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Preparation method of 4-bromomethylquinoline-2(H)-ketone

A technology of bromomethylquinoline and liquid bromine, applied in the direction of organic chemistry and the like, can solve problems such as excessive dibromide, achieve the effects of improving purity, optimizing bromination reaction, and improving selectivity

Inactive Publication Date: 2014-07-16
SUZHOU TIANMA SPECIALTY CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The object of the present invention is to provide a kind of preparation method of 4-bromomethylquinolin-2 (H)-ketone, mainly solve the problem that the bromination reaction in the prior art generates too many dibromides

Method used

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  • Preparation method of 4-bromomethylquinoline-2(H)-ketone
  • Preparation method of 4-bromomethylquinoline-2(H)-ketone
  • Preparation method of 4-bromomethylquinoline-2(H)-ketone

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Preparation of brominated acetoacetanilide shown in formula (3): at room temperature, dissolve 270kg of acetoacetanilide shown in formula (2) in 1200kg of dichloroethane, add 170kg of liquid bromine dropwise at 20~30°C, After 2 hours of dripping, keep stirring at 50~55°C for 2 hours, cool down to 20~30°C, add the remaining 86kg of liquid bromine dropwise, finish dropping in 2 hours, keep stirring at 50~55°C for 2 hours. After the reaction is completed, concentrate to dryness under reduced pressure, add 400kg of water, and at 10-20°C, add dropwise 20% sodium hydroxide solution to adjust the pH to 6-7, centrifuge, and wash with water until the pH is 7. Add the crude product to 1200kg of methanol, beat at 50-55°C for 1 hour, cool to 0°C, centrifuge, wash with cold methanol, and obtain 319kg of white solid with a yield of 81.7% and a purity of 97.6%. The dibromide represented by formula (4) 1.4% (HPLC area normalization method). Elemental analysis: found (calculated), C 45...

Embodiment 2

[0033] The preparation of 4-bromomethylquinolin-2(H)-one shown in formula (1): Slowly add brominated acetoacetanilide shown in 312kg formula (3) to 2400kg concentrated sulfuric acid, control temperature 10~ 20°C, after the addition, keep the reaction at 15~20°C for 3 hours. After the reaction is over, add the feed liquid to 2400kg of ice water under cooling, control the temperature below 20°C, stir for 30 minutes, centrifuge, wash with water to pH 2~3, add the solid to 1500kg of water, add 20% hydrogen dropwise at 10~20°C Adjust the pH to 6~7 with sodium oxide solution, centrifuge, wash with water until the pH is 7, and obtain the crude product. Add 2400kg of methanol to the crude product, beat at 20-30°C for 1 hour, centrifuge, wash with methanol, and dry under vacuum at 50°C to obtain 269.7kg of white powdery solid with a yield of 93.0% and a purity of 99.6%. -Bromo-4-bromomethylquinolin-2(H)-one 0.13% (HPLC area normalization method). Elemental analysis: found (calculated...

Embodiment 3

[0035]Preparation of brominated acetoacetanilide shown in formula (3): at room temperature, dissolve 45g of acetoacetanilide shown in formula (2) in 300g of chloroform, add 30g of liquid bromine dropwise at 20~30°C, drop for 2 hours After completion, keep stirring at 50-55°C for 2 hours, cool down to 20-30°C, add the remaining 16g of liquid bromine dropwise, finish dropping in 2 hours, and keep stirring at 50-55°C for 2 hours. After the reaction is completed, concentrate to dryness under reduced pressure, add 100 g of water, and at 10-20°C, add dropwise 10% sodium carbonate solution to adjust the pH to 6-7, centrifuge, and wash with water until the pH is 7. Add the crude product to 360g of isopropanol, beat at 50-55°C for 1 hour, cool to 0°C, centrifuge, and wash with cold isopropanol to obtain 50.2g of white solid with a yield of 77.2% and a purity of 96.5%. 2.7% of the indicated dibromide (HPLC area normalization method).

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Abstract

The invention discloses a preparation method of 4-bromomethylquinoline-2(H)-ketone. The preparation method comprises the following steps of I, with acetoacetanilide as a raw material, dissolving acetoacetanilide into an organic solvent, dropwise adding bromine twice, evaporating the solvent after the reaction is ended, adding water, regulating the pH value to 6-7 by using alkaline, centrifuging, washing to obtain a crude product, pulping the obtained crude product by using alcohol and drying to obtain acetoacetanilide bromide; II, slowly adding acetoacetanilide bromide obtained in the step I into concentrated sulfuric acid, after the reaction is ended, dropwise adding the reaction solution into water under cooling, centrifuging, washing, adding the obtained solid into water, regulating the pH value to 6-7 by using alkaline under cooling, centrifuging, washing to obtain a crude product, pulping the crude product by using alcohol, centrifuging and drying to obtain 4-bromomethylquinoline-2(H)-ketone. By using the preparation method, the problems of too many dibromides generated by bromination reaction and low product purity in the prior art are solved; in addition, the preparation method is high in product yield and product quality, low in production cost and capable of realizing large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of 4-bromomethylquinolin-2(H)-one. Background technique [0002] 4-Bromomethylquinolin-2(H)-one (1) is an important intermediate of the anti-gastrointestinal ulcer drug Rebamipide. Rebamipide is a drug that promotes epidermal growth factor (EFG), mainly by increasing gastric mucosal blood flow, prostaglandin E2 synthesis and gastric mucus secretion, and scavenging oxygen free radicals to promote the healing of digestive tract ulcers and the improvement of inflammation, and reduce the risk of ulcers. Relapse, increase the eradication rate of Helicobacter pylori. On May 16, 2003, the State Drug Administration has terminated the administrative protection of the rebamipide drug of Otsuka Pharmaceutical Co., Ltd. in Japan. At present, it has been mass-produced in China. - Ketones have a larger market. [0003] [0004] There are curre...

Claims

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Application Information

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IPC IPC(8): C07D215/227
CPCC07D215/227
Inventor 陆晓刘世领徐敏
Owner SUZHOU TIANMA SPECIALTY CHEM
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