CN105732494A - Synthetic method for quinolinone derivative - Google Patents
Synthetic method for quinolinone derivative Download PDFInfo
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- CN105732494A CN105732494A CN201610229058.2A CN201610229058A CN105732494A CN 105732494 A CN105732494 A CN 105732494A CN 201610229058 A CN201610229058 A CN 201610229058A CN 105732494 A CN105732494 A CN 105732494A
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- ketone derivative
- quinoline ketone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a synthetic method for a quinolinone derivative.According to a reaction mechanism, on the alkaline condition,a ring-closure reaction is conducted on a compound I under catalysis of a catalyst to generate a compound II, wherein R1 represents a C1-C6 alkyl group, or a C1-C6 alkoxy group, or an aryl group or a heterocyclic aryl group, R2 represents a C1-C6 alkyl group or a C1-C6 alkoxy group, and X represents halogen.An efficient multi-component catalyst system is adopted in the synthetic method, selectivity of an intramolecular cyclization reaction is improved, and the prepared target product is high in yield.The preparing method is easy to operate and high in production efficiency, environment conditions needed by the reaction is mild, and the synthetic method is suitable for large-scale industrial production.
Description
Technical field:
The present invention relates to medicine intermediate synthesis field, the synthetic method of a kind of quinoline ketone derivative.
Background technology:
Quinolinone is a kind of common wide spectrum heterocycle structure skeleton, exists with multiple natural product and drug molecule, has
There are significant biological activity and medical value.Present stage, quinoline ketone derivative has been widely used in multiple disease
In treatment, such as anticancer, blood pressure lowering, treatment gastric ulcer and antithrombotic etc..So, about the synthetic method of the derivant of quinolinones
Cause and study widely.
Chinese patent 201310064184.3 discloses the alkyl substd quinolines ketonic compound of a kind of band side chain, its chemistry knot
Structure such as formula I, its entitled 2-(4`-methyl-) heptane base-3-methyl-4 (1H)-quinolinone, its chemical formula is C18H22NO, name
For quinoline ketone in heptan.The present invention also provides for the pharmaceutical composition of described compound in preparation for preventing and/or treating H. pylori
Bacterium causes the purposes in the medicine that gastritis is sick.1 N of quinolinone of the present invention is not by hydroxylating, and 2 are replaced by 4 methyl-heptan bases.
Chinese patent CN200410025671.X discloses a kind of quinolinone compounds 4-methyl-6-(2,3-epoxy the third oxygen
Base)-2 (1H)-quinolinones, the chemosynthesis of Preparation Method And Their Intermediate.Described preparation method includes adding intermediate
In organic solvent and water, adding alkali metal soln, react 1～5 hour at-30 DEG C～0 DEG C, then acid adding neutralizes, and filters
And purification.4-methyl-6-(2,3-glycidoxy)-2 (1H)-quinolinone of the present invention can be used for the system of medicine intermediate
Standby.
Summary of the invention:
The present invention relates to the synthetic method of a kind of quinoline ketone derivative, have employed efficient multi-component catalyst systems,
Improving the selectivity of intramolecular cyclization reaction, prepared target product yield is high.Meanwhile, this preparation method is simple to operate, produces
Efficiency is high, and the required environmental condition of reaction is gentle, is very suitable for large-scale industrial production and uses.
For achieving the above object, the present invention is by the following technical solutions:
The preparation method of a kind of quinoline ketone derivative, it is characterised in that reaction mechanism is as follows: in the basic conditions, by
After catalyst, there is ring-closure reaction in compounds I, generates compound ii.
Wherein R1For C1-C6Alkyl, C1-C6Alkoxyl, aryl or heteroaryl, R2For C1-C6Alkyl or C1-C6Alkoxyl, X
For halogen.
Preferred as technique scheme, wherein said C1-C6Alkyl is the straight or branched containing 1-6 carbon atom
Alkyl.
Preferred as technique scheme, wherein said C1-C6Alkoxyl is containing 1-6 carbon atom and an oxygen
The straight or branched alkyl of atom.
Preferred as technique scheme, wherein said aryl is benzene, toluene or naphthalene.
Preferred as technique scheme, wherein said heteroaryl is pyridine or pyrans.
Preferred as technique scheme, the concrete operation step of wherein said preparation method is: dissolved by compounds I
In DMF, adding organic base, regulation pH is 8-9, then is added thereto to catalyst and hydrogen peroxide, increases the temperature to 60-80
DEG C, adding and turn/the rotating speed of min stirring with 70-90, after sustained response 12h, reaction terminates；Filter, by filtrate regulation to neutral,
After adding acetone extract, it is dried and concentrates, cross silica gel column chromatography, after being rinsed with the acetone-normal hexane mixed liquor of equal-volume ratio
Obtain compound ii.
Preferred as technique scheme, wherein said organic base is dimethylamine, in diethanol ammonium or potassium tert-butoxide
A kind of.
Preferred as technique scheme, wherein said catalyst is double (dibenzalacetone) palladium, sodium borate and four
The mol ratio of phenyl porphyrin is the mixture of 1:1:2.
Preferred as technique scheme, described compounds I is 1:0.08-0.15 with the mol ratio of catalyst.
Preferred as technique scheme, described compounds I is 1:1.2-1.5 with the mol ratio of hydrogen peroxide.
The method have the advantages that
The synthetic method of quinoline ketone derivative of the present invention, have employed three novel components and urges
Agent, reacts under alkaline environment, improves the output efficiency of purpose product and the purity of product, and improves anti-
Answering speed, the required environmental condition of reaction is gentle, is very suitable for large-scale industrial production.
Detailed description of the invention:
In order to be better understood from the present invention, below by embodiment, the present invention is further described, and embodiment is served only for solving
Release the present invention, the present invention will not be constituted any restriction.
Embodiment 1
Being dissolved in DMF by compounds I 100mmol in above formula, add dimethylamine, regulation pH is 8-9, then adds wherein
Enter 9mmol catalyst and 120mmol hydrogen peroxide, increase the temperature to 60 DEG C, add and stir with the rotating speed of 80 turns/min, continue anti-
After answering 12h, reaction terminates；Filter, by filtrate regulation to neutral, after adding acetone extract, be dried and concentrate, cross silica gel column chromatography,
The compound ii obtaining in above formula after being rinsed with the acetone-normal hexane mixed liquor of equal-volume ratio.
The purity of target product is 87.2%, and productivity is 94.1%.
Embodiment 2
Being dissolved in DMF by compounds I 100mmol in above formula, add potassium tert-butoxide, regulation pH is 8-9, more wherein
Add 12mmol catalyst and 130mmol hydrogen peroxide, increase the temperature to 70 DEG C, add and stir with the rotating speed of 90 turns/min, hold
After continuous reaction 12h, reaction terminates；Filter, by filtrate regulation to neutral, after adding acetone extract, be dried and concentrate, cross silica gel column chromatography
Post, the compound ii obtaining in above formula after being rinsed with the acetone-normal hexane mixed liquor of equal-volume ratio.
The purity of target product is 89.2%, and productivity is 95.7%.
Embodiment 3
Being dissolved in DMF by compounds I 100mmol in above formula, add diethanol ammonium, regulation pH is 8-9, more wherein
Add 15mmol catalyst and 140mmol hydrogen peroxide, increase the temperature to 80 DEG C, add and stir with the rotating speed of 90 turns/min, hold
After continuous reaction 12h, reaction terminates；Filter, by filtrate regulation to neutral, after adding acetone extract, be dried and concentrate, cross silica gel column chromatography
Post, the compound ii obtaining in above formula after being rinsed with the acetone-normal hexane mixed liquor of equal-volume ratio.
The purity of target product is 93.8%, and productivity is 96.5%.
Embodiment 4
Being dissolved in DMF by compounds I 100mmol in above formula, add dimethylamine, regulation pH is 8-9, then adds wherein
Enter 8mmol catalyst and 150mmol hydrogen peroxide, increase the temperature to 80 DEG C, add and stir with the rotating speed of 70 turns/min, continue anti-
After answering 12h, reaction terminates；Filter, by filtrate regulation to neutral, after adding acetone extract, be dried and concentrate, cross silica gel column chromatography,
The compound ii obtaining in above formula after being rinsed with the acetone-normal hexane mixed liquor of equal-volume ratio.
The purity of target product is 85.9%, and productivity is 96.7%.
Embodiment 5
Being dissolved in DMF by compounds I 100mmol in above formula, add diethanol ammonium, regulation pH is 8-9, more wherein
Add 12mmol catalyst and 120mmol hydrogen peroxide, increase the temperature to 80 DEG C, add and stir with the rotating speed of 80 turns/min, hold
After continuous reaction 12h, reaction terminates；Filter, by filtrate regulation to neutral, after adding acetone extract, be dried and concentrate, cross silica gel column chromatography
Post, the compound ii obtaining in above formula after being rinsed with the acetone-normal hexane mixed liquor of equal-volume ratio.
The purity of target product is 92.3%, and productivity is 92.9%.
Embodiment 6
Being dissolved in DMF by compounds I 100mmol in above formula, add potassium tert-butoxide, regulation pH is 8-9, more wherein
Add 9mmol catalyst and 130mmol hydrogen peroxide, increase the temperature to 80 DEG C, add and stir with the rotating speed of 90 turns/min, continue
After reaction 12h, reaction terminates；Filter, by filtrate regulation to neutral, after adding acetone extract, be dried and concentrate, cross silica gel column chromatography
Post, the compound ii obtaining in above formula after being rinsed with the acetone-normal hexane mixed liquor of equal-volume ratio.
The purity of target product is 88.7%, and productivity is 97.9%.
Claims (10)
1. the preparation method of a quinoline ketone derivative, it is characterised in that reaction mechanism is as follows: in the basic conditions, by changing
After catalyst, there is ring-closure reaction in compound I, generates compound ii；
Wherein R1For C1-C6Alkyl, C1-C6Alkoxyl, aryl or heteroaryl, R2For C1-C6Alkyl or C1-C6Alkoxyl, X is halogen
Element.
The preparation method of quinoline ketone derivative the most according to claim 1, it is characterised in that wherein said C1-C6Alkyl
For the straight or branched alkyl containing 1-6 carbon atom.
The preparation method of quinoline ketone derivative the most according to claim 1, it is characterised in that wherein said C1-C6Alcoxyl
Base is the straight or branched alkyl containing 1-6 carbon atom and an oxygen atom.
The preparation method of quinoline ketone derivative the most according to claim 1, it is characterised in that wherein said aryl is
Benzene, toluene or naphthalene.
The preparation method of quinoline ketone derivative the most according to claim 1, it is characterised in that wherein said heteroaryl is
Pyridine or pyrans.
The preparation method of quinoline ketone derivative the most according to claim 1, it is characterised in that wherein said preparation method
Concrete operation step be: compounds I is dissolved in DMF, add organic base, regulation pH is 8-9, then be added thereto to be catalyzed
Agent and hydrogen peroxide, increase the temperature to 60-80 DEG C, adds and turns/the rotating speed of min stirring, after sustained response 12h, reaction with 70-90
Terminate；Filter, by filtrate regulation to neutral, after adding acetone extract, be dried and concentrate, cross silica gel column chromatography, with equal-volume ratio
Acetone-normal hexane mixed liquor obtains compound ii after being rinsed.
The preparation method of quinoline ketone derivative the most according to claim 6, it is characterised in that wherein said organic base is
Dimethylamine, the one in diethanol ammonium or potassium tert-butoxide.
The preparation method of quinoline ketone derivative the most according to claim 6, it is characterised in that wherein said catalyst is
Double (dibenzalacetone) palladium, sodium borate and the mixture that mol ratio is 1:1:2 of tetraphenylporphyrin.
The preparation method of quinoline ketone derivative the most according to claim 6, it is characterised in that described compounds I with urge
The mol ratio of agent is 1:0.08-0.15；Described compounds I is 1:1.2-1.5 with the mol ratio of hydrogen peroxide.
10. the preparation-obtained quinoline of preparation method of a kind of quinoline ketone derivative according to any one of claim 1-9
Ketones derivant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201610229058.2A CN105732494A (en) | 2016-04-12 | 2016-04-12 | Synthetic method for quinolinone derivative |
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| CN201610229058.2A CN105732494A (en) | 2016-04-12 | 2016-04-12 | Synthetic method for quinolinone derivative |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011060036A1 (en) * | 2009-11-16 | 2011-05-19 | Schering Corporation | Bicyclic compounds and methods of use thereof |
| CN103694277A (en) * | 2013-12-12 | 2014-04-02 | 江西冠能光电材料有限公司 | Red-phosphorescence organic light emitting diode (LED) |
-
2016
- 2016-04-12 CN CN201610229058.2A patent/CN105732494A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011060036A1 (en) * | 2009-11-16 | 2011-05-19 | Schering Corporation | Bicyclic compounds and methods of use thereof |
| CN103694277A (en) * | 2013-12-12 | 2014-04-02 | 江西冠能光电材料有限公司 | Red-phosphorescence organic light emitting diode (LED) |
Non-Patent Citations (6)
| Title |
|---|
| E. ANDREAS LARSSON. ET AL.: "Fragment-Based Ligand Design of Novel Potent Inhibitors of Tankyrases", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| NORBERT B. ET AL.: "Synthesis of 7-ethyl-1,2-dihydroquinolinn-2-ones as Angiotensin II Receptor Antagonists", 《HETEROCYCLES》 * |
| RAJENDRAN M. ET AL.: "Ruthenium-Catalyzed Cyclization of Anilides with Substituted Propiolates or Acrylates: An Efficient Route to 2‑Quinolinones", 《ORGANIC LETTERS》 * |
| RUICHAO SHEN.ET AL.: "Lobatamide C: Total Synthesis, Stereochemical Assignment, Preparation of Simplified Analogues, and V-ATPase Inhibition Studies", 《JACS》 * |
| SABURO NAKANO: "Studies on 2,2-Biquinoline Derivatives", 《薬学雑誌》 * |
| V. R. SHAN.ET AL.: "Synthesis of Some Novel Quinoline and Pyrazolone Derivatives via Knorr Pyrazole and Quinoline Synthesis and Evaluation of their Antimicrobial Activities", 《INT.J.CHEM.SCI.》 * |
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