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The synthetic method of pantoprazole intermediate 4-difluoromethoxyacetanilide

A technique for the synthesis of difluoromethoxyacetanilide and its synthesis method, which is applied in the field of synthesis of pantoprazole intermediate 4-difluoromethoxyacetanilide, and can solve the problems of cumbersome operation process, solvent toxicity and expensive raw material cost , to achieve the effect of simple process operation, increased solubility and low cost

Active Publication Date: 2014-10-08
JIANGSU YUXIANG CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The process uses more expensive isopropanol, which is more expensive
[0008] In summary, there are various defects in the various existing synthetic methods, or the yield is low, or the cost of raw materials is relatively expensive, or the operation process is cumbersome, the solvent used is highly toxic, and the product quality is poor.
The existing technical routes need to be improved in terms of environmental friendliness and cost

Method used

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  • The synthetic method of pantoprazole intermediate 4-difluoromethoxyacetanilide
  • The synthetic method of pantoprazole intermediate 4-difluoromethoxyacetanilide
  • The synthetic method of pantoprazole intermediate 4-difluoromethoxyacetanilide

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Embodiment 1

[0020] In the autoclave, add 400g of water, 30.2g of paracetamol, 16g of sodium hydroxide and 1.5g of PEG400, and stir well. After the system was sealed, chlorodifluoromethane was introduced to react at 20° C. for 24 h under a reaction pressure of 0.5 MPa. After the reaction, the reaction liquid was filtered, and the filter cake was washed with 5% (weight fraction) NaOH solution alkali and then washed with water until neutral to obtain a crude product. The crude product was purified by 50% acetic acid aqueous solution (volume fraction) at 80°C to obtain 26.2 g of 4-difluoromethoxyacetanilide as a solid, with a yield of 65% and a melting point of 114-116°C.

Embodiment 2

[0022] In the autoclave, add 400g of water, 30.2g of paracetamol, 16g of sodium hydroxide and 1.5g of PEG400, and stir well. After sealing the system, pass through chlorodifluoromethane, and react at 80° C. for 2 h under the reaction pressure of 2.0 MPa. After the reaction, the reaction liquid was filtered, and the filter cake was washed with 5% (weight fraction) NaOH solution alkali and then washed with water until neutral to obtain a crude product. The crude product was purified by 50% acetic acid aqueous solution (volume fraction) at 80°C to obtain 29.8 g of 4-difluoromethoxyacetanilide as a solid, with a yield of 74% and a melting point of 114-116°C.

Embodiment 3

[0024] In the autoclave, add 400g of water, 30.2g of paracetamol, 16g of sodium hydroxide and 1.5g of PEG400, and stir well. After the system was sealed, chlorodifluoromethane was introduced to react at 40° C. for 12 hours under a reaction pressure of 1.0 MPa. After the reaction, the reaction liquid was filtered, and the filter cake was washed with 5% (weight fraction) NaOH solution alkali and then washed with water until neutral to obtain a crude product. The crude product was purified by 50% acetic acid aqueous solution (volume fraction) at 80°C to obtain 32.2 g of 4-difluoromethoxyacetanilide as a solid, with a yield of 80% and a melting point of 114-116°C.

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Abstract

The invention relates to a method for synthesis of a pantoprazole intermediate 4-difluoromethoxyacetanilide. The method is characterized in that based on a high-pressure enclosing technology, acetaminophen as a raw material and chlorodifluoromethane undergo a fluorine etherification reaction in an enclosed high-pressure kettle in the presence of water as a reaction solvent to produce the pantoprazole intermediate 4-difluoromethoxyacetanilide. The method greatly improves solubility of the raw material in the reaction solvent, utilizes insolubility of products in water, promotes reaction development towards product generation, utilizes water as a solvent, is environmentally friendly and has a low cost. Under high pressure, chlorodifluoromethane can greatly improve solubility in the reaction solvent so that a liquid phase is formed, improve a reactant concentration and a reaction rate, and promote reaction development. The method has simple processes and a total yield above 80%.

Description

technical field [0001] The invention relates to a method for synthesizing pantoprazole intermediate 4-difluoromethoxyacetanilide. Background technique [0002] 4-Difluoromethoxyacetanilide, the molecular formula is as follows: [0003] [0004] 4-Difluoromethoxyacetanilide is an important intermediate of pantoprazole. Pantoprazole is a proton pump inhibitor drug developed by Germany's Byk Gulden Company, mainly for the treatment of duodenal and gastric ulcers and for the relief of severe reflux esophagitis. An important side chain intermediate of pantoprazole is 2-mercapto-5-difluoromethoxybenzimidazole, and bibliographical reports mainly contain two kinds of synthetic methods of 2-mercapto-5-difluoromethoxybenzimidazole: The phenol method and the paracetamol method. [0005] The phenol method (US 4560693) uses phenol as a raw material to obtain 2-mercapto-5-difluoromethoxybenzimidazole through 8 steps of etherification, nitration, reduction, acetylation, nitration, hy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/25C07C231/12
Inventor 张治国李清龙程云涛程红伟
Owner JIANGSU YUXIANG CHEM