B and mechanism of degradation progress thereof " (Chinese Chinese materia medica information magazine, 2010 years the 17th volume the 12nd phases) of the people such as Zhu Jin wall; " heating pH value is on the impact of salvianolic acid B stability in the red sage root " (Chinese Chinese materia medica academic periodical of the people such as Shen Jianfang, 28th volume the 7th phase in 2010), point out that salvianolic acid B polarity is large, lipotropy difference and structural instability, this brings very large puzzlement to application.
Salvianolic acid B dimethyl ester is the structural modification thing of salvianolic acid B, stability is better, lipotropy is strong, but salvianolic acid B dimethyl ester mainly extracts from some natural products at present, the people's such as Wu Zhijun " polyphenolic compound of S. przewalskii " (Yunnan plant is studied, 21 volume 4 phases in 1999), " water soluble component of kidney tea " (Chinese natural drug of the people such as Wang Min, 5 volume 1 phases in 2007), " Herba Salviae Chinensis chemical constitution study " (CHINA JOURNAL OF CHINESE MATERIA MEDICA of the people such as Gao Junfeng, 38 volume 10 phases in 2013), but the equal extraction process of these methods is complicated, obtain the purity of product, yield is low, limit the application of salvianolic acid B dimethyl ester to a great extent.
Summary of the invention
For above-mentioned deficiency, the object of the present invention is to provide a kind of operating procedure simple, good product purity, the preparation method of the salvianolic acid B dimethyl ester that productive rate is high.
For solving the problems of the technologies described above, technical scheme provided by the invention is such:
The preparation method of described salvianolic acid B dimethyl ester, comprises the steps: successively
1) 1:1 ~ 5:1 ~ 5 take salvianolic acid B, methyl iodide, alkali respectively in molar ratio;
2) by step 1) salvianolic acid B that takes, methyl iodide, alkali dissolution in solvent, be 1-20 hour 25-50 DEG C of reaction times, obtain salvianolic acid B dimethyl ester crude product;
3) by step 2) cooling of the salvianolic acid B dimethyl ester crude product prepared, add water, then use organic solvent extraction, merge organic phase, wash with saturated common salt, steaming desolventizes, more successively through washing, sherwood oil is washed, then liquid is discarded, precipitate uses acetic acid ethyl dissolution on a small quantity, concentrating under reduced pressure, obtains salvianolic acid B dimethyl ester finished product.
Further, the preparation method of above-mentioned salvianolic acid B dimethyl ester, is characterized in that, described alkali is one of them or arbitrary combination of sodium hydroxide or potassium hydroxide or sodium carbonate or sodium bicarbonate or saleratus.
Further, the preparation method of above-mentioned salvianolic acid B dimethyl ester, described organic solvent be methyl-sulphoxide or DMF one of them.
Compared with prior art, the present invention can obtain the high product of purity by chemical synthesis, and yield reaches 80%, and for suitability for industrialized production provides feasible way, the product stability of gained is good, has positive meaning to raising bioavailability.
Accompanying drawing explanation
Fig. 1 is salvianolic acid B dimethyl ester prepared by the present invention
1h-NMR schemes;
Fig. 2 is salvianolic acid B dimethyl ester prepared by the present invention
13c-NMR schemes;
Fig. 3 is that salvianolic acid B dimethyl ester ESI-HRMS prepared by the present invention schemes.
Embodiment
Below in conjunction with embodiment; claim of the present invention is described in further detail; but do not form any limitation of the invention, the amendment of anyone limited number of time made within the claims in the present invention scope, still within claims of the present invention.
The reaction equation of salvianolic acid B dimethyl ester provided by the invention is as follows:
Embodiment 1
Get 2.00g salvianolic acid B and be dissolved in 30mlN, in dinethylformamide, add 0.56g saleratus and 0.88g methyl iodide under room temperature, be heated to 40 DEG C of reaction 3h, naturally cooling, add water 100ml, use 100ml extraction into ethyl acetate again three times, merge organic phase saturated common salt and wash, steaming desolventizes, oily matter is had to separate out, through washing, sherwood oil is washed, and after acetic acid ethyl dissolution, sherwood oil is separated out, discard liquid, repeat 3 times, precipitate uses acetic acid ethyl dissolution on a small quantity, concentrating under reduced pressure, obtain faint yellow indefiniteness powder, yield 83%.
Embodiment 2
Getting 2.00g salvianolic acid B is dissolved in 30ml methyl-sulphoxide, 0.78g potassium hydroxide and 1.0g methyl iodide is added under room temperature, be heated to 40 DEG C of reaction 3h, naturally cooling, adds water 100ml, then uses 100ml extraction into ethyl acetate three times, merge organic phase saturated common salt to wash, steaming desolventizes, and has oily matter to separate out, through washing, sherwood oil is washed, after acetic acid ethyl dissolution, sherwood oil is separated out, and discards liquid, repeats 3 times, precipitate uses acetic acid ethyl dissolution on a small quantity, concentrating under reduced pressure, obtains faint yellow indefiniteness powder, yield 89%.
Embodiment 3
Getting 2.00g salvianolic acid B is dissolved in 30ml methyl-sulphoxide, 0.24g sodium hydroxide and 1.59g methyl iodide is added under room temperature, be heated to 40 DEG C of reaction 3h, naturally cooling, adds water 100ml, then uses 100ml extraction into ethyl acetate three times, merge organic phase saturated common salt to wash, steaming desolventizes, and has oily matter to separate out, through washing, sherwood oil is washed, after acetic acid ethyl dissolution, sherwood oil is separated out, and discards liquid, repeats 3 times, precipitate uses acetic acid ethyl dissolution on a small quantity, concentrating under reduced pressure, obtains faint yellow indefiniteness powder, yield 94%.
Embodiment 4
Get 2.00g salvianolic acid B and be dissolved in 30mlN, in dinethylformamide, add 0.24g sodium bicarbonate and 1.5g methyl iodide under room temperature, be heated to 40 DEG C of reaction 3h, naturally cooling, add water 100ml, use 100ml extraction into ethyl acetate again three times, merge organic phase saturated common salt and wash, steaming desolventizes, oily matter is had to separate out, through washing, sherwood oil is washed, and after acetic acid ethyl dissolution, sherwood oil is separated out, discard liquid, repeat 3 times, precipitate uses acetic acid ethyl dissolution on a small quantity, concentrating under reduced pressure, obtain faint yellow indefiniteness powder, yield 87%.
Below in conjunction with Fig. 1 to Fig. 3, prove that the material of preparation in inventive embodiments 1 to 4 is salvianolic acid B dimethyl ester:
Fig. 1:
1h-NMR (600MHz.d-DMSO): δ 2.88-2.94 (m, 4H ,-2CH
2-), 3.53-3.58 (m, 6H ,-2OCH
3-), 4.46,5.65 (d, d 2H, furan nucleus H), 5.12 (m, 2H,-2CH-), 7.32,7.62 (d, d, 2H ,-CH=CH), 6.54-6.83 (m, 11H, Ar-H), 8.71-10.11 (m, 7H, phenyl ring phenolic group H).
Fig. 2:
13c-NMR (600MHz.d-DMSO): δ 142.70,144.12,144.98,144.99,145.40,145.69,147.13,163.08,165.74 (CH=CH-), 112.50,114.75,115.44,115.51,116.43,116.56,116.93,117.40,120.10,120.91,122.44,124.94,126.20,126.53,131.15 (CH=CH-), 72.97,73.86 (-2CH-), 35.80,36.17 (-2CH-), 54.71,85.80 (-2CH-), 51.91,52.00 (-OCH
3-), 169.09,169.86,170.23,170.36 (-CO-)
Fig. 3: ESI-HRMS:m/z 745.55 [M-H], composition graphs 1 to Fig. 3 can determine that molecular formula is: C
38h
34o
16.
Claims (4)
1. a preparation method for salvianolic acid B dimethyl ester, is characterized in that, comprises the steps: successively
1) 1:1 ~ 5:1 ~ 5 take salvianolic acid B, methyl iodide, alkali respectively in molar ratio;
2) by step 1) salvianolic acid B that takes, methyl iodide, alkali dissolution in solvent, be 1-20 hour 25-50 DEG C of reaction times, obtain salvianolic acid B dimethyl ester crude product;
3) by step 2) cooling of the salvianolic acid B dimethyl ester crude product prepared, add water, then use organic solvent extraction, merge organic phase, wash with saturated common salt, steaming desolventizes, more successively through washing, sherwood oil is washed, then liquid is discarded, precipitate uses acetic acid ethyl dissolution on a small quantity, concentrating under reduced pressure, obtains salvianolic acid B dimethyl ester finished product.
2. the preparation method of salvianolic acid B dimethyl ester according to claim 1, is characterized in that, described alkali is one of them or arbitrary combination of sodium hydroxide or potassium hydroxide or sodium carbonate or sodium bicarbonate or saleratus.
3. the preparation method of salvianolic acid B dimethyl ester according to claim 1, is characterized in that, described organic solvent be methyl-sulphoxide or DMF one of them.
4. the preparation method of salvianolic acid B dimethyl ester according to claim 1, is characterized in that, step 3) described in organic solvent be ethyl acetate.
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| CN201510408043.8A CN104926764A (en) | 2015-07-13 | 2015-07-13 | Method for preparing dimethyl lithospermate B |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100549058B1 (en) * | 2003-10-04 | 2006-02-06 | 학교법인 원광학원 | Lithospermic acid B methylester and the derivatives thereof, and a composition containing the lithospermic acid B methylester and the derivatives thereof for treating liver fibrosis/cirrhosis and liver injury |
| CN104072456A (en) * | 2014-04-24 | 2014-10-01 | 浙江永宁药业股份有限公司 | Preparation method of high-purity salvianolic acid B |
| CN104130226A (en) * | 2014-04-01 | 2014-11-05 | 王平 | Preparation method of high-content salvianolic acid B |
| CN104546821A (en) * | 2013-10-18 | 2015-04-29 | 复旦大学 | Application of danshinolic acid B in preparation of medicine of treating scleroderma |
-
2015
- 2015-07-13 CN CN201510408043.8A patent/CN104926764A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100549058B1 (en) * | 2003-10-04 | 2006-02-06 | 학교법인 원광학원 | Lithospermic acid B methylester and the derivatives thereof, and a composition containing the lithospermic acid B methylester and the derivatives thereof for treating liver fibrosis/cirrhosis and liver injury |
| CN104546821A (en) * | 2013-10-18 | 2015-04-29 | 复旦大学 | Application of danshinolic acid B in preparation of medicine of treating scleroderma |
| CN104130226A (en) * | 2014-04-01 | 2014-11-05 | 王平 | Preparation method of high-content salvianolic acid B |
| CN104072456A (en) * | 2014-04-24 | 2014-10-01 | 浙江永宁药业股份有限公司 | Preparation method of high-purity salvianolic acid B |
Non-Patent Citations (5)
| Title |
|---|
| FISH, JEFFREY M，等: "Dimethyl Lithospermate B, an Extract of Danshen, Suppresses Arrhythmogenesis Associated With the Brugada Syndrome", 《CIRCULATION》 * |
| MUHAMMAD IQBAL CHOUDHARY,等: "Phenyl Polypropanoids from Lindelofia stylosa", 《CHEM.PHARM.BULL.》 * |
| WANG MIN，等: "Water-Soluble Constituents of Clerodendranthus spicatus", 《中国天然药物》 * |
| 胡跃飞，等: "《现代有机合成试剂》", 30 April 2006 * |
| 高俊峰，等: "石见穿化学成分研究", 《中国中药杂志》 * |
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Application publication date: 20150923 |