CN105330631A - Method used for preparing n-butylphathlide via one pot method - Google Patents
Method used for preparing n-butylphathlide via one pot method Download PDFInfo
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- CN105330631A CN105330631A CN201510681946.3A CN201510681946A CN105330631A CN 105330631 A CN105330631 A CN 105330631A CN 201510681946 A CN201510681946 A CN 201510681946A CN 105330631 A CN105330631 A CN 105330631A
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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 the technical field of chemical synthesis, and more specifically relates to a method used for preparing n-butylphathlide via one pot method. The method comprises following steps: phthalic anhydride and valeric anhydride are subjected to a first step reaction under catalytic action of anhydrous sodium acetate, and generated n-pentanoic acid is collected via reduced pressure distillation; a sodium hydroxide solution of sodium borohydride is added into a reaction liquid for a second step of reaction; dichloromethane is used for extracting impurities; pH value is adjusted to be smaller than 7 with an acid for a third step of reaction, dichloromethane is used for extracting, and n-butylphathlide is obtained via concentration. The method is high in yield, low in cost, is safe, and is friendly to the environment.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to a kind of method that one kettle way prepares n butylphthalide.
Background technology
N butylphthalide, chemistry 3-butyl-1 (3H)-isobenzofuranone by name, also known as Butylphthalide, commodity are called En Bipu, belong to simple phthalide-type, for oily liquids, having celery fragrance, is the medicine being used for the treatment of cerebral infarction that China independently researches and develops out, and it has outstanding security individual structure, there is multiple pharmacological effect simultaneously, obviously can reduce the rear neurological deficit of infraction, improve minimal invasive treatment's capability state by complete treatment cerebral infarction.Due to its above advantage, cause people's common concern.
The technique preparing n butylphthalide of current bibliographical information mainly contains:
Route one: Tetra hydro Phthalic anhydride method, concrete technology route is as follows
Grignard reagent and phthalic anhydride is adopted to react in route one, reduce under alkaline condition, under acidic conditions, n butylphthalide is prepared in cyclization, the preparation of this technique grignard reagent requires anhydrous and oxygen-free, and preparation difficulty is higher and danger is comparatively large, and this route second step needs to react under alkalescence and acidic conditions respectively, the waste water obtaining product 60 ~ 100 times can be produced, be not suitable for suitability for industrialized production, be exactly this route yield 40% ~ 50% in addition, yield is on the low side.
Route two: adjacent formylbenzoate method, concrete technology route is as follows
Need to use grignard reagent in route two, higher and grignard reagent danger is higher to operational requirements such as anhydrous and oxygen-frees, most importantly yield is on the low side, is only about 38%.
Route three: n-Butyl Lithium technique, concrete technology route is as follows
Route three technique and route one technique similar, but temperature of reaction requires below-30 DEG C, production difficulty is comparatively large and use n-Butyl Lithium cost higher, and yield, lower than 40%, is not suitable for suitability for industrialized production.
Therefore, needing further, searching is simple and convenient, cost is low, yield is high, the preparation method of the n butylphthalide of safety and environmental protection.
Summary of the invention
In order to solve above-mentioned technical problem, the invention provides the method that one kettle way prepares n butylphthalide.The method overcome existing technologic deficiency, there is the advantage of the high and low cost of yield, safety and environmental protection.
The present invention is realized by following technical scheme:
One kettle way prepares the method for n butylphthalide, comprises the steps:
Phthalic anhydride and valeric anhydride are carrying out the first step reaction under anhydrous sodium acetate catalysis, decompression steams the positive valeric acid of generation, the sodium hydroxide solution adding sodium borohydride in reaction solution carries out second step reaction, dichloromethane extraction impurity, after be adjusted to acidity with acid and carry out three-step reaction, dichloromethane extraction, concentrates and obtains n butylphthalide.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, and the mol ratio of described acid anhydride and valeric anhydride is 1:1-2.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, and described the first step temperature of reaction is 150 DEG C-200 DEG C, and the reaction times is 3-10h.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, and the mol ratio of the sodium borohydride that described second step adds and raw material phthalic anhydride is 1-2:1.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, and the preparation method of the sodium hydroxide solution of described sodium borohydride is 6.5g sodium borohydride, 40.0g sodium hydroxide is dissolved in 100ml water.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, and the temperature of described second step reaction is 50 DEG C-100 DEG C, and the reaction times is 2-10h.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, and described acid is selected from the one in hydrochloric acid, sulfuric acid.
Preferably, above-mentioned one kettle way is prepared in the method for n butylphthalide, and described acid is preferably hydrochloric acid.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, and the temperature of described three-step reaction is 50 DEG C-100 DEG C, and the reaction times is 2-10h.
Above-mentioned one kettle way is prepared in the method for n butylphthalide, and described three-step reaction pH should control at 1-4.
Concrete preparation method is: add positive valeric anhydride after being mixed with anhydrous sodium acetate by Tetra hydro Phthalic anhydride, stirring is warming up to 200 DEG C, lower the temperature after reaction 3h, decompression steams the positive valeric acid of generation, obtains brown solidliquid mixture, adds the sodium hydroxide solution of sodium borohydride, react complete dichloromethane extraction impurity, after drip hydrochloric acid to pH=2, backflow 2h after dichloromethane extraction, concentrate and obtain n butylphthalide.
Reaction equation is as follows:
Beneficial effect of the present invention is,
(1) the present invention adopts one kettle way to prepare n butylphthalide, is separated, decreases purification step, improve product yield without intermediate.
(2) not anhydrous and oxygen-free, the strict working conditions such as-30 DEG C in n butylphthalide preparation process of the present invention, reaction conditions is gentle, without the need to risky operation, adds the degree of safety in production; Raw material used is all raw material conventional on market, is easy to buy, reduces cost, be more suitable for suitability for industrialized production.
(3) the present invention adopts one kettle way to prepare n butylphthalide, can not produce the waste water of product 60 ~ 100 times, environmentally friendly.
Embodiment
Below in conjunction with specific embodiment, the present invention is further described, so that those skilled in the art more understands the present invention, but does not therefore limit the present invention.
Embodiment 1
Phthalic anhydride 60.0g, valeric anhydride 113.2g, anhydrous sodium acetate 33.23g is dropped in 500ml reaction flask, be warming up to 200 DEG C of reaction 3h, react complete concentrating under reduced pressure and reclaim the positive valeric acid generated, be cooled to the sodium hydroxide solution (6.5g sodium borohydride, 40.0g sodium hydroxide are dissolved in 100ml water) that 30 DEG C slowly add sodium borohydride, 60 DEG C of reaction 5h, react complete dichloromethane extraction impurity, aqueous phase dilute hydrochloric acid regulates pH to 1,85 DEG C of insulation 3h, dichloromethane extraction after cooling, concentrate and obtain n butylphthalide 54.2g, yield 70.33%, liquid phase purity 98.36%.
Embodiment 2
Phthalic anhydride 60.0g is dropped in 500ml reaction flask, valeric anhydride 105.6g, anhydrous sodium acetate 33.23g, be warming up to 180 DEG C of reaction 3h, react complete concentrating under reduced pressure and reclaim the positive valeric acid generated, be cooled to 30 DEG C and slowly add 40.0g sodium hydroxide, 6.5g sodium borohydride, mixed solution (the 6.5g sodium borohydride of 100ml water, 40.0g sodium hydroxide is dissolved in 100ml water), 60 DEG C of reaction 5h, react complete dichloromethane extraction impurity, aqueous phase salt acid for adjusting pH to 1, 85 DEG C of insulation 3h, dichloromethane extraction after cooling, concentrate and obtain butylphthalide 52.4g, yield 68.0%, liquid phase purity 98.02%.
Embodiment 3
Phthalic anhydride 60.0g is dropped in 500ml reaction flask, valeric anhydride 113.2g, anhydrous sodium acetate 33.23g, be warming up to 200 DEG C of reaction 3h, react complete concentrating under reduced pressure and reclaim the positive valeric acid generated, be cooled to 30 DEG C and slowly add 40.0g sodium hydroxide, 5.5g sodium borohydride, mixed solution (the 6.5g sodium borohydride of 100ml water, 40.0g sodium hydroxide is dissolved in 100ml water), 60 DEG C of reaction 5h, react complete dichloromethane extraction impurity, aqueous phase salt acid for adjusting pH to 1, 65 DEG C of insulation 3h, dichloromethane extraction after cooling, concentrate and obtain butylphthalide 51.6g, yield 66.93%, liquid phase purity 96.95%.
Embodiment 4
Phthalic anhydride 60.0g is dropped in 500ml reaction flask, valeric anhydride 113.3g, anhydrous sodium acetate 33.23g, be warming up to 200 DEG C of reaction 4h, react complete concentrating under reduced pressure and reclaim the positive valeric acid generated, be cooled to 30 DEG C and slowly add 40.0g sodium hydroxide, 6.5g sodium borohydride, mixed solution (the 6.5g sodium borohydride of 100ml water, 40.0g sodium hydroxide is dissolved in 100ml water), 60 DEG C of reaction 6h, react complete dichloromethane extraction impurity, aqueous phase salt acid for adjusting pH to 1, 85 DEG C of insulation 4h, dichloromethane extraction after cooling, concentrate and obtain butylphthalide 53.9g, yield 69.94%, liquid phase purity 99.32%.
Claims (10)
1. one kettle way prepares the method for n butylphthalide, it is characterized in that, comprises the steps:
Phthalic anhydride and valeric anhydride are carrying out the first step reaction under anhydrous sodium acetate catalysis, decompression steams the positive valeric acid of generation, the sodium hydroxide solution adding sodium borohydride in reaction solution carries out second step reaction, dichloromethane extraction impurity, after carry out three-step reaction with acid for adjusting pH to acidity, dichloromethane extraction, concentrates and obtains n butylphthalide.
2. one kettle way according to claim 1 prepares the method for n butylphthalide, it is characterized in that, the mol ratio of described acid anhydride and valeric anhydride is 1:1-2.
3. one kettle way according to claim 1 prepares the method for n butylphthalide, it is characterized in that, described the first step temperature of reaction is 150 DEG C-200 DEG C, and the reaction times is 3-10h.
4. one kettle way according to claim 1 prepares the method for n butylphthalide, it is characterized in that, the mol ratio of the sodium borohydride that described second step adds and raw material phthalic anhydride is 1-2:1.
5. one kettle way according to claim 1 prepares the method for n butylphthalide, it is characterized in that, the preparation method of the sodium hydroxide solution of described sodium borohydride is 6.5g sodium borohydride, 40.0g sodium hydroxide is dissolved in 100ml water.
6. one kettle way according to claim 1 prepares the method for n butylphthalide, it is characterized in that, the temperature of described second step reaction is 50 DEG C-100 DEG C, and the reaction times is 2-10h.
7. one kettle way according to claim 1 prepares the method for n butylphthalide, it is characterized in that, described acid is selected from the one in hydrochloric acid, sulfuric acid, and adjustment pH is 1-4.
8. one kettle way according to claim 7 prepares the method for n butylphthalide, it is characterized in that, described acid is preferably hydrochloric acid.
9. one kettle way according to claim 1 prepares the method for n butylphthalide, it is characterized in that, the temperature of described three-step reaction is 50 DEG C-100 DEG C, and the reaction times is 2-10h.
10. one kettle way according to claim 1 prepares the method for n butylphthalide, it is characterized in that, concrete grammar is:
Positive valeric anhydride is added after being mixed with anhydrous sodium acetate by Tetra hydro Phthalic anhydride, stirring is warming up to 200 DEG C, lower the temperature after reaction 3h, decompression steams the positive valeric acid of generation, obtains brown solidliquid mixture, adds the sodium hydroxide solution of sodium borohydride, react complete dichloromethane extraction impurity, after drip hydrochloric acid to pH=2, backflow 2h after dichloromethane extraction, concentrate and obtain n butylphthalide.
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Citations (2)
| 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 |
| JP2011201818A (en) * | 2010-03-26 | 2011-10-13 | Kao Corp | Potential-dependent cation channel inhibitor |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011201818A (en) * | 2010-03-26 | 2011-10-13 | Kao Corp | Potential-dependent cation channel inhibitor |
| 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》 * |
| 杨静 等: "新型5-HT重摄取抑制剂的设计、合成及活性评价", 《高等学校化学学报》 * |
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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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