Synthesis method of lornoxicam

A technology of lornoxicam and synthetic method, which is applied in the field of drug synthesis, can solve the problems of destroying the stability of 2-aminopyridine, the decrease of yield, and the increase of reaction by-products, so as to improve production efficiency and product yield, and reduce activation Can, avoid the effect of coking

Inactive Publication Date: 2021-04-02
BEIJING JINCHENG TAIER PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

And reaction under high temperature can destroy the stability of reaction material 2-aminopyridine, cause reaction by-product to increase, and yield declines

Method used

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  • Synthesis method of lornoxicam
  • Synthesis method of lornoxicam
  • Synthesis method of lornoxicam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045]Under nitrogen protection, xylene was added 200ml, 6-chloro-4-hydroxy-2-methyl-2-H-thiophene and [2,3-E] -1,2-thiazine carboxarboxes were added to 500 ml of four-mouth flasks. Ester-1,1-dioxide 10g, 2-aminopyridine 3.65 g, 0.6 g of methylbenzenesulfonic acid. Heat until 130 ° C insulation ammonia reaction for 4 hours. Sampling HPLC detection, when the reaction feedstock 6-chloro-4-hydroxy-2-methyl-2-H-thiophene and [2,3-E] -1, 2-thiazine carboxylate-1, 1- When the content of the dioxide is ≤ 2%, the reaction is stopped.

[0046]The reaction solution was cooled to 50 ° C, at this temperature, the pressure was -0.07 MPa, advanced decompression concentrated to the solvent, concentrated the reaction liquid to 30 mL, stop concentration; cool down to 20 ° C, mixed solution of dichloromethane and methanol 50 ml, wherein the volume ratio of dichloromethane and methanol is 4: 1; heating to 80 ° C, the heat preservation is 2 hours; after cooling to 30 ° C, it is obtained to obtain chlorovo...

Embodiment 2

[0049]Under nitrogen protection, xylene 400 ml of xylene, 6-chloro-4-hydroxy-2-methyl-2-H-thiophene [2,3-E] -1,2-thiazine is added to 1 L of 400 ml, 6-chloro-4-hydroxy-2-methyl-2-H-thiophene [2,3-E] -1,2-thiazine Acid methyl ester-1,1-dioxide 20g, 2-aminopyridine 7.3 g, 1.2 g of methylbenzenesulfonic acid. Heat until 115 ° C insulation ammonia reaction for 5 hours. Sampling HPLC detection, when the reaction feedstock 6-chloro-4-hydroxy-2-methyl-2-H-thiophene and [2,3-E] -1, 2-thiazine carboxylate-1, 1- When the content of the dioxide is ≤ 2%, the reaction is stopped.

[0050]The reaction solution was cooled to 65 ° C, at this temperature, the pressure was -0.09 MPa, first transdermally concentrated the solvent, concentrated the reaction solution to 100 ml, stop concentration; cool down to 25 ° C, mixed solution of dichloromethane and methanol 100 ml, wherein the volume ratio of dichloromethane and methanol is 4: 1; heating to 65 ° C, the heat preservation is 3 hours; then cool down to ...

Embodiment 3

[0053]Under nitrogen protection, xylene 800 ml, 6-chloro-4-hydroxy-2-methyl-2-H-thiophene [2,3-E] -1,2-thiazine carboxarboxes were added to a 4L four-mouth bottle. Acid methyl ester-1,1-dioxide 40g, 2-aminopyridine 14.6 g, 2.4 g of methylbenzenesulfonic acid. Heat until 110 ° C insulation ammonia reaction for 6 hours. Sampling HPLC detection, when the reaction feedstock 6-chloro-4-hydroxy-2-methyl-2-H-thiophene and [2,3-E] -1, 2-thiazine carboxylate-1, 1- When the content of the dioxide is ≤ 2%, the reaction is stopped.

[0054]The reaction liquid was cooled to 80 ° C, at this temperature, the pressure was -0.1MPa, advanced decompression concentrated to the solvent, concentrated the reaction liquid to 120 mL, stop concentration; cool down to 30 ° C, mixed solution of dichloromethane and methanol 200 ml, wherein the volume ratio of dichloromethane and methanol is 4: 1; heating to 50 ° C, the heat preservation is 5 hours; then cool down to 20 ° C to obtain chlorovoxic. The crude material...

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Abstract

The invention relates to the technical field of medicine synthesis, and particularly relates to a synthesis method of lornoxicam. The method comprises the steps of taking 6-chlorine-4-hydroxyl-2-methyl-2-H-thieno[2,3-e]-1,2-thiazine carboxylic acid methyl ester-1,1-dioxide and 2-aminopyridine as raw materials and dimethylbenzene as a solvent, adding a stabilizer, performing heating reflux to perform ammonolysis reaction, reducing the temperature, performing reduced pressure concentration to remove the solvent, adding an organic solvent, pulping, and filtering to obtain a lornoxicam crude product; and refining to obtain the lornoxicam. According to the method, p-toluenesulfonic acid is used as a stabilizer, the reaction temperature is reduced, meanwhile, the reaction is promoted to be carried out forwards, and the product quality and yield are improved; and meanwhile, the dosage of an industrial solvent is reduced, the post-treatment process is optimized, and the three-waste treatment cost is reduced.

Description

Technical field[0001]The present invention relates to the field of pharmaceutical synthesis, and more particularly to a synthetic method of chlorovacatronics.Background technique[0002]With the rapid development of artificial intelligence technology and industrial modernization, people's quality and health status are constantly improving. For many diseases that plague human diseases and various pain, especially pain, pain, postoperative pain, and ossentine pain Wait, there is a need for a large amount of anti-inflammatory analgesic drug to improve. Current treatment of moderate or severe pain drugs, morphine, Du Regentin and other products have counterfeit, respiratory inhibition and sedative, and is subject to hospital control.[0003]Norwegian NYCOMEDs developed by Chloroboxico was listed in Danish in October 1997. Not only is a tablet, but also a venous injection, a muscle injection. For moderate and severe low back pain, rheumatoid arthritis, pain after surgery, pain in osteoarthri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04
CPCC07D513/04
Inventor 刘镇邢冬野韩延功崔娅丽王立茹刘洪亮弭岩李莉唐金钢康毅
Owner BEIJING JINCHENG TAIER PHARMA CO LTD
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