CN1041725C - Method for synthetising 3-butenyl phthalide - Google Patents
Method for synthetising 3-butenyl phthalide Download PDFInfo
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- CN1041725C CN1041725C CN 92113016 CN92113016A CN1041725C CN 1041725 C CN1041725 C CN 1041725C CN 92113016 CN92113016 CN 92113016 CN 92113016 A CN92113016 A CN 92113016A CN 1041725 C CN1041725 C CN 1041725C
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- phthalide
- present
- phenylenediformic
- analogs
- butenyl
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention relates to a method for synthesizing 3-butenyl phthalide which is separated from medicinal plant angelica, etc. at present and has the obvious effect on relieving asthma. Some analogs thereof containing hydroxyl also have obvious bioactivity. In the present invention, the 3-butenyl phthalide is prepared from butyl lithium p-o-phenylenediformic anhydride by direct alkylation and elimination reaction. Compared with all of the present methods, the synthetic method of the present invention has the advantages of simplicity, high yield, low cost, large-scale preparation, etc. The analog of 3-alkylidene phthalide can be prepared from different alkyl lithium p-o-phenylenediformic analogs by alkylation by the same method.
Description
Patent of the present invention belongs to the synthetic method of 3-butylidene phthalide in medicine industry and the organic synthesis and analogue thereof.
The 3-butylidene phthalide is to separate the compound that obtains from medicinal plants such as Radix Angelicae Sinensis, is the phthalide analogue, has the five-membered ring lactone structure.3-butylidene phthalide and analogue 3-vinyl phthalide thereof, 3-propenyl phthalide, 3-isobutenyl phthalide and 3-n-butene base phthalide all have significant relexation to the animal tracheal smooth muscle, and the hydroxyl analogue of 3-butylidene phthalide also has biological activity clearly.Though for the existing several synthetic methods of this compounds, these synthetic methods are not that yield is very low, reaction product is separated comparatively difficulty; Raw materials used exactly being difficult to obtain needs could synthesize it through a few step reactions.These method costs are all very high in a word, and operation also bothers.We intend 3-alkylidene phthalide is synthesized in the direct alkylation of O-phthalic acid-like substance.We have selected multiple alkyl metal cpd such as cadion, Tong Shiji, azoviolet etc. for use, all can not react with the O-phthalic acid-like substance under the condition of gentleness; And under more violent reaction conditions, again at the alkyl of introducing on the O-phthalic acid-like substance more than two.Used lithium alkylide afterwards instead, just succeedd at a certain temperature.
The relevant documents of the present invention is as follows:
1. Cui's is expensive, Song Yongtian, Wang Wenlie etc.The antiasthmatic effect of Radix Angelicae Sinensis composition butylidenephalide derivative.Herbal medicine, 1982,13 (2), 17.
2．Elio?Napolitano，Guido?Spinelli，Rita?Fiaschi，Antonio?Marsili．Synthesis?ofdimethyl?phthalide-3-phosphonate?and?their?use?in?the?regiospecific?synthesis?of3-ylidenephthalides．Synthesis，1985，(1)，39。
3. Li Shao is white, Zhang Shaoming, Li Yulin.Synthesizing of (±)-Butylphthalide.Lanzhou University's journal (certainly), 1990,26 (1), 118.
4．?Gijbels?M．J．M．，Svendsen?A．Baerhein．Phthalides?in?Umbelliferae?Aetherischeoele?Ergeb?Int?Arbeitstag，1979-1980(pub．1982)，149-157．(Eng．)
To the direct alkylation of O-phthalic acid-like substance, take place eliminating reaction again, synthetic (E, Z)-the method yield height of existing synthetic this compounds of method of 3-alkylidene phthalide, method is simple, practical with lithium alkylide in the present invention.The present invention also provides a kind of method easy, with low cost for synthetic other phthalide analog compounds.
The chemical reaction that the present invention comprised is as follows:
R is H or C in the formula
1-C
5Straight chain or the alkyl of band side chain, R ' is hydroxyl, amino or is equipped with hydroxyl, the amino of protecting, one of them is halogen for X, Y, another is an alkoxyl group, perhaps the two all is a halogen, perhaps one of them or two of X, Y are metal-salts, or acid anhydrides.
The present invention adds 200～300 milliliters of tetrahydrofuran (THF)s with 1 mole O-phthalic acid-like substance (ester or carboxylic acid halides or acid anhydrides); under protection of inert gas; start stirring; at 60～70 ℃ of solution that drip 1 mole of lithium alkylide; drip off back restir 10 minutes to 2 hours, add the water stopped reaction then, regulate pH=6～2 with hydrochloric acid; tell organic layer, CH
2Cl
2Aqueous layer extracted for several times merges organic phase, anhydrous sodium sulfate drying, filtration, concentrate crude product, silica gel column chromatography separating purification, 3-alkyl-3-hydroxy phthalein or its analogue.
Above-mentioned gained compound is dissolved in the benzene, adds the tosic acid of catalytic amount, reflux 1～5 hour is told water that reaction generates etc. with water trap simultaneously, after generation reacts completely, adds saturated NaHCO
3The aqueous solution is washed 2 times, wash 1 time with saturated NaCl, with anhydrous sodium sulfate drying, concentrate 3-alkylidene phthalide, yield about 70～30%.
Under at mild conditions, divide water to eliminate the mixture that reaction can obtain Z, E-alkylidene phthalide.
The present invention has an embodiment as follows:
5.29 the Tetra hydro Phthalic anhydride (0.04 mole) of gram adds 20 milliliters of tetrahydrofuran (THF)s, drip butyllithium (about 0.035 mole hexane solution 25ml) under the room temperature, stirred then 10 minutes, after question response is finished, add the diluted acid stopped reaction, to pH=4, tell water, with extracted with diethyl ether for several times, merge organic phase, add anhydrous sodium sulfate drying a few hours.Filter, concentrate, add the benzene dissolving again, a small amount of tosic acid reflux is divided water outlet with water trap simultaneously, after question response is complete, adds saturated NaHCO
3Wash 2 times, the saturated NaCl aqueous solution is washed 1 time, adds anhydrous sodium sulfate drying, concentrates, and silica gel column chromatography separates, and purifying gets 4.4g 3Z-butylidene phthalide.
Claims (1)
- A kind of synthesis method of synthetic 3-butylidene phthalide is characterized in that: present method with butyllithium at room temperature to the direct butylation of phthalic acid, adds tosic acid again, reaction takes place to eliminate obtain (Z)-3-butylidene phthalide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92113016 CN1041725C (en) | 1992-11-12 | 1992-11-12 | Method for synthetising 3-butenyl phthalide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92113016 CN1041725C (en) | 1992-11-12 | 1992-11-12 | Method for synthetising 3-butenyl phthalide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1086814A CN1086814A (en) | 1994-05-18 |
| CN1041725C true CN1041725C (en) | 1999-01-20 |
Family
ID=4946203
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 92113016 Expired - Fee Related CN1041725C (en) | 1992-11-12 | 1992-11-12 | Method for synthetising 3-butenyl phthalide |
Country Status (1)
| Country | Link |
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| CN (1) | CN1041725C (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI568724B (en) | 2014-10-16 | 2017-02-01 | 長弘生物科技股份有限公司 | Method for preparing isobenzofuran-1(3h)-one based compound |
| CN105524032B (en) * | 2014-10-16 | 2019-05-03 | 长弘生物科技股份有限公司 | Method for producing isobenzofuran-1(3H) -one compound |
| CN106491632A (en) * | 2016-12-23 | 2017-03-15 | 郑州莉迪亚医药科技有限公司 | A kind of pharmaceutical composition for treating asthma |
| CN106581038A (en) * | 2016-12-23 | 2017-04-26 | 郑州莉迪亚医药科技有限公司 | Asthma treatment medicine |
| CN107929266B (en) * | 2017-11-24 | 2020-07-03 | 浙江大学 | Patch for treating chronic obstructive pulmonary disease |
| CN108084127A (en) * | 2017-12-25 | 2018-05-29 | 中山市榄商置业发展有限公司 | A kind of method for synthesizing 3- butylidene phthalides |
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1992
- 1992-11-12 CN CN 92113016 patent/CN1041725C/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CN1086814A (en) | 1994-05-18 |
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