CN102816116A - Synthetic method of 6-hydroxyl-2(1H)-quinolinone compound - Google Patents
Synthetic method of 6-hydroxyl-2(1H)-quinolinone compound Download PDFInfo
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- CN102816116A CN102816116A CN2012102358002A CN201210235800A CN102816116A CN 102816116 A CN102816116 A CN 102816116A CN 2012102358002 A CN2012102358002 A CN 2012102358002A CN 201210235800 A CN201210235800 A CN 201210235800A CN 102816116 A CN102816116 A CN 102816116A
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- hydroxyanilines
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- BSOFYGBKUCCONA-UHFFFAOYSA-N N=C(C=Cc1c2)Oc1ccc2O Chemical compound N=C(C=Cc1c2)Oc1ccc2O BSOFYGBKUCCONA-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a synthetic method of a 6-hydroxyl-2(1H)-quinolinone compound, comprising the following steps of: mixing 4-hydroxy aniline and cinnamoyl chloride, performing a reaction with stirring under the action of a gemini surfactant at the temperature of 50-150 DEG C for 1-20 h, and carrying out post-processing on a reacting liquid after the reaction, so as to obtain the 6-hydroxyl-2(1H)-quinolinone compound. The synthetic method provided by the invention is simple, has an advantage of cheap and easily available raw materials, is environmentally friendly, requires low cost, and is suitable for industrial operation.
Description
(1) technical field
The present invention relates to the method for the synthetic 6-hydroxyl-2 (1H) of catalysis-quinolinone compounds in a kind of double ion surfactant system.
(2) background technology
6-hydroxyl-2 (1H)-quinolinones compound is thrombocyte cAMP specific phosphodiesterase enzyme (PDE) suppressor factor; Ability is anticoagulant effectively; Owing to also have cAMP PDE in cardiac muscle and the vascular smooth muscle, its suppressor factor can strengthen myocardial contraction and vasodilation simultaneously.Therefore; Many 2 (1H)-quinolinones compounds all have in various degree cardiac stimulant, hypotensive effect; Wherein 6-hydroxyl-2 (1H)-quinolinones compound all has the effect of good restraining platelet aggregation, and is significant to preventing and treating cardiovascular disordeies such as myocardial infarction, apoplexy.
Gemini surface active agent is the tensio-active agent with one type of special construction of two hydrophilic radicals and two lipophilic groups, than conventional surfactant (having only a hydrophilic radical and a lipophilic group) higher better surfactivity is arranged.Gemini surface active agent is the remarkable novel surfactant of one type of performance, has high surfactivity.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 technology always, therefore utilizes the Gemini surface active agent system in the present invention, has invented a kind of new synthetic method of synthesizing series quinolinone pharmaceutical intermediate.
Compound method about 6-hydroxyl-2 (1H)-quinolinone mainly contains following four kinds at present:
1894, the Gattermann reported first through electroreduction 2-nitro-5-hydroxycinnamic acid, obtained 6-hydroxyl-2 (1H)-quinolinone.
1954, Richard R.Holmes etc. reported from N-oxidation-6-methoxy quinoline, through chloro, and acidifying and obtain 6-hydroxyl-2 (1H)-quinolinone.
In order effectively to make N-oxidation quinoline change 6-hydroxyl-2 (1H)-quinolinone into; RichardR.Holmes and Henze attempt obtaining 6-methoxy quinoline ketone to N-oxidation-6-methoxy quinoline and Benzoyl chloride 99min. direct reaction under alkaline condition; But not success is not had to a HMP and is insoluble to the compound of alkali.
1969; Kobayashi.Y etc. have reported through the 6-hydroxyquinoline and have got N-oxidation-6-hydroxyquinoline with MCPBA (3-chloroperoxybenzoic acid) oxidation; Get 6-acetyl oxygen-2-copper 8hydroxyquinolate with acetic anhydride then, hydrolysis obtains 6-hydroxyl-2 (1H)-quinolinone under alkaline condition again.Though this synthetic route is more direct, total recovery has only 17%.
Manabe.Yoshiaki and Tai_chi Wang etc. all reported through P-nethoxyaniline and cinnamyl chloride under alkaline condition, react 4-methoxyl group-N-cinnyl aniline, it issues in catalysis of aluminum trichloride (anhydrous) in chlorobenzene solution and gives birth to intramolecular Fu-gram and react and obtain 6-hydroxyl-2 (1H)-quinolinone.
(3) summary of the invention
The object of the invention provides a kind of method of in the Gemini surface active agent system, synthesizing 6-hydroxyl-2 (1H)-quinolinone compounds, and this method helps large-scale industrial production, reaches energy-saving and emission-reduction and eco-friendly purpose.
The technical scheme that the present invention adopts is:
The compound method of a kind of 6-hydroxyl-2 (1H)-quinolinone compounds; Said method is: the 4-hydroxyanilines is mixed with cinnamyl chloride; Under the face of Shuangzi shown in formula II influence of surfactant, 50 ~ 150 ℃ of following stirring reaction 1 ~ 20h are after reaction finishes; With the reaction solution aftertreatment, obtain said 6-hydroxyl-2 (1H)-quinolinone compounds;
Further, said 4-hydroxyanilines is 1:1～3 with the ratio of the amount of substance that feeds intake of cinnamyl chloride, more preferably 1:1 ~ 1.5, most preferably 1:1.5.
Further, the weight ratio that feeds intake of said 4-hydroxyanilines and Gemini surface active agent is 1:3～10.
Further; The method of reaction solution aftertreatment is in the compound method of said 6-hydroxyl-2 (1H)-quinolinone compounds: after reaction finishes; Extract with toluene after reaction solution is cooled to room temperature; Extraction liquid is concentrated into no toluene solvant and flows out, and enriched material gets said 6-hydroxyl-2 (1H)-quinolinone compounds with methyl alcohol (preferred industrial methanol) recrystallization.
Further; The compound method of said 6-hydroxyl-2 (1H)-quinolinone compounds recommends to carry out according to the following steps: the 4-hydroxyanilines is mixed with ratio 1:1 ~ 1.5 of amount of substance with cinnamyl chloride; Add the face of Shuangzi shown in formula II tensio-active agent again, at 50 ~ 150 ℃ of following stirring reaction 5 ~ 20h, after reaction finishes; Extract with toluene after reaction solution is cooled to room temperature; Extraction liquid is concentrated into no toluene solvant outflow and gets final product, and enriched material gets said 6-hydroxyl-2 (1H)-quinolinone compounds with methyl alcohol (preferred industrial methanol) recrystallization; The weight ratio of said 4-hydroxyanilines and Shuangzi face tensio-active agent is 1:5 ~ 6.
The structural formula of 6-hydroxyl-2 of the present invention (1H)-quinolinone compounds is shown in formula I:
The reaction formula of described 6-hydroxyl-2 (1H)-quinolinone compounds is following:
Gemini surface active agent of the present invention is the ditane Gemini surface active agent, and concrete preparation method prepares 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 adds ditane and anhydrous AlC1 in the four-hole reaction flask of electric mixer, TM, reflux condensing tube, tap funnel is housed
3, fully stirring is uniformly dispersed catalyzer, at 45-50 ℃, drips laurylene hydrocarbon (alkene is 2:1 with the ratio of the amount of substance of ditane); The dropping time is controlled at 20-30min and drips, and gradually temperature of reaction is risen to 70 ℃ then, and remains unchanged, reaction 8h; Reaction transfers to neutrality with reaction solution, extracted in toluene, anhydrous magnesium sulfate drying after finishing; Filter, concentrate alkylate, be used for step sulfonation down;
2) sulfonation adds the alkylate of above-mentioned acquisition in the four-hole reaction flask of electric mixer, TM, reflux condensing tube, tap funnel is housed, and under violent stirring, dropwise adds 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, promptly get sulfonated products;
3) neutralization reaction is equipped with the sulfonated products adding in the four-hole reaction flask of electric mixer, TM, reflux condensing tube, tap funnel; With the water-bath control reaction temperature at 35～40 ℃; With tap funnel mass concentration 15% aqueous sodium hydroxide solution is slowly added; The conditioned reaction system pH is 7～8, makes sulfonic acid all generate sodium sulfonate and is the Gemini surface active agent product.
Compared with prior art, beneficial effect of the present invention:
The present invention has avoided using a large amount of liquid soda acids and organic solvent, in the Gemini surface active agent reaction system, and simple synthetic method; Raw material cheaply is easy to get; The employing Gemini surface active agent is environmentally friendly, and production cost is low, and Technology is suitable for carrying out suitability for industrialized production.
(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 adds ditane 16.8g (0.1mol), anhydrous AlC1 in the four-hole reaction flask that electric mixer, TM, reflux condensing tube, tap funnel, HCl gas access equipment are housed
313g, fully stirring is uniformly dispersed catalyzer, at 45-50 ℃, drips laurylene hydrocarbon 34g (0.2mol); The dropping time is controlled at 20-30min and drips, and gradually temperature of reaction is risen to 70 ℃ then, and remains unchanged, reaction 8h; Reaction transfers to neutrality with reaction solution, extracted in toluene after finishing; Anhydrous magnesium sulfate drying filters, and concentrates to such an extent that alkylate is used for step sulfonation down;
2) sulfonation adds the alkylate of above-mentioned acquisition in the four-hole reaction flask of electric mixer, TM, reflux condensing tube, tap funnel is housed, and under violent stirring, dropwise adds chlorsulfonic acid 24g (0.2mol); The dropping time is lh; Temperature of reaction is controlled at 20-25 ℃, reacts 2 hours, make the abundant sulfonation of alkylate after; Place, the HCl of generation is discharged as much as possible promptly get sulfonated products;
3) neutralization reaction is equipped with the sulfonated products adding in the four-hole reaction flask of electric mixer, TM, reflux condensing tube, tap funnel; With the water-bath control reaction temperature at 35～40 ℃; With tap funnel mass concentration 15% aqueous sodium hydroxide solution is slowly added; The conditioned reaction system pH is 7～8, makes sulfonic acid all generate sodium sulfonate and is Gemini surface active agent.
The preparation of embodiment 2:6-hydroxyl-2 (1H)-quinolinone compounds
In the 150ml there-necked flask, add 4-hydroxyanilines 3.27g (0.3mol), cinnamyl chloride 5.3g (0.32mol); The Gemini surface active agent 9.8g of embodiment 1 method preparation, reaction is 10 hours under 100 ℃ of stirrings, after reaction finishes reaction solution is cooled to room temperature (25 ℃) back with toluene 30mL extraction three times; The combining methylbenzene layer is evaporated to no toluene and flows out, and enriched material is used industrial recrystallizing methanol; Get white solid 1.2g; Be 6-hydroxyl-2 (1H)-quinolinone compounds, yield 61%, m.p.>300 ℃.IR(KBr):3108,2852,1658,1629,1429,1298cm
-1.
1HNMR(DMSO-d
6)δ:6.48(1H，d,J=9.52,H-3),7.16~7.25(3H,m,ArH),7.81(1H，d,J=9.52,H-4),9.46(1H，s,OH),11.64(1H，s,H-1)。
The preparation of embodiment 3:6-hydroxyl-2 (1H)-quinolinone compounds
In the 150ml there-necked flask, add 4-hydroxyanilines 3.27g (0.3mol), cinnamyl chloride 7.5g (0.45mol); The Gemini surface active agent 33g of embodiment 1 method preparation, reaction is 10 hours under 150 ℃ of stirrings, and reaction finishes afterreaction liquid with toluene 30mL extraction three times; The combining methylbenzene layer is concentrated into no toluene and flows out, and enriched material is used industrial recrystallizing methanol again; White solid 1.1g, i.e. 6-hydroxyl-2 (1H)-quinolinone compounds, yield 59%.
The preparation of embodiment 4:6-hydroxyl-2 (1H)-quinolinone compounds
In the 150ml there-necked flask, add 4-hydroxyanilines 3.27g (0.3mol), cinnamyl chloride 4.99g (0.3mol); The Gemini surface active agent 16g of embodiment 1 method preparation, reaction is 20 hours under 50 ℃ of stirrings, and other is operated with embodiment 2; Get white solid 1.0g, yield 52%.
The preparation of embodiment 5:6-hydroxyl-2 (1H)-quinolinone compounds
In the 150ml there-necked flask, add 4-hydroxyanilines 3.27g (0.3mol), cinnamyl chloride 15g (0.9mol); The Gemini surface active agent 33g of embodiment 1 method preparation, reaction is 5 hours under 150 ℃ of stirrings, and other is operated with embodiment 2; Get white solid 1.2g, yield 62%.
Claims (6)
1. the compound method of a 6-hydroxyl-2 (1H)-quinolinone compounds; It is characterized in that said method is: the 4-hydroxyanilines is mixed with cinnamyl chloride; Under the face of Shuangzi shown in formula II influence of surfactant, 50 ~ 150 ℃ of following stirring reaction 1 ~ 20h are after reaction finishes; With the reaction solution aftertreatment, obtain said 6-hydroxyl-2 (1H)-quinolinone compounds;
2. the compound method of 6-hydroxyl-2 (1H)-quinolinone compounds according to claim 1 is characterized in that the said 4-hydroxyanilines and the ratio of the amount of substance that feeds intake of cinnamyl chloride are 1:1～3.
3. like the compound method of the said 6-hydroxyl-2 of claim 2 (1H)-quinolinone compounds, it is characterized in that the said 4-hydroxyanilines and the ratio of the amount of substance that feeds intake of cinnamyl chloride are 1:1～1.5.
4. the compound method of 6-hydroxyl-2 (1H)-quinolinone compounds according to claim 1 is characterized in that the weight ratio that feeds intake of said 4-hydroxyanilines and Gemini surface active agent is 1:3～10.
5. the compound method of 6-hydroxyl-2 (1H)-quinolinone compounds according to claim 1; The method that it is characterized in that said reaction solution aftertreatment is: after reaction finishes; Reaction solution is extracted with toluene; Extraction liquid concentrates, and gets enriched material and uses recrystallizing methanol again, obtains said 6-hydroxyl-2 (1H)-quinolinone compounds.
6. the compound method of 6-hydroxyl-2 (1H)-quinolinone compounds according to claim 1; It is characterized in that said method carries out according to the following steps: the 4-hydroxyanilines is mixed with ratio 1:1～1.5 of amount of substance with cinnamyl chloride; Add the face of Shuangzi shown in formula II tensio-active agent again, at 50～150 ℃ of following stirring reaction 5 ~ 20h, after reaction finishes; Extract with toluene after reaction solution is cooled to room temperature; Extraction liquid concentrates, and uses recrystallizing methanol again, gets said 6-hydroxyl-2 (1H)-quinolinone compounds; The weight ratio of said 4-hydroxyanilines and Shuangzi face tensio-active agent is 1:5～6.
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Cited By (2)
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| CN108299254A (en) * | 2018-03-19 | 2018-07-20 | 青岛大学 | A kind of N- alkyl urea groups anionic gemini surfactant and preparation method thereof |
| CN115611807A (en) * | 2022-09-02 | 2023-01-17 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of cilostazol intermediate |
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| 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 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108299254A (en) * | 2018-03-19 | 2018-07-20 | 青岛大学 | A kind of N- alkyl urea groups anionic gemini surfactant and preparation method thereof |
| CN108299254B (en) * | 2018-03-19 | 2020-06-30 | 青岛大学 | N-alkyl ureido anionic gemini surfactant and preparation method thereof |
| CN115611807A (en) * | 2022-09-02 | 2023-01-17 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of cilostazol intermediate |
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