Synthesis method of lornoxicam intermediate 5-chloro-3-methylsulfonamide thiophene-2-carboxylic acid methyl ester

A technology of methylsulfonamide and methyl carboxylate, which is applied in the field of drug synthesis, can solve problems such as pollution and unenvironmental protection of the process, and achieve the effect of reducing pollution and environmental protection of the process

Inactive Publication Date: 2021-04-13
BEIJING JINCHENG TAIER PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The use of phosphorous reagent phosphorus pentachloride and highly toxic solvent chloroform in this synthesi

Method used

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  • Synthesis method of lornoxicam intermediate 5-chloro-3-methylsulfonamide thiophene-2-carboxylic acid methyl ester
  • Synthesis method of lornoxicam intermediate 5-chloro-3-methylsulfonamide thiophene-2-carboxylic acid methyl ester
  • Synthesis method of lornoxicam intermediate 5-chloro-3-methylsulfonamide thiophene-2-carboxylic acid methyl ester

Examples

Experimental program
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Effect test

Embodiment 1

[0042] Under the protection of nitrogen, add 250ml of dichloromethane and 50.0g of 5-chloro-3-methylsulfonamide thiophene-2-carboxylic acid into a 100mL four-necked bottle, and add N,N-dimethylformaldehyde at a temperature of 0-5°C Amide 14.0g, temperature control 0-5°C, add 46.5g of thionyl chloride dropwise, after the dropwise addition, slowly raise the temperature to 45°C and reflux, keep warm and reflux for 4 hours, control the temperature at 45-50°C, add dropwise 150ml of methanol, and then 50ml of triethylamine was added to continue the incubation and reflux reaction for 4 hours.

[0043] After the solvent was removed under reduced pressure at a temperature of 30-35°C, the crude product of methyl 5-chloro-3-methylsulfonamide thiophene-2-carboxylate was obtained, which was transferred to 5-chloro-3-methylsulfonamide thiophene-2-carboxylate Add 150ml of methanol to the crude methyl ester and heat up to 50°C until the system is completely dissolved. After 1 hour of heat pre...

Embodiment 2

[0045] Under the protection of nitrogen, add 250ml of dichloromethane and 50.0g of 5-chloro-3-methylsulfonamide thiophene-2-carboxylic acid into a 100mL four-necked bottle, and add N,N-dimethylformaldehyde at a temperature of 0-5°C Amide 14.1g, temperature control 0-5°C, add 69.8g of thionyl chloride dropwise, after the dropwise addition, slowly raise the temperature to 50°C and reflux, keep warm and reflux for 2 hours, control the temperature at 45-50°C, add dropwise 150ml of methanol, and then 50ml of triethylamine was added to continue the incubation and reflux reaction for 2 hours.

[0046]After the solvent was removed under reduced pressure at a temperature of 30-35°C, the crude product of methyl 5-chloro-3-methylsulfonamidethiophene-2-carboxylate was obtained, which was transferred to 5-chloro-3-methylsulfonamidethiophene-2-carboxylate Add 150ml of methanol to the crude methyl ester and raise the temperature to 40°C until the system is completely dissolved. After 1 hour ...

Embodiment 3

[0048] Under nitrogen protection, add 250ml of dichloromethane and 50.0g of 5-chloro-3-methylsulfonamide thiophene-2-carboxylic acid into a 100mL four-necked bottle, and add N,N-dimethylformaldehyde at a temperature of 0-5°C Amide 14.2g, temperature control 0-5°C, add 46.7g of thionyl chloride dropwise, after the dropwise addition, slowly raise the temperature to 48°C to reflux, keep warm and reflux for 4 hours, control the temperature to 45-50°C, add dropwise 150ml of methanol, and then Add 75ml triethylamine and continue to insulate and reflux the reaction for 6 hours.

[0049] After the solvent was removed under reduced pressure at a temperature of 30-35°C, the crude product of methyl 5-chloro-3-methylsulfonamidethiophene-2-carboxylate was obtained, which was transferred to 5-chloro-3-methylsulfonamidethiophene-2-carboxylate Add 150ml of methanol to the crude methyl ester and raise the temperature to 60°C until the system is completely dissolved. After 1 hour of heat preser...

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthetic method of a lornoxicam intermediate 5-chloro-3-methyl sulfonamide thiophene-2-carboxylic acid methyl ester. The method comprises the following steps: by taking 5-chloro-3-methyl sulfonamide thiophene-2-carboxylic acid as an initial raw material, dichloromethane as a solvent, N,N-dimethylformamide as a catalyst and thionyl chloride as a chlorination reagent, reacting to generate an acyl chloride active intermediate, then adding triethylamine and methanol, and reacting to generate the 5-chloro-3-methyl sulfonamide thiophene-2-carboxylic acid methyl ester. According to the method, thionyl chloride is used as the chlorination reagent, so that the use of phosphorus pentachloride which is a phosphorus-containing reagent in the traditional process is avoided, and the process is more environment-friendly; meanwhile, dichloromethane is used as a solvent instead of high-toxicity chloroform, so that the pollution of the process to the environment is further reduced.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of lornoxicam intermediate 5-chloro-3-methylsulfonamide thiophene-2-carboxylate. Background technique [0002] Lornoxicam, whose chemical name is 6-chloro-4-hydroxy-2-methyl-3-(2-pyridinecarbamoyl)-2H-thieno[2,3-e]-1 ,2-thiazine-1,1-dioxide, the molecular formula is C 13 h 10 ClN 3 o 4 S 2 , with a molecular weight of 371.82, is the chloride of tenoxicam, its effect is similar to that of tenoxicam, it has analgesic, anti-inflammatory and antipyretic effects, it can selectively inhibit COX-2, and its strength is slightly stronger than that of tenoxicam Weak, activates the opioid neuropeptide system and exerts central analgesic effect. The antipyretic effect of this product is weak, and the required dose is 10 times the anti-inflammatory dose; oral absorption is slow, and the peak plasma concentration is reached within 24 hours; food ...

Claims

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Application Information

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IPC IPC(8): C07D333/38
CPCC07D333/38
Inventor 李洁赵庆勇邢冬野韩延功崔娅丽王立茹刘洪亮刘畅李莉唐金钢
Owner BEIJING JINCHENG TAIER PHARMA CO LTD
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