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Preparation method of lornoxicam impurity

A technology for lornoxicam and impurities, which is applied in the field of preparation of lornoxicam impurities, can solve the problems of process impurities, side reactions of methyl bromoacetate, etc., and achieve short synthesis routes, high product purity, and simple synthesis methods Effect

Pending Publication Date: 2022-03-08
BEIJING JINCHENG TAIER PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The synthesis of 5-chloro-3-(N-(2-methoxy-3-oxyethyl)-N-methylsulfamoyl)thiophene-2-carboxylate usually adopts 5-chloro-3-( N-methylsulfamoyl) thiophene-2-carboxylate is that starting material and methyl bromoacetate are synthesized with potassium carbonate in acetone, and the excessive addition of methyl bromoacetate in this process will cause side reactions The occurrence of process impurities
[0005] The products prepared by the above-mentioned patents are all lornoxicam intermediates, so far, there is no report on the impurity produced in the synthesis process of lornoxicam

Method used

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  • Preparation method of lornoxicam impurity
  • Preparation method of lornoxicam impurity
  • Preparation method of lornoxicam impurity

Examples

Experimental program
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Effect test

Embodiment 1

[0043] (1) Under the protection of nitrogen, add 200ml of acetonitrile and 20.00g of 5-chloro-3-methylsulfonamidethiophene-2-carboxylic acid into a 500mL four-necked bottle, cool down to 0-5°C, and add 24.43g of phosphorus pentachloride Reaction 1h, obtains the acetonitrile solution of intermediate 1;

[0044] (2) Control the temperature at 0-5°C, add 8.46 g of methyl glycolate dropwise to the acetonitrile solution of intermediate 1, after the dropwise addition, slowly raise the temperature to 22°C, and keep it warm for 4 hours, TLC detects the reaction, 5-chloro - The reaction of 3-methylsulfonamidethiophene-2-carboxylic acid is complete, the reaction system is cooled to 0-5°C, 200ml of purified water is added dropwise, and after 2 hours of heat preservation at 0-5°C, 25.30g of intermediate 2 wet product is obtained by suction filtration After vacuum drying at 40°C for 6 hours, 21.80 g of intermediate 2 was obtained with a yield of 85% and a purity of 97.2%;

[0045] (3) Und...

Embodiment 2

[0047] (1) Under the protection of nitrogen, add 500ml of acetonitrile and 50.00g of 5-chloro-3-methylsulfonamidethiophene-2-carboxylic acid into a 1000mL four-necked bottle, cool down to 0-5°C, and add 61.03g of phosphorus pentachloride Reaction 0.5h, obtains the acetonitrile solution of intermediate 1;

[0048](2) Control the temperature at 0-5°C, add 21.14 g of methyl glycolate dropwise to the acetonitrile solution of intermediate 1, after the addition is complete, slowly raise the temperature to 24°C, and keep it warm for 2 hours, TLC detects the reaction, 5-chloro - The reaction of 3-methylsulfonamidethiophene-2-carboxylic acid is complete, the reaction system is lowered to 0-5°C, 200ml of purified water is added dropwise, and after 3 hours of heat preservation at 0-5°C, 62.18g of intermediate 2 wet product is obtained by suction filtration , after vacuum drying at 45°C for 5 hours, 55.76g of intermediate 2 was obtained with a yield of 87% and a purity of 97.5%;

[0049]...

Embodiment 3

[0051] (1) Under the protection of nitrogen, add 1000ml of acetonitrile and 100.00g of 5-chloro-3-methylsulfonamidethiophene-2-carboxylic acid into a 2000mL four-necked bottle, cool down to 0-5°C, and add 122.16g of phosphorus pentachloride Reaction 3h, obtains the acetonitrile solution of intermediate 1;

[0052] (2) Control the temperature at 0-5°C, add 42.28 g of methyl glycolate dropwise to the acetonitrile solution of intermediate 1, after the dropwise addition, slowly raise the temperature to 20°C, and keep it warm for 5 hours, TLC detects the reaction, 5-chloro - The reaction of 3-methylsulfonamidethiophene-2-carboxylic acid is complete, the reaction system is cooled to 0-5°C, 1000ml of purified water is added dropwise, and after 1 hour of heat preservation at 0-5°C, 120.55g of intermediate 2 wet product is obtained by suction filtration After vacuum drying at 55°C for 3 hours, 112.30 g of intermediate 2 was obtained, with a yield of 88% and a purity of 96.8%;

[0053]...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of lornoxicam impurities. The method comprises the following steps: by taking acetonitrile as a solvent, reacting 5-chloro-3-methyl sulfonamide thiophene-2-carboxylic acid with phosphorus pentachloride to obtain an intermediate 1; in the presence of a solvent acetonitrile, reacting the intermediate 1 with methyl glycolate to obtain an intermediate 2; taking acetone as a solvent, potassium carbonate as alkali and tetrabutylammonium bromide as a catalyst, and reacting the intermediate 2 with methyl bromoacetate to obtain the lornoxicam impurity. The synthetic route is short, the synthetic method is simple, the product purity is high, the prepared lornoxicam impurity can be used as a standard sample for positioning the impurity in the lornoxicam synthesis process, and the lornoxicam intermediate and the lornoxicam product are subjected to quality research and quality standard formulation.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a preparation method of lornoxicam impurities. Background technique [0002] In the process development and research of raw materials, impurity research is a very important work content, and the research on process impurities is the focus of impurity research. The preparation of lornoxicam involves multiple reaction steps and post-treatment steps, wherein 5-chloro-3-(N-(2-methoxy-3-oxyethyl)-N-methylsulfamoyl)thiophene- As a key intermediate, methyl 2-carboxylate, its quality research plays a very important role in the synthesis of the whole lornoxicam bulk drug. The synthesis of 5-chloro-3-(N-(2-methoxy-3-oxyethyl)-N-methylsulfamoyl)thiophene-2-carboxylate usually adopts 5-chloro-3-( N-methylsulfamoyl) thiophene-2-carboxylic acid methyl ester is that starting material and methyl bromoacetate are synthesized with potassium carbonate in acetone, and the excessive a...

Claims

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Application Information

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IPC IPC(8): C07D333/38
CPCC07D333/38
Inventor 张忠政赵庆勇邢冬野刘畅陆通李莉崔娅丽王立茹
Owner BEIJING JINCHENG TAIER PHARMA CO LTD
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