CN102924374A - Preparation method for quinoline-4-carboxylic acid derivative - Google Patents
Preparation method for quinoline-4-carboxylic acid derivative Download PDFInfo
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- CN102924374A CN102924374A CN2012100335472A CN201210033547A CN102924374A CN 102924374 A CN102924374 A CN 102924374A CN 2012100335472 A CN2012100335472 A CN 2012100335472A CN 201210033547 A CN201210033547 A CN 201210033547A CN 102924374 A CN102924374 A CN 102924374A
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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 the 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 important application is arranged.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 such as norfloxicin, Gatifloxacin, and the important intermediate of antipyretic-antalgic anti-inflammatory agent such as 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 the 2-methyl-3-hydroxy-6-isopropyl quinolyl-4-carboxylic acid.This paper is take isatin as starting raw material, 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:
The method of a kind of 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) with Isatine derivatives under the highly basic condition with acetone open loop condensation reaction, obtain compound (II),
(2) compound (II) and phenylformic acid are obtained compound (III) by addition reaction,
(3) compound (III) dewatered under the acid anhydrides condition obtain (IV),
(4) compound (IV) oxidation under the strong oxidizer effect is obtained compound (V),
(5) compound (V) decarboxylic reaction is obtained 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) add isatin, highly basic and water in reaction vessel, 25-35 ℃ of lower the stirring, then add acetone, reflux 5-15 hour, PH=5-6 was transferred in cooling, and suction filtration gets 2-toluquinoline-4-carboxylic acid;
(2) add 2-toluquinoline-4-carboxylic acid and phenyl aldehyde in reaction vessel, be warming up to 95-105 ℃ of reaction 1-6 hour, filter, drying gets 2-vinyl-4-quinoline carboxylic acid one water thing;
(3) adding 2-vinyl-4-quinoline carboxylic acid's water thing and a diacetyl oxide in reaction vessel is warming up to 115-125 ℃ of reaction 2-8 hour, filters, and drying gets 2-vinyl-4-quinoline carboxylic acid;
(4) in reaction vessel, add 2-vinyl-4-quinoline carboxylic acid, potassium permanganate solution and sodium hydroxide solution), reaction is 2-8 hour under 35-45 ℃ of condition, filters, hcl acidifying is to PH=1-2, and standing over night is filtered, drying gets quinoline-2, the 4-dicarboxylic acid;
(5) add quinoline-2 in reaction vessel, 4-dicarboxylic acid and m-xylene add and reflux, and are cooled to room temperature, filter to get the Cinchonic Acid.
Compared with prior art, the used raw material of the synthesis technique of the Cinchonic Acid's derivative that the present invention relates to is cheap and easy to get, and reaction conditions is gentle, and is easy and simple to handle, process stabilizing, and cost is low.Therefore, method of the present invention is a kind of method of suitable suitability for industrialized production.
Embodiment
Synthetic example below by the Cinchonic Acid further specifies the present invention, i.e. X=H in the general molecular structural formula (I), the situation during Y=H.The preparation method who it should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, and the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.
The preparation of embodiment 1 2-toluquinoline-4-carboxylic acid
In the 500ml there-necked flask, add 25g isatin (0.17mol), 54.4g sodium hydroxide (1.36mol) and 110ml water, 25-35 ℃ of lower the stirring 0.5 hour, then add acetone, reflux 10 hours, PH=5-6 is transferred in cooling, suction filtration gets 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 acid's preparation
Add 7.5g 2-toluquinoline-4-carboxylic acid (0.04mol), 24ml phenyl aldehyde (0.24mol) in the 250ml there-necked flask, be warming up to 100 ℃ of reactions 3 hours, filter, drying gets 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 acid
The water thing (0.07mol) and the 350ml diacetyl oxide (3.7mol) that in the 500ml there-necked flask, add 21g 2-vinyl-4-quinoline carboxylic acid, be warming up to 120 ℃ of reactions 5 hours, filter drying, get 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 the 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), reaction is 5 hours under 35-45 ℃ of condition, filter, hcl acidifying is to PH=1-2, and standing over night is filtered, dry, get 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
Add 28g quinoline-2 in the 250ml there-necked flask, 4-dicarboxylic acid (0.13mol) and 40ml m-xylene add and refluxed 2 hours, are cooled to room temperature, filter to get 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 (5)
1. the method for a 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) with Isatine derivatives under the highly basic condition with acetone open loop condensation reaction, obtain compound (II),
(2) compound (II) and phenylformic acid are obtained compound (III) by addition reaction,
(3) compound (III) dewatered under the acid anhydrides condition obtain (IV),
(4) compound (IV) oxidation under the strong oxidizer effect is obtained compound (V),
(5) compound (V) decarboxylic reaction is obtained compound (I),
2. method according to claim 1 is characterized in that: 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.
3. method according to claim 1, it is characterized in that: the described acid anhydrides of step (3) is acetic anhydride.
4. method according to claim 1 is characterized in that: 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.
5. method according to claim 1 is characterized in that: comprise the steps:
(1) add isatin, highly basic and water in reaction vessel, 25-35 ℃ of lower the stirring, then add acetone, reflux 5-15 hour, PH=5-6 was transferred in cooling, and suction filtration gets 2-toluquinoline-4-carboxylic acid;
(2) add 2-toluquinoline-4-carboxylic acid and phenyl aldehyde in reaction vessel, be warming up to 95-105 ℃ of reaction 1-6 hour, filter, drying gets 2-vinyl-4-quinoline carboxylic acid one water thing;
(3) adding 2-vinyl-4-quinoline carboxylic acid's water thing and a diacetyl oxide in reaction vessel is warming up to 115-125 ℃ of reaction 2-8 hour, filters, and drying gets 2-vinyl-4-quinoline carboxylic acid;
(4) in reaction vessel, add 2-vinyl-4-quinoline carboxylic acid, potassium permanganate solution and sodium hydroxide solution), reaction is 2-8 hour under 35-45 ℃ of condition, filters, hcl acidifying is to PH=1-2, and standing over night is filtered, drying gets quinoline-2, the 4-dicarboxylic acid;
(5) add quinoline-2 in reaction vessel, 4-dicarboxylic acid and m-xylene add and reflux, and are cooled to room temperature, filter to get the Cinchonic Acid.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017500333A (en) * | 2013-12-20 | 2017-01-05 | バイエル・ファルマ・アクティエンゲゼルシャフト | Glucose transport inhibitor |
| CN106883174A (en) * | 2017-02-17 | 2017-06-23 | 泰力特医药（湖北）有限公司 | A kind of preparation method of the carboxylic acid derivates of 3 oxyquinoline 4 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0026894B1 (en) * | 1979-10-05 | 1983-03-30 | BASF Aktiengesellschaft | Process for the preparation of erythro-alpha-2-piperidyl-2,8-bis (trifluoromethyl)-4-quinoline methanol |
| US5869673A (en) * | 1997-02-28 | 1999-02-09 | Merck & Co., Inc. | Process for 3-(2-(7-chloro-2-quinolinyl)ethenyl) - benzaldehyde |
| EP0973741B1 (en) * | 1997-02-28 | 2003-06-11 | AMER, M. Samir | S-2'-(2-(1-methyl-2-piperidyl) ethyl) cinnamanilide as a 5-ht2 receptor antagonist |
| WO2010010149A1 (en) * | 2008-07-23 | 2010-01-28 | Bioalliance Pharma | Styrylquinolines, their process of preparation and their therapeutic uses |
| US20100022777A1 (en) * | 2008-07-23 | 2010-01-28 | Sterling Biotech Limited | Process for the Preparation of E-3-[2-(7-Chloro-2-Quinolinyl)Ethenyl]Benzaldehyde |
-
2012
- 2012-02-15 CN CN201210033547.2A patent/CN102924374B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0026894B1 (en) * | 1979-10-05 | 1983-03-30 | BASF Aktiengesellschaft | Process for the preparation of erythro-alpha-2-piperidyl-2,8-bis (trifluoromethyl)-4-quinoline methanol |
| US5869673A (en) * | 1997-02-28 | 1999-02-09 | Merck & Co., Inc. | Process for 3-(2-(7-chloro-2-quinolinyl)ethenyl) - benzaldehyde |
| EP0973741B1 (en) * | 1997-02-28 | 2003-06-11 | AMER, M. Samir | S-2'-(2-(1-methyl-2-piperidyl) ethyl) cinnamanilide as a 5-ht2 receptor antagonist |
| WO2010010149A1 (en) * | 2008-07-23 | 2010-01-28 | Bioalliance Pharma | Styrylquinolines, their process of preparation and their therapeutic uses |
| US20100022777A1 (en) * | 2008-07-23 | 2010-01-28 | Sterling Biotech Limited | Process for the Preparation of E-3-[2-(7-Chloro-2-Quinolinyl)Ethenyl]Benzaldehyde |
Non-Patent Citations (3)
| Title |
|---|
| HUI ZHU，等: "Facile and efficient synthesis of quinoline-4-carboxylic acids under microwave irradiation", 《CHINESE CHEMICAL LETTERS》 * |
| M. N. ZEMTSOVA1，等: "A Procedure for Preparation of 2-Methylquinoline-4-carboxylic Acids", 《RUSSIAN JOURNAL OF ORGANIC CHEMISTRY》 * |
| R.IQBAL，等: "OXIDATION OF ISOMERIC STILBAZOLES WITH POTASSIUM-PERMANGANATE", 《JOURNAL OF THE CHEMICAL SOCIETY OF PAKISTAN》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017500333A (en) * | 2013-12-20 | 2017-01-05 | バイエル・ファルマ・アクティエンゲゼルシャフト | Glucose transport inhibitor |
| CN106883174A (en) * | 2017-02-17 | 2017-06-23 | 泰力特医药（湖北）有限公司 | A kind of preparation method of the carboxylic acid derivates of 3 oxyquinoline 4 |
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| CN102924374B (en) | 2014-04-16 |
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