CN102924374B - Preparation method for quinoline-4-carboxylic acid derivative - Google Patents
Preparation method for quinoline-4-carboxylic acid derivative Download PDFInfo
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- CN102924374B CN102924374B CN201210033547.2A CN201210033547A CN102924374B CN 102924374 B CN102924374 B CN 102924374B CN 201210033547 A CN201210033547 A CN 201210033547A CN 102924374 B CN102924374 B CN 102924374B
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Abstract
The present invention relates to a preparation method for a quinoline-4-carboxylic acid derivative, wherein an isatin derivative is adopted as a starting material, and ring opening, condensation, addition, elimination, oxidation and decarboxylation are performed under a basic condition to obtain the quinoline-4-carboxylic acid derivative. The preparation method has characteristics of cheap and easily-available synthetic raw materials, mild reaction conditions and stable process, and is suitable for industrial production.
Description
Technical field
The invention belongs to compou nd synthesis technical field, relate to a kind of preparation method of medicine intermediate, particularly a kind of preparation method of Cinchonic Acid's derivative.
Background technology
Cinchonic Acid's derivative, has another name called 4-carboxylic acid quinoline, its general molecular structural formula (I)
Cinchonic Acid's derivative is an important pharmaceutical intermediate, in pharmaceutical industries, has important application.It is one of synthesis material of the medicines such as VLA-4 antagonist, Urotensin II antagonist, tachykinin antagenists, synthetic anti-platelet aggregation agent, also be Comprecin as norfloxicin, Gatifloxacin, and antipyretic-antalgic anti-inflammatory agent is as the important intermediate of Viophan.
At present, the disclosed synthesis technique about Cinchonic Acid's derivative of prior art seldom, synthetic method (the number of patent application: 200510046748.6 and number of patent application: 200510048123.3), and do not have about the research of other Cinchonic Acid's derivatives that only has 2-methyl-3-hydroxy-6-isopropyl quinolyl-4-carboxylic acid.Take isatin as starting raw material herein, and the method for synthesis of quinoline-4-carboxylic acid derivative belongs to pioneering at home and abroad, and cost is low, and yield is high.
Summary of the invention
In view of the deficiencies in the prior art, the object of the present invention is to provide a kind of efficient, easy, synthesis preparation method of being adapted to industrialized Cinchonic Acid's derivative.
To achieve these goals, the present invention studies by lot of experiments, has obtained following technical scheme:
A method for preparation formula (I) compound,
Wherein during X=H, Y=Cl, Br,
or during Y=H, X=H, Cl, Br,
or when X=Cl, Br, Y=Cl, Br;
The method comprises the steps:
(1) by Isatine derivatives under highly basic condition with acetone open loop condensation reaction, obtain compound (II),
(2) compound (II) and phenylformic acid are obtained to compound (III) by addition reaction,
(3) compound (III) is dewatered and obtains (IV) under acid anhydrides condition,
(4) compound (IV) is oxidized and obtains compound (V) under strong oxidizer effect,
(5) compound (V) decarboxylic reaction is obtained to compound (I),
Preferably, the described highly basic of step (1) is selected from following one or more: sodium hydroxide, sodium methylate, potassium hydroxide, sodium ethylate, potassium tert.-butoxide.
Preferably, the described acid anhydrides of step (3) is acetic anhydride.
Preferably, the described strong oxidizer of step (4) is selected from following one or more: potassium permanganate, trivalent cobalt salt, persulphate, superoxide, potassium bichromate, oxygen hydrochlorate, the vitriol oil.
Further preferably, method of the present invention comprises the steps:
(1) in reaction vessel, add isatin, highly basic and water, at 25-35 ℃, stir, then add acetone, reflux 5-15 hour, cooling, adjusts PH=5-6, and suction filtration obtains 2-toluquinoline-4-carboxylic acid;
(2) in reaction vessel, add 2-toluquinoline-4-carboxylic acid and phenyl aldehyde, be warming up to 95-105 ℃ of reaction 1-6 hour, filter, dry, obtain 2-vinyl-4-quinoline carboxylic acid one water thing;
(3) in reaction vessel, add 2-vinyl-4-quinoline carboxylic acid's water thing and a diacetyl oxide, be warming up to 115-125 ℃ of reaction 2-8 hour, filter, dry, obtain 2-vinyl-4-quinoline carboxylic acid;
(4) in reaction vessel, add 2-vinyl-4-quinoline carboxylic acid, potassium permanganate solution and sodium hydroxide solution), under 35-45 ℃ of condition, react 2-8 hour, filter, hcl acidifying is to PH=1-2, and standing over night, filters, dry, obtain quinoline-2,4-dicarboxylic acid;
(5) in reaction vessel, add quinoline-2,4-dicarboxylic acid and m-xylene, add backflow, is cooled to room temperature, filters to obtain Cinchonic Acid.
Compared with prior art, the synthesis technique of the Cinchonic Acid's derivative the present invention relates to raw material used is cheap and easy to get, and reaction conditions is gentle, easy and simple to handle, process stabilizing, and cost is low.Therefore, method of the present invention is a kind of method of applicable suitability for industrialized production.
Embodiment
Synthetic example below by Cinchonic Acid further illustrates the present invention, i.e. X=H in general molecular structural formula (I), situation during Y=H.The preparation method who it should be understood that the embodiment of the present invention is only used for illustrating the present invention, rather than limitation of the present invention, under design prerequisite of the present invention, preparation method's of the present invention simple modifications is all belonged to the scope of protection of present invention.
The preparation of embodiment 1 2-toluquinoline-4-carboxylic acid
In 500ml there-necked flask, add 25g isatin (0.17mol), 54.4g sodium hydroxide (1.36mol) and 110ml water, at 25-35 ℃, stir 0.5 hour, then add acetone, reflux 10 hours, cooling, adjusts PH=5-6, suction filtration obtains 2-toluquinoline-4-carboxylic acid 31.5g, (C
11h
9nO
2, FW:187.19), m.p.238-240 ℃, yield is 99%.
1H-NMR(400MHz，DMSO-d6/ppm)：8.127(7，1H，ddd，J＝7.256，J＝1.845，J＝0.594)，7.692(8，1H，ddd，J＝7.658，J＝7.256，J＝1.862)，7.574(9，1H，ddd，J＝8.323，J＝7.658，J＝1.845)，8.468(10，1H，dddd，J＝8.323，J＝1.862，J＝1.511，J＝0.594)，8.418(13，1H，d，J＝1.511)，2.587(14，3H).
Embodiment 2 2-vinyl phenyl-4-quinoline carboxylic acids' preparation
In 250ml there-necked flask, add 7.5g 2-toluquinoline-4-carboxylic acid (0.04mol), 24ml phenyl aldehyde (0.24mol), be warming up to 100 ℃ of reactions 3 hours, filter, dry, obtain yellow solid 2-vinyl-4-quinoline carboxylic acid one water thing 10g, (C
18h
15nO
3, FW:293.32), m.p.294-295 ℃, yield 85%.
PMR(d
6-DMSO)：8.08(d，8-H，
3J
8-H，
7-H＝8.5Hz)，8.23(s，3-H)，8.62ppm(d，5-H，
3J
5-H，
6-H＝8.3Hz)；Found：C?73.9；H?5.0；N?4.8；H
2O7.0％.IR：3345cm
-1(OH)，965cm
-1(C＝CH-trans).C
18H
15NO
3.Calculated：C?73.7；H?5.1；N4.8；H2O?6.1％.
Embodiment 3 2-vinyl-4-quinoline carboxylic acids
The water thing (0.07mol) and the 350ml diacetyl oxide (3.7mol) that in 500ml there-necked flask, add 21g 2-vinyl-4-quinoline carboxylic acid, be warming up to 120 ℃ of reactions 5 hours, filter, dry, obtain yellow solid 2-vinyl-4-quinoline carboxylic acid 18.41g, (C
18h
13nO
2, FW:275.30672), m.p.295-296 ℃, yield is 93.4%.
IR：2480cm
-1(OH)，965cm
-1(C＝CH-trans).Found：C?78.4；H?4.7；N?4.7％.C
18H
13NO
2.Calculated：C?78.5；H?4.8；N?5.1％.
Embodiment 4 quinoline-2, the preparation of 4-dicarboxylic acid
In 500ml there-necked flask, add 12g 2-vinyl-4-quinoline carboxylic acid (0.044mol), potassium permanganate solution (12g potassium permanganate (0.076mol), 180ml 3mol/L sodium hydroxide solution) reacts 5 hours under 35-45 ℃ of condition, filter, hcl acidifying is to PH=1-2, and standing over night, filters, dry, obtain yellow solid quinoline-2,4-dicarboxylic acid 8.9g, (C
11h
7nO
4, FW:217.18), m.p.245-246 ℃, yield is 94%.
1H-NMR(400MHz，DMSO-d6/ppm)：8.764(9，1H，d，J＝0.629)，8.179(13，1H，ddd，J＝7.233，J＝1.889，J＝1.727)，7.869(14，1H，ddd，J＝7.744，J＝7.233，J＝1.844)，7.718(15，1H，ddd，J＝8.478，J＝7.744，J＝1.889)，8.586(16，1H，dddd，J＝8.478，J＝1.844，J＝1.727，J＝0.629).
Embodiment 5 Cinchonic Acids' preparation
In 250ml there-necked flask, add 28g quinoline-2,4-dicarboxylic acid (0.13mol) and 40ml m-xylene, add and reflux 2 hours, is cooled to room temperature, filters to obtain pale yellow powder Cinchonic Acid 12.7g, (C
10h
7nO
2, FW:173.17) yield is 57%, fusing point is 254-257 ℃.
1H-NMR(400MHz，DMSO-d6/ppm)：8.046(7，1H，dddd，J＝7.708，J＝1.845，J＝1.740，J＝1.408)，7.735(8，1H，ddd，J＝7.708，J＝7.654，J＝1.866)，7.574(9，1H，ddd，J＝8.408，J＝7.654，J＝1.845)，8.683(10，1H，dddd，J＝8.408，J＝1.866，J＝1.568，J＝1.408)，8.923(12，1H，dd，J＝5.032，J＝1.740)，8.047(13，1H，dd，J＝5.032，J＝1.568).
Claims (1)
1. a method of preparing formula I compound,
（Ⅰ）
X=H wherein, Y=H;
The method comprises the steps:
(1) by isatin under highly basic condition with acetone open loop condensation reaction, obtain compound (II),
(2) compound (II) and phenyl aldehyde are obtained to compound (III) by addition reaction,
(3) compound (III) is dewatered and obtains (IV) under diacetyl oxide condition,
(4) compound (IV) is oxidized and obtains compound (V) under potassium permanganate solution effect,
(5) compound (V) decarboxylic reaction is obtained to compound (I),
The method specifically comprises the steps:
(1) in reaction vessel, add isatin, highly basic and water, at 25-35 ℃, stir, then add acetone, reflux 5-15 hour, cooling, adjusts pH=5-6, and suction filtration obtains 2-toluquinoline-4-carboxylic acid; Described highly basic is selected from following one or more: sodium hydroxide, sodium methylate, potassium hydroxide, sodium ethylate, potassium tert.-butoxide;
(2) in reaction vessel, add 2-toluquinoline-4-carboxylic acid and phenyl aldehyde, be warming up to 95-105 ℃ of reaction 1-6 hour, filter, dry, obtain 2-vinyl-4-quinoline carboxylic acid one water thing;
(3) in reaction vessel, add 2-vinyl-4-quinoline carboxylic acid's water thing and a diacetyl oxide, be warming up to 115-125 ℃ of reaction 2-8 hour, filter, dry, obtain 2-vinyl-4-quinoline carboxylic acid;
(4) in reaction vessel, add 2-vinyl-4-quinoline carboxylic acid, potassium permanganate solution and sodium hydroxide solution, under 35-45 ℃ of condition, react 2-8 hour, filter, hcl acidifying is to pH=1-2, and standing over night, filters, dry, obtains quinoline-2,4-dicarboxylic acid;
(5) in reaction vessel, add quinoline-2,4-dicarboxylic acid and m-xylene, add backflow, is cooled to room temperature, filters to obtain Cinchonic Acid.
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| US5780487A (en) * | 1995-08-07 | 1998-07-14 | Amer Moh Samir | S-2'- 2-(1-methyl-2-piperidyl) ethyl! cinnamanilide |
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