CN101805260B - Preparation method of gefarnate - Google Patents
Preparation method of gefarnate Download PDFInfo
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- CN101805260B CN101805260B CN 201010151582 CN201010151582A CN101805260B CN 101805260 B CN101805260 B CN 101805260B CN 201010151582 CN201010151582 CN 201010151582 CN 201010151582 A CN201010151582 A CN 201010151582A CN 101805260 B CN101805260 B CN 101805260B
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Abstract
The invention provides a preparation method of gefarnate, comprising the following steps: nerolidol, triethyl orthoacetate and acid catalyst are mixed and heated, thus obtaining a first intermediate product; the first intermediate product is added to ethanol solution of alkali and heated, thus obtaining a second intermediate product; the second intermediate product is dissolved by water, and then the PH value of the solution is regulated to 1-4, thus obtaining a third intermediate product; and geraniol is added after the third intermediate product is dissolved by organic solvent and heated, thus obtaining the gefarnate. By adopting the method in the invention to prepare the gefarnate, the solvent used in the production process and the produced by-products have low toxicity, and the ethanol which is produced in the reaction can be reused, thus reducing the pollution to the environment and enhancing the utilization ratio of raw materials.
Description
Technical field
The present invention relates to field of medicaments, particularly a kind of preparation method of gefarnate.
Background technology
Gefarnate (Gefarnate) is chemical to be called (4E, 8E)-5,9,13-trimethylammonium-4,8,12-14 trienic acids-(2E)-3, and 7-dimethyl-2,6-octadiene ester, its chemical structural formula is suc as formula shown in the VII.
Gefarnate is the compound with isoprene structure, is fat-soluble oily mater.Gefarnate has the stomach and intestine of adjustment function, strengthens the provide protection of gastric mucosa, can control hydrochloric acid in gastric juice, removes stomach Qi, goes gasteremphraxis, remove stomachache, therefore is widely used in treating gastrointestinal illnesss such as flatulence, stomach ulcer and duodenal ulcer.
Chinese patent CN101475476A discloses a kind of synthetic method of gefarnate, all contain methyl alcohol in the first step reaction of this method and the by product of second step reaction, methyl alcohol has bigger toxicity and volatile, human body can cause damage and affect one's power of vision after sucking methanol steam respiratory mucosa, second go on foot the solvent N that uses in the reaction simultaneously, N dimethyl formamide (DMF) also has big toxicity and is difficult for Ex-all.Therefore, adopt the pollution level height of method for preparing gefarnate to environment.
Summary of the invention
In order to solve above technical problem, the invention provides a kind of preparation method of gefarnate, adopt method provided by the invention to prepare gefarnate, the by product of solvent of Shi Yonging and generation all has hypotoxicity in process of production, and then the minimizing pollution on the environment, described preparation method of gefarnate comprises:
A), with nerolidol, triethly orthoacetate and acid catalyst mixing post-heating, obtain first intermediate product of formula III structure; Described acid catalyst is an isopropylformic acid;
B), in the ethanolic soln of alkali ROH, add the first intermediate product post-heating, obtain second intermediate product of formula IV structure;
C), with the second intermediate product water dissolution, then with regulator solution pH value to 1～4, obtain the 3rd intermediate product of formula V structure;
D), the 3rd intermediate product is added the Geraniol heating after with organic solvent dissolution, obtain gefarnate.
Preferably, the blending ratio of nerolidol and triethly orthoacetate is counted 1:1.5～3.5 by mole among the step a.
Preferably, described acid catalyst is an isopropylformic acid.
Preferably, the mass ratio of described acid catalyst and nerolidol is 1:10～20.
Preferably, the Heating temperature among the step a is 130 ℃～160 ℃.
Preferably, the ethanolic soln of alkali is the ethanolic soln of sodium hydroxide or the ethanolic soln of potassium hydroxide among the step b.
Preferably, the mol ratio of first intermediate product that adds among the step b and sodium hydroxide or potassium hydroxide is 1:1.1～1.8.
Preferably, the Heating temperature of step b is 60 ℃～90 ℃.
Preferably, the mol ratio of Geraniol and described the 3rd intermediate product is 1:1.1～2.0 in the steps d.
Preferably, the Heating temperature in the steps d is 130 ℃～160 ℃.
The invention provides a kind of preparation method of gefarnate, it was that feedstock production goes out first intermediate product with nerolidol and triethly orthoacetate before this, and the by product of this step reaction is an ethanol, and not only nontoxic but also recovery also can be directly used in the next step; Then first intermediate product is added the reaction that is hydrolyzed in the ethanolic soln of alkali, solvent toxicity that this step reaction is used is low, and alcohol can directly adopt the ethanol that goes on foot recovery.Therefore adopt method provided by the invention to prepare gefarnate, can improve raw material availability, and the solvent toxicity that preparation process is used is lower, can also reduce the generation that toxic byproduct is arranged, feature of environmental protection height simultaneously.
Embodiment
In order further to understand the present invention, below in conjunction with embodiment the preferred embodiment of the invention is described, but should be appreciated that these describe just to further specifying the features and advantages of the present invention, rather than to the restriction of claim of the present invention.
The embodiment of the invention discloses a kind of preparation method of gefarnate, comprising:
A), with nerolidol, triethly orthoacetate and acid catalyst mixing post-heating, obtain first intermediate product of formula III structure; Described acid catalyst is an isopropylformic acid;
B), in the ethanolic soln of alkali ROH, add the first intermediate product post-heating, obtain second intermediate product of formula IV structure;
C), with the second intermediate product water dissolution, regulator solution pH value to 1～4 then obtain the 3rd intermediate product of formula V structure;
D), the 3rd intermediate product is added the Geraniol heating after with organic solvent dissolution, obtain gefarnate.
The reaction formula of step a is:
According to the present invention, the mol ratio of nerolidol I and triethly orthoacetate II is preferably 1:1.5～3.5, and Heating temperature is preferably 130 ℃～160 ℃, and the reaction times is 5 hours～20 hours, obtains the first intermediate product III.Described acid catalyst can be acetate, propionic acid or isopropylformic acid, and the present invention preferably adopts isopropylformic acid, because the isopropylformic acid boiling point is higher, can prevents in reaction process volatilization and influence speed of reaction that the mass ratio of isopropylformic acid and nerolidol I is preferably 1:10～20.The first intermediate product III purified to be method well known to those skilled in the art, be specifically as follows: reclaim under reduced pressure by product ethanol, unreacted nerolidol, triethly orthoacetate and isopropylformic acid, the cut that 130 ℃～160 ℃/0.4mmHg is collected in decompression obtains the first intermediate product E, E-farnesyl ethyl acetate III.
The reaction formula of step b is:
According to the present invention, the ethanolic soln of alkali is preferably the ethanolic soln of sodium hydroxide or the ethanolic soln of potassium hydroxide, wherein the mol ratio of sodium hydroxide or potassium hydroxide and the first intermediate product III is preferably 1.1～1.8:1, Heating temperature is preferably 60 ℃～90 ℃, reaction times is 1～3 hour, obtains the second intermediate product IV.The method of second purifying intermediate products can be method well known to those skilled in the art, be specially: reclaim under reduced pressure by product ethanol is pulled an oar with ether to doing the back, and centrifugation obtains white solid then, is the second intermediate product IV.
The process of regulator solution pH value to 1～4 is preferably among the step c: adding sulfuric acid in solution, solution is acidified to pH value is 1～4, obtains the 3rd intermediate product V, and equation that this step reacts is:
The method that the 3rd intermediate product V is purified can be method well known to those skilled in the art, is specially: add ether and extract after scouring, drying, the reclaim under reduced pressure ether obtains the 3rd intermediate product V.
The reaction formula of steps d is:
According to the present invention, the organic solvent that uses in this step can be preferably dimethylbenzene as dimethylbenzene or dme, the mol ratio of the 3rd intermediate product V and Geraniol VI is preferably 1.1～2.0:1, Heating temperature is preferably 130 ℃～160 ℃, and the reaction times is 8～15 hours, obtains the gefarnate VII.The method that the gefarnate VII is purified can be method well known to those skilled in the art, be specifically as follows: reclaim under reduced pressure organic solvent and unreacted Geraniol, adding saturated sodium bicarbonate solution in residual solution stirs, add extracted with diethyl ether, washing, drying, filtration, the reclaim under reduced pressure ether, evaporate to dryness after adding silica gel stirs in the residual solution, go up 60 orders～100 purpose silicagel columns then, elutriant is that mass ratio is normal hexane and the isopropyl ether of 30:70, collects the product elutriant and reclaim organic solvent to obtain faint yellow oily thing and be the gefarnate VII.
In order further to understand the present invention, gefarnate preparation method provided by the invention is described below in conjunction with embodiment.
Embodiment 1
1, in reactor, adds 241g nerolidol, 535.6g triethly orthoacetate and 21mL isopropylformic acid, 145 ℃ of heated and stirred, react and stop heating after 12 hours, decompression recycling ethanol, unreacted nerolidol, triethly orthoacetate and isopropylformic acid, the cut that 130 ℃～160 ℃/0.4mmHg is collected in decompression obtains first intermediate product.
2, the potassium hydroxide and the 1.8L ethanol that in reactor, add 90.7g, wherein part ethanol is reclaimed by step 1 and obtains, add first intermediate product that 277g step 1 makes after the stirring and dissolving, stop heating after 2 hours 75 ℃ of following back flow reaction, decompression recycling ethanol is pulled an oar with ether to doing the back, and centrifugation obtains second intermediate product then.
3, it is 40% sulfuric acid that second intermediate product that step 2 is made adds massfraction after with water dissolution, solution is acidified to pH most 1, add ether then and extract after washing to neutral, with suction filtration behind the anhydrous sodium sulfate drying, underpressure distillation is reclaimed ether and is obtained the 3rd intermediate product.
4, in reactor, add the 3rd intermediate product that 151.0g step 3 makes, 114g Geraniol and 125mL dimethylbenzene, stop heating after 10 hours at 145 ℃ of heating reflux reactions, isolate the water that reaction generates, decompression heats up and reclaims dimethylbenzene and excessive Geraniol, adding saturated sodium bicarbonate solution in residual solution stirs, add extracted with diethyl ether, washing, use anhydrous sodium sulfate drying, suction filtration, filtrate decompression reclaims ether, evaporate to dryness after adding silica gel stirs in the residual solution, go up 80 purpose silicagel columns then, elutriant is that mass ratio is normal hexane and the isopropyl ether of 30:70, collect the product elutriant and reclaim organic solvent and obtain faint yellow oily thing and be the gefarnate VII, measure through high performance liquid chromatograph, product purity is 99.7%.
Embodiment 2
1, in reactor, adds 500g nerolidol, 1100g triethly orthoacetate and 45mL isopropylformic acid, 135 ℃ of heated and stirred, react and stop heating after 10 hours, decompression recycling ethanol, unreacted nerolidol, triethly orthoacetate and isopropylformic acid, the cut that 130 ℃～160 ℃/0.4mmHg is collected in decompression obtains first intermediate product.
2, the sodium hydroxide and the 3.8L ethanol that in reactor, add 192g, wherein part ethanol is reclaimed by step 1 and obtains, add first intermediate product that 587g step 1 makes after the stirring and dissolving, stop heating after 2 hours 65 ℃ of following back flow reaction, decompression recycling ethanol is pulled an oar with ether to doing the back, and centrifugation obtains second intermediate product then.
3, it is 40% sulfuric acid that second intermediate product that step 2 is made adds massfraction after with water dissolution, solution is acidified to pH most 2, add then ether extract after washing to neutral, with suction filtration behind the anhydrous sodium sulfate drying, underpressure distillation is reclaimed ether and is obtained the 3rd intermediate product.
4, in reactor, add the 3rd intermediate product that 345g step 3 makes, 365g Geraniol and 285mL dimethylbenzene, stop heating after 9 hours at 135 ℃ of heating reflux reactions, isolate the water that reaction generates, decompression heats up and reclaims dimethylbenzene and excessive Geraniol, adding saturated sodium bicarbonate solution in residual solution stirs, add extracted with diethyl ether, washing, use anhydrous sodium sulfate drying, suction filtration, filtrate decompression reclaims ether, evaporate to dryness after adding silica gel stirs in the residual solution, go up 70 purpose silicagel columns then, elutriant is that mass ratio is normal hexane and the isopropyl ether of 30:70, collect the product elutriant and reclaim organic solvent and obtain faint yellow oily thing and be the gefarnate VII, measure through high performance liquid chromatograph, product purity is 99.5%.
Embodiment 3
1, in reactor, adds 1000g nerolidol, 2200g triethly orthoacetate and 90mL isopropylformic acid, 155 ℃ of heated and stirred, react and stop heating after 18 hours, decompression recycling ethanol, unreacted nerolidol, triethly orthoacetate and isopropylformic acid, the cut that 130 ℃～160 ℃/0.4mmHg is collected in decompression obtains first intermediate product.
2, the potassium hydroxide and the 7.7L ethanol that in reactor, add 393g, wherein part ethanol is reclaimed by step 1 and obtains, add first intermediate product that 1200g step 1 makes after the stirring and dissolving, stop heating after 2 hours 85 ℃ of following back flow reaction, decompression recycling ethanol is pulled an oar with ether to doing the back, and centrifugation obtains second intermediate product then.
3, it is 40% sulfuric acid that second intermediate product that step 2 is made adds massfraction after with water dissolution, solution is acidified to pH most 3, add then ether extract after washing to neutral, with suction filtration behind the anhydrous sodium sulfate drying, underpressure distillation is reclaimed ether and is obtained the 3rd intermediate product.
4, in reactor, add the 3rd intermediate product that 716g step 3 makes, 757g Geraniol and 588mL dimethylbenzene, stop heating after 12 hours at 155 ℃ of heating reflux reactions, isolate the water that reaction generates, decompression heats up and reclaims dimethylbenzene and excessive Geraniol, adding saturated sodium bicarbonate solution in residual solution stirs, add extracted with diethyl ether, washing, use anhydrous sodium sulfate drying, suction filtration, filtrate decompression reclaims ether, evaporate to dryness after adding silica gel stirs in the residual solution, go up 90 purpose silicagel columns then, elutriant is that mass ratio is normal hexane and the isopropyl ether of 30:70, collect the product elutriant and reclaim organic solvent and obtain faint yellow oily thing and be the gefarnate VII, measure through high performance liquid chromatograph, product purity is 99.6%.
The explanation of above embodiment just is used for helping to understand method of the present invention and core concept thereof.Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of claim of the present invention.
By foregoing description as can be known, adopt method provided by the invention to prepare gefarnate, the by product of solvent of Shi Yonging and generation all has hypotoxicity in process of production, and the ethanol that generates in the reaction also can reuse, and therefore can reduce pollution on the environment and improve raw material availability.
To the above-mentioned explanation of the disclosed embodiments, make this area professional and technical personnel can realize or use the present invention.Multiple modification to these embodiment will be conspicuous concerning those skilled in the art, and defined herein General Principle can realize under the situation that does not break away from the spirit or scope of the present invention in other embodiments.Therefore, the present invention will can not be restricted to these embodiment shown in this article, but will meet and principle disclosed herein and features of novelty the wideest corresponding to scope.
Claims (9)
1. preparation method of gefarnate comprises:
A), with nerolidol, triethly orthoacetate and acid catalyst mixing post-heating, obtain first intermediate product of formula III structure; Described acid catalyst is an isopropylformic acid;
B), in the ethanolic soln of alkali ROH, add the first intermediate product post-heating, obtain second intermediate product of formula IV structure;
C), with the second intermediate product water dissolution, then with regulator solution pH value to 1～4, obtain the 3rd intermediate product of formula V structure;
D), the 3rd intermediate product is added the Geraniol heating after with organic solvent dissolution, obtain gefarnate.
2. preparation method according to claim 1 is characterized in that the blending ratio of nerolidol and triethly orthoacetate is counted 1:1.5～3.5 by mole among the step a.
3. preparation method according to claim 2 is characterized in that, the mass ratio of described acid catalyst and nerolidol is 1:10～20.
4. preparation method according to claim 1 is characterized in that, the Heating temperature among the step a is 130 ℃～160 ℃.
5. preparation method according to claim 1 is characterized in that, the ethanolic soln of alkali is the ethanolic soln of sodium hydroxide or the ethanolic soln of potassium hydroxide among the step b.
6. preparation method according to claim 5 is characterized in that, first intermediate product that adds among the step b and the mol ratio of sodium hydroxide or potassium hydroxide are 1:1.1～1.8.
7. preparation method according to claim 1 is characterized in that, the Heating temperature of step b is 60 ℃～90 ℃.
8. preparation method according to claim 1 is characterized in that, the mol ratio of Geraniol and described the 3rd intermediate product is 1:1.1～2.0 in the steps d.
9. preparation method according to claim 1 is characterized in that, the Heating temperature in the steps d is 130 ℃～160 ℃.
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| CN102146039B (en) * | 2011-01-19 | 2013-06-05 | 北京莱瑞森医药科技有限公司 | Process for synthesizing gefarnate compound |
| CN102399141A (en) * | 2011-09-09 | 2012-04-04 | 南京瑞尔医药有限公司 | Preparation method of novel gefarnate key intermediate |
| CN103012140B (en) * | 2013-01-08 | 2016-02-17 | 湖南方盛制药股份有限公司 | The preparation method of gefarnate |
| CN104370731A (en) * | 2013-08-15 | 2015-02-25 | 南京瑞尔医药有限公司 | Gefarnate key intermediate refining or reaction solution direct post-processing method |
| CN103614426B (en) * | 2013-11-20 | 2016-06-15 | 湖北理工学院 | A kind of method preparing gefarnate |
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| CN101475476A (en) * | 2009-01-21 | 2009-07-08 | 海南美大制药有限公司 | Gefarnate compound and method for synthesizing the same |
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| CN101475476A (en) * | 2009-01-21 | 2009-07-08 | 海南美大制药有限公司 | Gefarnate compound and method for synthesizing the same |
Non-Patent Citations (1)
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| Jie Jack Li.0.《有机人名反应及机理》.华东理工大学出版社,2003, * |
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