CN1084851A - The synthetic method of Z-ligustilide - Google Patents
The synthetic method of Z-ligustilide Download PDFInfo
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- CN1084851A CN1084851A CN 92111278 CN92111278A CN1084851A CN 1084851 A CN1084851 A CN 1084851A CN 92111278 CN92111278 CN 92111278 CN 92111278 A CN92111278 A CN 92111278A CN 1084851 A CN1084851 A CN 1084851A
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- ligustilide
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- butylphthalide
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Abstract
The present invention synthetic obtains having very strong spasmolysis through the general chemical raw material through four steps, relieving asthma, calm effect, can treat bronchitis and gynaecopathia, Chinese medicinal materials effective constituent ligusticumic wood lactone.Characteristics such as this synthetic route has route short, and cost is low, and method is easy can be synthesized in a large number.
Description
The invention belongs to the synthetic method of Z-ligustilide in medicine industry and the organic synthesis industry.
Z-ligustilide extensively is present in the medicinal plants such as Radix Angelicae Sinensis, Ligusticum wallichii, the root of Dahurain angelica.Very strong spasmolysis arranged, relieving asthma, calm effect, can be used for treating bronchitis and gynaecopathia clinically; Because it has tangible relexation to unstriated muscle, can be used for treating eyestrain and skin wrinkle resisting; Find also that recently this compound has effects such as the body temperature of reduction, treatment vasculitis and cerebral thrombosis.
Up to the present, also do not seen bibliographical information with the synthetic Z-ligustilide of manual method, thereby the present invention has initiative.
From natural phant, extract Z-ligustilide and be subjected to resource limit, and Z-ligustilide is a kind of unstable compounds, thus difficulty of pure product from plant, separated, thus limited its use range.With method of the present invention synthetic it to have method simple, be not subjected to resource limit, gained finished product purity height, characteristics such as with low cost.
The present invention at first obtains the phenylformic acid mixture of suitable, anti-neighbour-2-alkene amyl group with 2-carboxybenzaldehyde and potassium tert.-butoxide and the reaction of bromination butyl triphenyl microcosmic salt mixed solution, turn usefulness into through peroxy oxygen such as Peracetic Acid again, obtain Soviet Union's formula, the mixture of erythro form 8-hydroxyl-3-butylphthalide, then obtain Soviet Union's formula, erythro form 4 with the Birch reduction again, 5-dihydro-8-hydroxyl-3-butylphthalide mixture takes place to eliminate reaction at last at ambient temperature and obtains Z-ligustilide.
Synthetic route of the present invention is:
The embodiment of the invention is as follows:
1, the preparation of cis, trans neighbour-2-alkene amylbenzene formic acid mixtures:
4.8 gram butyl bromination triphenyl phosphorus salt is dissolved in 30 milliliters of anhydrous tetrahydro furans, room temperature splashes into 20 milliliters of potassium tert.-butoxide solution, stirred 20 minutes, 1.6 gram 2-carboxybenzaldehydes are dissolved in 20 milliliters of tetrahydrofuran (THF)s, splash in the reaction flask, stirring at room 1 hour, add 20 ml waters and decompose pressure reducing and steaming solvent, acidifying, with extracted with diethyl ether for several times, merge organic layer, anhydrous sodium sulfate drying, pressure reducing and steaming solvent, get yellow oil 5.2 grams, column chromatography purification must suitable, anti-neighbour-2-alkene amylbenzene formic acid 1.39 gram mixtures.
2, the preparation of Soviet Union's formula, erythro form 8-hydroxyl-3-butylphthalide mixture.
0.38 suitable, the anti-neighbour-2-alkene amylbenzene formic acid of gram, be dissolved in 7 milliliters of glacial acetic acids, the hydrogen peroxide that adds 7 milliliter 30%, room temperature was placed three days, and the pressure reducing and steaming solvent adds 10 milliliters of ether, be washed till PH=5～6 with saturated solution of sodium bicarbonate, use anhydrous magnesium sulfate drying, concentrate to such an extent that oily matter 0.55 restrains, column chromatography purification De Sushi, erythro form 8-hydroxyl-3-butylphthalide 0.52 gram mixture.
3, Soviet Union's formula, erythro form 4, the preparation of 5-dihydro-8-hydroxyl-3-butylphthalide.
0.3 Ke Sushi, erythro form 8-hydroxyl-3-butylphthalide are dissolved in 5 milliliters of tetrahydrofuran (THF)s, be chilled to-78 ℃ and add the 0.37 gram trimethyl carbinol, then add 50 milliliters of liquefied ammonia, add 0.14 gram sodium Metal 99.5 at-70 ℃, low temperature stirred 3 hours down, add 2 gram ammonium chlorides, restir 1 hour steams ammonia then, adds 40 ml waters, be neutralized to PH=5～6 with 10% hydrochloric acid, with extracted with diethyl ether for several times, use anhydrous magnesium sulfate drying, concentrate to such an extent that colorless oil 0.4 restrains, column chromatography De Sushi, erythro form 4,5-dihydro-8-hydroxyl-3-butylphthalide 0.18 gram mixture.
The preparation of Z-ligustilide
4,85 milligrams of Soviet Union's formulas, erythro form 4,5-dihydro-8-hydroxyl-3-butylphthalide is dissolved in 4 milliliters of anhydrous pyridines, adds 1.6 milliliters of acetic anhydride; argon shield, stirring at room 4 hours, the frozen water cooling adds 8 milliliters of anhydrous methanols down; stirring at room 7 hours; add saturated aqueous solution of sodium bicarbonate and ether, be neutralized to PH=8, extracted with diethyl ether for several times; anhydrous magnesium sulfate drying; the pressure reducing and steaming solvent gets 145 milligrams of yellow oil, and column chromatography purification gets 40 milligrams of Z-ligustilides.
Claims (5)
1, a kind of method of synthetic Z-ligustilide, it is characterized in that: the present invention at first obtains suitable, anti-neighbour-2-alkene amylbenzene formic acid mixtures with 2-carboxybenzaldehyde and potassium tert.-butoxide and bromination butyl triphenyl microcosmic salt mixture reaction, turn usefulness into through peroxy oxygen such as Peracetic Acid again, obtain Soviet Union's formula, erythro form 8-hydroxyl-3-butylphthalide mixture, then obtain Soviet Union's formula, erythro form 4 with the reduction of sodium ammonia again, 5-dihydro-8-hydroxyl-3-butylphthalide mixture takes place to eliminate reaction at last at ambient temperature and obtains Z-ligustilide.
2, according to claim 1, the method of said a kind of synthetic Z-ligustilide, said suitable, anti-neighbour-2-alkene amylbenzene formic acid mixtures, turn usefulness into through peroxy oxygen such as Peracetic Acid again, obtain the mixture of Soviet Union's formula, erythro form 8-hydroxyl-3-butylphthalide, it is characterized in that through superoxide on the phthalide skeleton 3 and 8 of the oxidation of two keys being introduced two hydroxyls simultaneously, carboxyl promptly closes with 3 hydroxyls and encircles into lactone, and 8 hydroxyls are as 3,8 pairs of keys of potential.
3, according to claim 1, the method of said a kind of synthetic Z-ligustilide, the mixture of said Soviet Union formula, erythro form 8-hydroxyl-3-butylphthalide, then obtain Soviet Union's formula with the reduction of sodium ammonia, erythro form 4,5-dihydro-8-hydroxyl-3-butylphthalide is characterized in that setting up on the carbon skeleton conjugated diolefine structure in the ring with the Birch reduction.
4, according to claim 1, the method of said a kind of synthetic Z-ligustilide, said Soviet Union formula, erythro form 4, reaction takes place to eliminate and obtains Z-ligustilide in 5-dihydro-8-hydroxyl-3-butylphthalide at ambient temperature, it is characterized in that with 8 hydroxyls of potential double bond functional group reaction taking place under mild conditions at last to eliminate obtains 3,8 two keys and synthetic Z-ligustilide.
5, according to claim 1,2,3,4, the method for said a kind of synthetic Z-ligustilide is characterized in that with synthetic Z-ligustilide of synthetic route of the present invention and synthetic relevant with Z-ligustilide intermediate Soviet Union formula, erythro form 8-hydroxyl-3-butylphthalide; Soviet Union's formula, erythro form 4,5-dihydro-8-hydroxyl-3-butylphthalide are as the intermediate of profitability, perhaps as synthetic other the profitability compounds of intermediate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN92111278A CN1035327C (en) | 1992-09-30 | 1992-09-30 | Synthetic method for rhizoma ligustici internal ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN92111278A CN1035327C (en) | 1992-09-30 | 1992-09-30 | Synthetic method for rhizoma ligustici internal ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1084851A true CN1084851A (en) | 1994-04-06 |
| CN1035327C CN1035327C (en) | 1997-07-02 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92111278A Expired - Fee Related CN1035327C (en) | 1992-09-30 | 1992-09-30 | Synthetic method for rhizoma ligustici internal ester |
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| CN (1) | CN1035327C (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004106318A1 (en) * | 2003-06-03 | 2004-12-09 | Yang, Xifeng | The extract method of cis-ligustilide and the pharmaceutical use of the same |
| CN1321638C (en) * | 2003-08-18 | 2007-06-20 | 天津药物研究院 | Ligustilide oil and its preparation |
| CN100430387C (en) * | 2006-06-15 | 2008-11-05 | 兰州大学 | 6,7-dihydroligustilide and alkylidene phthalide synthesis method |
| CN105505856A (en) * | 2014-09-17 | 2016-04-20 | 国玺干细胞应用技术股份有限公司 | Application of ligustilide |
-
1992
- 1992-09-30 CN CN92111278A patent/CN1035327C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004106318A1 (en) * | 2003-06-03 | 2004-12-09 | Yang, Xifeng | The extract method of cis-ligustilide and the pharmaceutical use of the same |
| CN1321638C (en) * | 2003-08-18 | 2007-06-20 | 天津药物研究院 | Ligustilide oil and its preparation |
| CN100430387C (en) * | 2006-06-15 | 2008-11-05 | 兰州大学 | 6,7-dihydroligustilide and alkylidene phthalide synthesis method |
| CN105505856A (en) * | 2014-09-17 | 2016-04-20 | 国玺干细胞应用技术股份有限公司 | Application of ligustilide |
| CN105505856B (en) * | 2014-09-17 | 2019-10-18 | 国玺干细胞应用技术股份有限公司 | Application of ligustilide |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1035327C (en) | 1997-07-02 |
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