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Method for synthesizing lornoxicam intermediate by one-pot method

A technology for lornoxicam and intermediates, which is applied in the field of one-pot synthesis of lornoxicam intermediates, can solve problems such as complicated operation process, and achieve the effects of improving product yield, cheap reagents, and low energy consumption

Active Publication Date: 2018-06-29
BEIJING JINCHENG TAIER PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the patent shortens the synthetic route, the operation process is still complicated

Method used

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  • Method for synthesizing lornoxicam intermediate by one-pot method
  • Method for synthesizing lornoxicam intermediate by one-pot method
  • Method for synthesizing lornoxicam intermediate by one-pot method

Examples

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Embodiment 1

[0033] N 2 Add 100ml of methanol, 10g of methyl 5-chloro-3-methylsulfonamidethiophene-2-carboxylate, and 6.82g of methyl bromoacetate into a 250ml four-necked flask under protection, stir until completely dissolved, and add 28wt.% methanol dropwise Sodium methanol solution 8g, slightly exothermic, the color of the solution turns yellow, stir at room temperature 25°C, and react for 24 hours; then add 8g of 28wt.% sodium methoxide methanol solution dropwise, the solution color changes from yellow to orange red, stir at room temperature 25°C , reacted for 12 hours; then ice-thawed, adjusted the pH of the solution to 4 with concentrated hydrochloric acid, extracted three times with dichloromethane, combined the organic phases, washed once with water, dried over anhydrous magnesium sulfate, filtered, concentrated to obtain a light yellow solid, and recrystallized from methanol , filtered, and dried under vacuum to obtain 6-chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine-3-c...

Embodiment 2

[0035] N 2 Add 100ml of methanol, 10g of methyl 5-chloro-3-methylsulfonamide thiophene-2-carboxylate, and 12.4g of methyl bromoacetate into a 250ml four-neck flask under protection, stir until completely dissolved, and add 28wt.% methanol dropwise 14g of sodium methanol solution, slightly exothermic, the color of the solution turned yellow, stirred at 45°C, and reacted for 12 hours; then 14g of 28wt.% sodium methylate methanol solution was added dropwise, the color of the solution changed from yellow to orange red, stirred at room temperature at 25°C, Reacted for 12 hours; then ice-thawed, adjusted the pH of the solution to 4 with concentrated phosphoric acid, extracted three times with dichloromethane, combined the organic phases, washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a light yellow solid, which was then recrystallized from methanol. Filter and dry in vacuum to get 6-chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-...

Embodiment 3

[0037] N 2 Add 200ml of methanol, 20g of methyl 5-chloro-3-methylsulfonamide thiophene-2-carboxylate, and 13.64g of methyl bromoacetate into a 500ml four-neck flask under protection, stir until completely dissolved, and add 28wt.% methanol dropwise 16g of sodium methanol solution, slightly exothermic, the color of the solution turns yellow, stir and react at 50°C for 12 hours; then add 16g of 28wt.% sodium methoxide methanol solution dropwise, the color of the solution changes from yellow to orange red, stir and react at 50°C 6 hours; then ice-thawed, adjusted the pH of the solution to 4 with dilute sulfuric acid, extracted three times with ethyl acetate, combined the organic phases, washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a light yellow solid, then recrystallized with methanol, filtered , and dried in vacuum to obtain 6-chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-di Ox...

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Abstract

The invention belongs to the technical field of drug synthesis, and in particular relates to a method for synthesizing a lornoxicam intermediate by a one-pot method. The method is as follows: using 5-chloro-3-methylsulfonamidethiophene-2-carboxylic acid methyl ester as a raw material, and adding methyl bromoacetate and sodium methoxide for alkylation reaction; adding again the sodium methoxide forcyclization reaction to obtain 6-chloro-4-hydroxy-2-methyl-2H-thieno [2,3-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide. The lornoxicam intermediate is synthesized by the one-pot methodby alkylation and cyclization two-step reaction, use of dangerous reagents such as dimethyl sulfate and sodium hydride can be avoided, no dangerous gas is produced during the reaction, side reactionsare reduced, production environment is improved, production safety is ensured, operation is simplified, and product yield is improved.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a method for synthesizing an intermediate of lornoxicam in one pot. Background technique [0002] Lornoxicam, an anti-inflammatory analgesic, was developed by Nycomed, a Norwegian company, and was included in the analgesic ladder program formulated by the World Health Organization. Lornoxicam can be taken orally or injected, and is mainly used for the treatment of mild to moderate pain caused by rheumatoid arthritis, rheumatoid arthritis or routine surgery, low back pain, etc. [0003] An important intermediate of Lornoxicam 6-Chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1 -There are two following synthetic routes for the dioxide: [0004] Route 1: The synthetic route listed in Denmark by Nycomed Company of Norway in 1997: [0005] [0006] This route uses 2,5-dichlorothiophene as the starting material, and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04
CPCC07D513/04
Inventor 孙滨王坤张治中张彤于宇航游亚新
Owner BEIJING JINCHENG TAIER PHARMA CO LTD
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