Preparation method for quinoline-4-carboxylic acid derivative

A technology of quinoline carboxylic acid and acid anhydride, applied in the field of preparation of quinoline-4-carboxylic acid derivatives, can solve the problem of no quinoline-4-carboxylic acid derivatives, few quinoline-4-carboxylic acid derivatives, etc. problems, achieve the effect of low cost, stable process and mild reaction conditions

CN102924374AInactive Publication Date: 2013-02-13湖北欣瑞康医药科技有限公司
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Publication Date
2013-02-13
Estimated Expiration
Not applicable · inactive patent

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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.
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Description

technical field

[0001] The invention belongs to the technical field of compound synthesis, and relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of quinoline-4-carboxylic acid derivatives. Background technique

[0002] Quinoline-4-carboxylic acid derivatives, also known as 4-carboxylic acid quinoline derivatives, its general molecular structure formula (I)

[0003]

[0004] Quinoline-4-carboxylic acid derivatives are important pharmaceutical intermediates and have important applications in the pharmaceutical industry. It is one of the raw materials for the synthesis of drugs such as VLA-4 antagonists, Urotensin II antagonists, tachykinin antagonists, and synthetic antiplatelet aggregation agents. An important intermediate of analgesic and anti-inflammatory drugs such as Xin Kefen.

[0005] At present, there are few synthetic techniques about quinoline-4-carboxylic acid derivatives disclosed in the prior art, only the...

Examples

Embodiment 1

[0033] The preparation of embodiment 1 2-methylquinoline-4-carboxylic acid

[0034] In a 500ml three-necked flask, add 25g of isatin (0.17mol), 54.4g of sodium hydroxide (1.36mol) and 110ml of water, stir at 25-35°C for 0.5 hours, then add acetone, heat and reflux for 10 hours, cool down, adjust PH=5-6, suction filtration gives 31.5g of 2-methylquinoline-4-carboxylic acid, (C 11 h 9 NO 2 , FW: 187.19), m.p.238-240°C, the yield was 99%.

[0035] 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

[0036] Example 2 Preparation of 2-vinylphenyl-4-quinolinecarboxylic acid

[0037] Add 7.5g of 2-methylquinoline-4-carboxylic acid (0.04mol) and 24ml of benzaldehyde (0.24mol) into a 250ml three-necked flask, heat up to 100°C for 3 hours, filter, and dry to obtain 2-ethylene as a yellow solid Base-4-quinolinecarboxylic acid monohydrate 10g, (C 18 h 15 NO 3 , FW: 293.32), m.p.294-295°C, yield 85%.

[0038] PMR(d 6 -DMSO): 8.08 (d, 8-H, 3 J 8 -H, 7 -H=8.5Hz), 8.23(s, 3-H), 8.62ppm(d, 5-H, 3 J 5 -H, 6 -H=8.3Hz); Found: C 73.9; H 5.0; N 4.8; H 2 O7.0%.IR: 3345cm -1 (OH), 965cm -1 (C=CH-trans).C 18 h 15 NO 3 .Calculated: C 73.7; H 5.1; N 4.8; H2O 6.1%.

Embodiment 3

[0039] Example 3 2-vinyl-4-quinolinecarboxylic acid

[0040] Add 21g of 2-vinyl-4-quinolinecarboxylic acid monohydrate (0.07mol) and 350ml of acetic anhydride (3.7mol) into a 500ml three-necked flask, heat up to 120°C for 5 hours, filter, and dry to obtain a yellow solid 2-vinyl-4-quinolinecarboxylic acid 18.41g, (C 18 h 13 NO 2 , FW: 275.30672), m.p.295-296°C, the yield was 93.4%.

[0041] IR: 2480cm -1 (OH), 965cm -1 (C=CH-trans).Found: C 78.4; H 4.7; N 4.7%.C 18 h 13 NO 2 .Calculated: C 78.5; H 4.8; N 5.1%.