CN105330631B - The method that one kettle way prepares n butylphthalide - Google Patents
The method that one kettle way prepares n butylphthalide Download PDFInfo
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- CN105330631B CN105330631B CN201510681946.3A CN201510681946A CN105330631B CN 105330631 B CN105330631 B CN 105330631B CN 201510681946 A CN201510681946 A CN 201510681946A CN 105330631 B CN105330631 B CN 105330631B
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- butylphthalide
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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
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
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Abstract
The invention belongs to chemosynthesis technical field, and in particular to a kind of method that one kettle way prepares n butylphthalide.This method comprises the following steps：Phthalic anhydride and valeric anhydride are carrying out first step reaction under anhydrous sodium acetate catalysis, decompression steams the positive valeric acid of generation, the sodium hydroxide solution that sodium borohydride is added into reaction solution carries out second step reaction, dichloromethane extracting impurities, after with acid for adjusting pH to acidity carry out three-step reaction, dichloromethane extracts, and concentrates up to n butylphthalide.This method has the advantages that high income, low cost, safety and environmental protection.
Description
Technical field
The invention belongs to chemosynthesis technical field, and in particular to a kind of method that one kettle way prepares n butylphthalide.
Background technology
N butylphthalide, also known as entitled 3- butyl -1 (the 3H)-isobenzofuranone of chemistry, Butylphthalide, trade name grace
Must be general, belong to simple phthalide-type, be oily liquids, there is celery fragrance, be China independently research and develop out be used for treat ischemic
The medicine of property cerebral apoplexy, it has outstanding security monolithic entity structure, while has multiple pharmacological effect, being capable of complete treatment
Cerebral arterial thrombosis significantly reduces neurological deficit, improvement minimal invasive treatment's capability state after infraction.Due to its above advantage, draw
People's common concern is played.
The technique for preparing n butylphthalide of document report mainly has at present：
Route one：Phthalic anhydride method, concrete technology route are as follows
Reacted using grignard reagent and phthalic anhydride in route one, reduced under alkaline condition, under acid condition cyclization prepare positive fourth
Base phthalide, prepared by this technique grignard reagent requires anhydrous and oxygen-free, and preparation difficulty is higher and dangerous larger, this route second step point
Do not need to react under alkalescence and acid condition, can produce to obtain the waste water of 60 ~ 100 times of product, be not suitable for industrialized production,
Also it is exactly this route yield 40% ~ 50%, yield is relatively low.
Route two：Adjacent formylbenzoate method, concrete technology route are as follows
Need to use grignard reagent in route two, to anhydrous and oxygen-free etc. operate more demanding and grignard reagent it is dangerous compared with
Height, most importantly yield is relatively low, is only 38% or so.
Route three：N-BuLi technique, concrete technology route are as follows
Three technique of route is similar with one technique of route, but reaction temperature requirement, below -30 DEG C, production difficulty is larger simultaneously
And it is higher using n-BuLi cost, yield is less than 40%, is not suitable for industrialized production.
Therefore, it is necessary to further find, simple and convenient, cost is low, the preparation of the n butylphthalide of high income, safety and environmental protection
Method.
The content of the invention
In order to solve above-mentioned technical problem, the present invention provides the method that one kettle way prepares n butylphthalide.This method
The deficiency in existing process is overcome, there is high income, low cost, safety and environmental protection.
The present invention is realized by following technical solutions：
The method that one kettle way prepares n butylphthalide, includes the following steps：
Phthalic anhydride and valeric anhydride are carrying out first step reaction under anhydrous sodium acetate catalysis, and decompression steams the positive valeric acid of generation,
Into reaction solution add sodium borohydride sodium hydroxide solution carry out second step reaction, dichloromethane extracting impurities, after use
Acid adjusts to acidity and carries out three-step reaction, and dichloromethane extraction, concentrates up to n butylphthalide.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, and the molar ratio of the acid anhydride and valeric anhydride is 1：1-2.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, and the first step reaction temperature is 150 DEG C -200 DEG C, instead
It is 3-10h between seasonable.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, the sodium borohydride that the second step adds and raw material phthalic anhydride
Molar ratio be 1-2：1.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, the preparation side of the sodium hydroxide solution of the sodium borohydride
Method is 6.5g sodium borohydrides, 40.0g sodium hydroxides are dissolved in 100ml water.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, and the temperature of the second step reaction is 50 DEG C -100 DEG C,
Reaction time is 2-10h.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, the one kind of the acid in hydrochloric acid, sulfuric acid.
Preferably, above-mentioned one kettle way is prepared in the method for n butylphthalide, and the acid is preferably hydrochloric acid.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, and the temperature of the three-step reaction is 50 DEG C -100 DEG C,
Reaction time is 2-10h.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, and the three-step reaction pH should be controlled in 1-4.
Specifically preparation method is：Positive valeric anhydride is added after phthalic anhydride is mixed with anhydrous sodium acetate, stirring rises
Temperature cools down to 200 DEG C after reacting 3h, and decompression steams the positive valeric acid of generation, obtains brown solidliquid mixture, adds sodium borohydride
Sodium hydroxide solution, reaction finish dichloromethane extracting impurities, after hydrochloric acid is added dropwise to pH=2, dichloromethane extracts after the 2h that flows back
Take, concentrate up to n butylphthalide.
Reaction equation is as follows：
The beneficial effects of the present invention are,
（1）The present invention prepares n butylphthalide using one kettle way, is separated without intermediate, reduces purification step, improves
Product yield.
（2）The present invention n butylphthalide preparation process in should not anhydrous and oxygen-free, the stringent working conditions such as -30 DEG C, instead
Mild condition is answered, without risky operation, adds the degree of safety in production；Raw material used is all the common raw material of in the market,
It is easy to buy, reduces cost, more suitable for industrialized production.
（3）The present invention prepares n butylphthalide using one kettle way, will not produce the waste water of 60 ~ 100 times of product, to environment friend
It is good.
Embodiment
The present invention is further described with reference to specific embodiment, so that those skilled in the art knows more about
The present invention, but be not intended to limit the present invention.
Embodiment 1
Phthalic anhydride 60.0g, valeric anhydride 113.2g, anhydrous sodium acetate 33.23g are put into 500ml reaction bulbs, is warming up to 200 DEG C
3h is reacted, reaction finishes the positive valeric acid for the recycling generation that is concentrated under reduced pressure, is cooled to 30 DEG C of sodium hydroxides for being slowly added to sodium borohydride
Solution（6.5g sodium borohydrides, 40.0g sodium hydroxides are dissolved in 100ml water）, 60 DEG C of reaction 5h, react and finish dichloromethane extraction
Impurity, water mutually adjust pH to 1 with dilute hydrochloric acid, and 85 DEG C of insulation 3h, dichloromethane extracts after cooling, concentrates up to n butylphthalide
54.2g, yield 70.33%, liquid phase purity 98.36%.
Embodiment 2
Phthalic anhydride 60.0g, valeric anhydride 105.6g, anhydrous sodium acetate 33.23g are put into 500ml reaction bulbs, is warming up to 180 DEG C
3h is reacted, reaction finishes the positive valeric acid for the recycling generation that is concentrated under reduced pressure, is cooled to 30 DEG C and is slowly added to 40.0g sodium hydroxides, 6.5g
The mixed liquor of sodium borohydride, 100ml water（6.5g sodium borohydrides, 40.0g sodium hydroxides are dissolved in 100ml water）, 60 DEG C of reaction 5h,
Reaction finishes dichloromethane extracting impurities, and water phase salt acid for adjusting pH is to 1,85 DEG C of insulation 3h, and dichloromethane extracts after cooling, concentration
Up to butylphthalide 52.4g, yield 68.0%, liquid phase purity 98.02%.
Embodiment 3
Phthalic anhydride 60.0g, valeric anhydride 113.2g, anhydrous sodium acetate 33.23g are put into 500ml reaction bulbs, is warming up to 200 DEG C
3h is reacted, reaction finishes the positive valeric acid for the recycling generation that is concentrated under reduced pressure, is cooled to 30 DEG C and is slowly added to 40.0g sodium hydroxides, 5.5g
The mixed liquor of sodium borohydride, 100ml water（6.5g sodium borohydrides, 40.0g sodium hydroxides are dissolved in 100ml water）, 60 DEG C of reaction 5h,
Reaction finishes dichloromethane extracting impurities, and water phase salt acid for adjusting pH is to 1,65 DEG C of insulation 3h, and dichloromethane extracts after cooling, concentration
Up to butylphthalide 51.6g, yield 66.93%, liquid phase purity 96.95%.
Embodiment 4
Phthalic anhydride 60.0g, valeric anhydride 113.3g, anhydrous sodium acetate 33.23g are put into 500ml reaction bulbs, is warming up to 200 DEG C
4h is reacted, reaction finishes the positive valeric acid for the recycling generation that is concentrated under reduced pressure, is cooled to 30 DEG C and is slowly added to 40.0g sodium hydroxides, 6.5g
The mixed liquor of sodium borohydride, 100ml water（6.5g sodium borohydrides, 40.0g sodium hydroxides are dissolved in 100ml water）, 60 DEG C of reaction 6h,
Reaction finishes dichloromethane extracting impurities, and water phase salt acid for adjusting pH is to 1,85 DEG C of insulation 4h, and dichloromethane extracts after cooling, concentration
Up to butylphthalide 53.9g, yield 69.94%, liquid phase purity 99.32%.
Claims (5)
1. the method that one kettle way prepares n butylphthalide, it is characterised in that include the following steps：
Phthalic anhydride and valeric anhydride are carrying out first step reaction under anhydrous sodium acetate catalysis, and decompression steams the positive valeric acid of generation, to anti-
Answer in liquid add sodium borohydride sodium hydroxide solution carry out second step reaction, dichloromethane extracting impurities, after with acid adjust
Save pH and carry out three-step reaction to acidity, dichloromethane extraction, concentrates up to n butylphthalide；
The first step reaction temperature is 200 DEG C, reaction time 3-10h；
The temperature of the second step reaction is 50 DEG C -100 DEG C, reaction time 2-10h；
The temperature of the three-step reaction is 50 DEG C -100 DEG C, reaction time 2-10h；
The molar ratio of the phthalic anhydride and valeric anhydride is 1：1-2；
The molar ratio of the sodium borohydride that the second step adds and raw material phthalic anhydride is 1-2：1.
2. the method that one kettle way according to claim 1 prepares n butylphthalide, it is characterised in that the sodium borohydride
The preparation method of sodium hydroxide solution is 6.5g sodium borohydrides, 40.0g sodium hydroxides are dissolved in 100ml water.
3. the method that one kettle way according to claim 1 prepares n butylphthalide, it is characterised in that the acid is selected from salt
One kind in acid, sulfuric acid, adjusting pH is 1-4.
4. the method that one kettle way according to claim 3 prepares n butylphthalide, it is characterised in that the acid is preferably salt
Acid.
5. the method that one kettle way according to claim 1 prepares n butylphthalide, it is characterised in that specific method is：
Positive valeric anhydride is added after phthalic anhydride is mixed with anhydrous sodium acetate, stirring is warming up to 200 DEG C, is dropped after reacting 3h
Temperature, decompression steam the positive valeric acid of generation, obtain brown solidliquid mixture, add the sodium hydroxide solution of sodium borohydride, reacted
Finish dichloromethane extracting impurities, after hydrochloric acid is added dropwise to pH=2, dichloromethane extracts after the 2h that flows back, and concentrates up to n-butylbenzene
Phthalein.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101962374A (en) * | 2010-10-21 | 2011-02-02 | 上海应用技术学院 | Preparation method of butylphthalide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101962374A (en) * | 2010-10-21 | 2011-02-02 | 上海应用技术学院 | Preparation method of butylphthalide |
Non-Patent Citations (2)
| Title |
|---|
| Rodrigo Juliano Oliveira 等.A novel cytosporone 3-Heptyl-4,6-dihydroxy-3H-isobenzofuran-1-one: synthesis;toxicological, apoptotic and immunomodulatory properties；and potentiation of mutagenic damage.《BMC Cancer》.2015,第15卷1-15. * |
| 新型5-HT重摄取抑制剂的设计、合成及活性评价;杨静 等;《高等学校化学学报》;20070831;第28卷(第8期);1503-1507 * |
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Inventor after: Ge Zhengquan Inventor after: Wang Sulan Inventor after: Li Yuedong Inventor after: Zhang Wei Inventor after: Chen Hongxiang Inventor after: Sun Baoliang Inventor before: Zhang Wei Inventor before: Wang Sulan Inventor before: Li Yuedong Inventor before: Chen Hongxiang Inventor before: Sun Baoliang |
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Denomination of invention: Method used for preparing n-butylphathlide via one pot method Effective date of registration: 20200522 Granted publication date: 20180515 Pledgee: Jinan area branch of Shandong free trade zone of Qilu Bank Co.,Ltd. Pledgor: Jinan Chenghuishuangda Chemical Industry Co.,Ltd. Registration number: Y2020370000084 |
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Date of cancellation: 20230811 Granted publication date: 20180515 Pledgee: Jinan area branch of Shandong free trade zone of Qilu Bank Co.,Ltd. Pledgor: JINAN CHENGHUISHUANGDA CHEMICAL INDUSTRY Co.,Ltd. Registration number: Y2020370000084 |
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