CN102816115B - Synthetic method of hydroxy-substituted-3,4-dihydro-2(1H)-quinolinone compound - Google Patents
Synthetic method of hydroxy-substituted-3,4-dihydro-2(1H)-quinolinone compound Download PDFInfo
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Abstract
The invention discloses a synthetic method of a hydroxy-substituted-3,4-dihydro-2(1H)-quinolinone compound, comprising the following steps of: mixing hydroxy-substituted aniline and propionyl chloride; reacting under the action of a gemini surfactant as shown in the formula (II) at the temperature of 100-150 DEG C for 1-20 h; and carrying out post-processing on the reaction solution after the reaction so as to obtain the hydroxy-substituted-3,4-dihydro-2(1H)-quinolinone compound. The synthetic method provided by the invention is simple, has advantages of cheap and easily available raw materials, good yield, low cost and repeatedly usable reaction system, and is suitable for industrial operation.
Description
(1) technical field
The present invention relates in a kind of double ion surfactant system, to catalyze and synthesize hydroxyl and replace-3,4-dihydro-2(1H) method of-quinolinone compounds.
(2) background technology
Hydroxyl replaces-3,4-dihydro-2 (1H)-quinolinones compound has certain physiologically active, it is thrombocyte cAMP (cyclic monophosphate) specific phosphodiesterase enzyme (PDE-III or IV hypotype) inhibitor, effective anticoagulant, owing to also having cAMP-PDE in cardiac muscle and vascular smooth muscle, its inhibitor can strengthen myocardial contraction vasodilation simultaneously, therefore most hydroxyls replace-3,4-dihydro-2 (1H)-quinolinones compound all has cardiac stimulant, hypotensive effect to some extent, is widely used in the treatment of cardiovascular disorder.But traditional synthetic method has larger impact to environment, aftertreatment technology is complicated, and developing green chemical synthesising technology has a extensive future.
Gemini surface active agent is the tensio-active agent with a class special construction of two hydrophilic radicals and two lipophilic groups, than conventional surfactant (only having a hydrophilic radical and a lipophilic group), has higher better surfactivity.Gemini surface active agent is the novel surfactant of a class performance brilliance, has high surfactivity.The good multiple advantages such as water-soluble and rheological, have wide practical use.In recent years, our seminar is devoted to the research and development of green chemical industry technique always, therefore utilizes in the present invention Gemini surface active agent system, has invented a kind of new synthetic method of synthesizing series quinolinone pharmaceutical intermediate.The method is convenient to operation and processing, easily reclaims, and is expected to solve the pollution problem occurring in chemical reaction process.
(3) summary of the invention
The object of the invention is to provide a kind of in Gemini surface active agent system, catalyzes and synthesizes hydroxyl and replaces-3,4-dihydro-2(1H) method of-quinolinones compound, the method is conducive to large-scale industrial and produces.
The technical solution used in the present invention is:
A kind of hydroxyl replaces-3, the synthetic method of 4-dihydro-2(1H)-quinolinones compound, described method is: hydroxyl-substituted amine and propionyl chloride are mixed, under the effect of Gemini surface active agent shown in formula II, in 100 ~ 150 ℃ of reaction 1 ~ 20h, after reaction finishes, by reaction solution aftertreatment, obtain the hydroxyl shown in described formula I and replace-3,4-dihydro-2(1H)-quinolinones compound; R shown in described formula I in compound is OH, described in be substituted by ortho position, contraposition or a position replaces; The ortho position that is substituted by aniline of described hydroxyl-substituted amine, contraposition or a position are replaced by hydroxyl;
Further, described hydroxyl-substituted amine is 1:1～2 with the ratio of the amount of substance that feeds intake of propionyl chloride, preferably 1:1 ~ 1.2, most preferably 1:1.
Further, described Gemini surface active agent and hydroxyl-substituted amine mass ratio are 3～15:1, preferably 10～12:1.
Further, described temperature of reaction is preferably 110 ~ 130 ℃, and the described reaction times is preferably 8 ~ 15h, more preferably 10 ~ 12h.
Further, described hydroxyl replaces-3, in the synthetic method of 4-dihydro-2(1H)-quinolinones compound, reaction solution post-treating method is: after reaction finishes, reaction solution is cooled to room temperature, with toluene extraction, extraction liquid is evaporated to solvent-free outflow again, methyl alcohol for enriched material (preferably industrial methanol) recrystallization, obtain described hydroxyl and replace-3,4-dihydro-2(1H)-quinolinones compound.
Further, described hydroxyl replaces-3, the synthetic method of 4-dihydro-2(1H)-quinolinones compound recommends to carry out as follows: hydroxyl-substituted amine and propionyl chloride are mixed with ratio 1:1 ~ 1.2 of the amount of substance that feeds intake, under the effect of Gemini surface active agent shown in formula II, in 110 ~ 130 ℃ of reaction 8 ~ 15h, after reaction finishes, reaction solution is cooled to room temperature, with toluene, extract again, extraction liquid is evaporated to solvent-free outflow, with methyl alcohol (preferably industrial methanol) recrystallization, obtain described hydroxyl and replace-3,4-dihydro-2(1H)-quinolinones compound; Described Gemini surface active agent and hydroxyl-substituted amine mass ratio are 10～12:1.
Hydroxyl replacement-3, the 4-dihydro-2(1H for preparing of the present invention) reaction formula of-quinolinones compound is as follows:
Gemini surface active agent of the present invention is ditane Gemini surface active agent, and concrete preparation method is prepared as follows with reference to " the synthetic and performance study of Shuangzi face tensio-active agent, Hu Longjiang, Daqing Petroleum Institute's Master's thesis (2004) ":
1) alkylation, in the four-hole reaction flask of electric mixer, thermometer, reflux condensing tube, dropping funnel is housed, adds ditane and anhydrous AlC1
3, fully stir catalyzer be uniformly dispersed, at 45-50 ℃, drip benzene (alkene is 2:1 with the ratio of the amount of substance of ditane), time for adding is controlled at 20-30min and drips, and then temperature of reaction is risen to 70 ℃ gradually, and remain unchanged, reaction 8h, after reaction finishes, reaction solution is adjusted to neutrality, toluene extraction, anhydrous magnesium sulfate drying, filters, concentrate to obtain alkylate, for lower step sulfonation;
2) sulfonation is in being equipped with the four-hole reaction flask of electric mixer, thermometer, reflux condensing tube, dropping funnel, the alkylate that adds above-mentioned acquisition, under violent stirring, dropwise add chlorsulfonic acid, the molar ratio of alkylate and chlorsulfonic acid is 2:1, time is lh, and temperature of reaction is controlled at 20-25 ℃, reacts 2 hours, place, obtain sulfonated products;
3) neutralization reaction adds sulfonated products in the four-hole reaction flask that electric mixer, thermometer, reflux condensing tube, dropping funnel are housed, with water-bath, control temperature of reaction at 35～40 ℃, with dropping funnel, mass concentration 15% aqueous sodium hydroxide solution is slowly added, regulating pH value of reaction system is 7～8, makes sulfonic acid all generate sodium sulfonate and is Gemini surface active agent product.
Compared with prior art, beneficial effect of the present invention is mainly reflected in: simple synthetic method of the present invention, and raw material is cheaply easy to get, and yield is good, and cost is low, and reaction system is reusable, is suitable for carrying out industrialization operation.
(4) embodiment
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this:
The preparation of embodiment 1 Shuangzi face tensio-active agent
1) alkylation, in the four-hole reaction flask of electric mixer, thermometer, reflux condensing tube, dropping funnel, HCl gas access equipment is housed, adds ditane 16.8g(0.1mol), anhydrous AlC1
313g, fully stirs catalyzer is uniformly dispersed, at 45-50 ℃, drip benzene 34g(0.2mol), time for adding is controlled at 20-30min and drips, and then temperature of reaction is risen to 70 ℃ gradually, and remain unchanged, reaction 8h, after reaction finishes, is adjusted to neutrality by reaction solution, toluene extraction, anhydrous magnesium sulfate drying, filters, concentrated that alkylate is used for lower step sulfonation;
2) sulfonation is in being equipped with the four-hole reaction flask of electric mixer, thermometer, reflux condensing tube, dropping funnel, the alkylate that adds above-mentioned acquisition, under violent stirring, dropwise add chlorsulfonic acid 24g(0.2mol), time for adding is lh, temperature of reaction is controlled at 20-25 ℃, reacts 2 hours, makes after the abundant sulfonation of alkylate, place, make the HCl generating discharge as much as possible and obtain sulfonated products;
3) neutralization reaction adds sulfonated products in the four-hole reaction flask that electric mixer, thermometer, reflux condensing tube, dropping funnel are housed, with water-bath, control temperature of reaction at 35～40 ℃, with dropping funnel, mass concentration 15% aqueous sodium hydroxide solution is slowly added, regulating pH value of reaction system is 7～8, makes sulfonic acid all generate sodium sulfonate and is Gemini surface active agent.
Embodiment 2 6-hydroxyl-3,4-dihydro-2(1H) preparation of-quinolinone
In 150mL there-necked flask, add para hydroxybenzene amine 10.9g (0.1mol), Gemini surface active agent 109g prepared by embodiment 1 method, propionyl chloride 12.7g (0.1mol), at 110 ℃, stirring reaction 10 hours, after reaction finishes, reaction solution is cooled to room temperature (25 ℃), then extracts three times with toluene 20mL, extraction liquid is evaporated to solvent-free outflow, the industrial recrystallizing methanol of enriched material, the dry white solid 14.2g that to obtain, i.e. 6-hydroxyl-3,4-dihydro-2(1H)-quinolinone, yield 87%, m.p.235～237 ℃.MS?m/z:163(M
+)；IR(KBr):3214,1652，1504,1397,1290,1253，949,815,779cm
-1；
1HNMRδ:2.34～2.49(2H),2.74～2.78(2H),6.52～6.66(3H),8.90(1H),9.70(1H)ppm。
Embodiment 3 7-hydroxyl-3,4-dihydro-2(1H) preparation of-quinolinone
In 150mL there-necked flask, add a hydroxyanilines 10.9g (0.1mol), Gemini surface active agent 109g prepared by embodiment 1 method, propionyl chloride 12.7g (0.1mol), at 130 ℃, stirring reaction is 12 hours, other operations are with embodiment 2, white solid 13.7g, i.e. 7-hydroxyl-3,4-dihydro-2(1H)-quinolinone, yield 84%, m.p.228～230 ℃.MS?m/z:163(M
+)；IR(KBr):3279,1657，1605，1523,1397,1192，866，837,805cm
-1。
1HNMRδ:2.39(2H)，2.73(2H),6.3(2H),6.9(1H),9.24(1H)，9.93(1H)ppm。
Embodiment 4 8-hydroxyl-3,4-dihydro-2(1H) preparation of-quinolinone
In 150mL there-necked flask, add ortho-aminophenol 10.9g (0.1mol), Gemini surface active agent 109g prepared by embodiment 1 method, propionyl chloride 12.7g (0.1mol), 110 ℃ of stirring reactions 12 hours, other operations are with embodiment 2, white solid 13.4g, i.e. 8-hydroxyl-3,4-dihydro-2(1H)-quinolinone, yield 82%, m.p.193～195 ℃.MS?m/z:163(M
+)；IR(KBr):3223,1642，1587,1492，1397,1309，877,795,716cm
-1；
1HNMRδ:2.43(2H),2.83(2H),6.7(3H),8.77(1H)，9.63(1H)ppm。
Embodiment 5 8-hydroxyl-3,4-dihydro-2(1H) preparation of-quinolinone
In 150mL there-necked flask, add ortho-aminophenol 10.9g (0.1mol), Gemini surface active agent 163.5g prepared by embodiment 1 method, propionyl chloride 15.3g (0.11mol), 110 ℃ of stirring reactions 12 hours, other operations are with embodiment 2, white solid 13.4g, i.e. 8-hydroxyl-3,4-dihydro-2(1H)-quinolinone, yield 82%, m.p.193～195 ℃.MS?m/z:163(M
+)；IR(KBr):3223,1642，1587,1492，1397,1309，877,795,716cm
-1；
1HNMRδ:2.43(2H),2.83(2H),6.7(3H),8.77(1H)，9.63(1H)ppm。
Embodiment 6 7-hydroxyl-3,4-dihydro-2(1H) preparation of-quinolinone
In 150mL there-necked flask, add a hydroxyanilines 10.9g (0.1mol), Gemini surface active agent 33g prepared by embodiment 1 method, propionyl chloride 12.7g (0.1mol), at 120 ℃, stirring reaction is 12 hours, other operations are with embodiment 2, white solid 13.7g, i.e. 7-hydroxyl-3,4-dihydro-2(1H)-quinolinone, yield 84%, m.p.228～230 ℃.MS?m/z:163(M
+)；IR(KBr):3279,1657，1605，1523,1397,1192，866，837,805cm
-1。
1HNMRδ:2.39(2H)，2.73(2H),6.3(2H),6.9(1H),9.24(1H)，9.93(1H)ppm。
Claims (7)
1. a hydroxyl replaces-3, the synthetic method of 4-dihydro-2(1H)-quinolinone compounds, it is characterized in that described method is: hydroxyl-substituted amine and 3-chlorpromazine chloride are mixed, under the effect of Gemini surface active agent shown in formula II, in 100～150 ℃ of reaction 1～20h, after reaction finishes, by reaction solution aftertreatment, obtain described hydroxyl and replace-3,4-dihydro-2(1H)-quinolinone compounds;
（Ⅱ）。
2. hydroxyl replaces-3,4-dihydro-2(1H as claimed in claim 1) synthetic method of-quinolinone compounds, it is characterized in that described hydroxyl-substituted amine and the ratio of the amount of substance that feeds intake of 3-chlorpromazine chloride are 1:1～2.
3. hydroxyl replaces-3,4-dihydro-2(1H as claimed in claim 1) synthetic method of-quinolinone compounds, it is characterized in that described hydroxyl-substituted amine and the ratio of the amount of substance that feeds intake of 3-chlorpromazine chloride are 1:1～1.2.
4. hydroxyl replaces-3,4-dihydro-2(1H as claimed in claim 1) synthetic method of-quinolinone compounds, it is characterized in that described Gemini surface active agent and hydroxyl-substituted amine mass ratio are 3～15:1.
5. hydroxyl replaces-3,4-dihydro-2(1H as claimed in claim 1) synthetic method of-quinolinone compounds, it is characterized in that described temperature of reaction is 110～130 ℃, the described reaction times is 8～15h.
6. hydroxyl replaces-3 as claimed in claim 1, the synthetic method of 4-dihydro-2(1H)-quinolinone compounds, it is characterized in that described reaction solution post-treating method is: after reaction finishes, reaction solution is cooling, with toluene extraction, get extraction liquid concentrating under reduced pressure, enriched material recrystallizing methanol, obtain described hydroxyl and replace-3,4-dihydro-2(1H)-quinolinone compounds.
7. hydroxyl replaces-3 as claimed in claim 1, the synthetic method of 4-dihydro-2(1H)-quinolinone compounds, it is characterized in that described method carries out as follows: hydroxyl-substituted amine and 3-chlorpromazine chloride are mixed with ratio 1:1～1.2 of the amount of substance that feeds intake, under the effect of Gemini surface active agent shown in formula II, in 110～130 ℃ of reaction 8～15h, after reaction finishes, reaction solution is cooled to room temperature, with toluene, extract again, extraction liquid concentrating under reduced pressure, enriched material recrystallizing methanol, obtains described hydroxyl and replaces-3,4-dihydro-2(1H)-quinolinone compounds; Described Gemini surface active agent and hydroxyl-substituted amine mass ratio are 10～12:1.
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| CN1890248A (en) * | 2003-12-05 | 2007-01-03 | 阿斯利康(瑞典)有限公司 | Novel compounds |
| CN102030706A (en) * | 2010-12-22 | 2011-04-27 | 江苏食品职业技术学院 | Method for preparing 6-hydroxy-2(1H)-quinolone in ionic liquid by using one-pot method |
| CN102424669A (en) * | 2011-10-28 | 2012-04-25 | 池州方达科技有限公司 | Preparation method of 6-hydroxy-2(1H)-quinolinone compound |
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| CN1890248A (en) * | 2003-12-05 | 2007-01-03 | 阿斯利康(瑞典)有限公司 | Novel compounds |
| CN102030706A (en) * | 2010-12-22 | 2011-04-27 | 江苏食品职业技术学院 | Method for preparing 6-hydroxy-2(1H)-quinolone in ionic liquid by using one-pot method |
| CN102424669A (en) * | 2011-10-28 | 2012-04-25 | 池州方达科技有限公司 | Preparation method of 6-hydroxy-2(1H)-quinolinone compound |
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| "Gemini surfactants: A distinct class of self-assembling molecules";S. K. Hait et al.;《CURRENT SCIENCE》;20020510;第82卷(第9期);第1101-1111页 * |
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