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Industrial preparation method of anti-asthma drug pranlukast intermediate

An intermediate and industrial technology, which is applied in the field of medical chemical drugs, can solve the problems of low total yield, low purity, and poor color of pranlukast, and achieve the effect of good color, high purity, and high yield

Inactive Publication Date: 2020-03-31
CHONGQING SHENGHUAXI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The inventors have found in a large number of practices that the Pranlukast prepared by this route has poor color, low total yield, and low purity, which cannot meet the quality requirements of the preparation for raw materials; Pranlukast was developed and marketed in the form of plain tablets. In order to increase the compliance and safety of patients, very strict requirements were put forward for the color and impurities of pranlukast API (the color is white, and the total impurities are less than 0.1%)
The inventor conducted traceability research on impurities and color, and the inventor found that the main reason for the poor color and low purity of prankast was caused by the dehydration reaction step

Method used

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  • Industrial preparation method of anti-asthma drug pranlukast intermediate

Examples

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Effect test

Embodiment 1

[0020] Example 1 Preparation of Pranlukast intermediate N-(2-cyano-4-oxo-4H-chromen-8-yl)-4-(4-butoxyphenyl)benzamide

[0021] Purification of phosphorus oxychloride: 100 kg of commercially available industrial grade phosphorus oxychloride is added to the distillation tower, and 20 kg of the former fraction is evaporated under normal pressure, leaving 80 kg of phosphorus oxychloride for use.

[0022] Add 400kg of DMF to the dry reaction kettle, cool to 0°C, add 67kg (4 equivalents) of purified phosphorus oxychloride dropwise, control the temperature within 10°C, keep stirring for 30min after dropping, add 4-oxo-8 -[4-(4-butoxyphenyl)benzamide]-4H-chromene-2-carboxamide 50kg, continue to keep warm for 4 hours. Add 1500 kg of ice-brine to another reaction kettle, slowly transfer the reaction solution into ice-brine, the temperature does not exceed 10°C, stir for 30 minutes, press filter, wash the filter cake to neutral, and dry to obtain N-(2-cyanide Base-4-oxo-4H-chromen-8-yl)...

Embodiment 2

[0023] The preparation of embodiment 2 pranlukast intermediate N-(2-cyano-4-oxo-4H-chromen-8-yl)-4-(4-butoxyphenyl)benzamide

[0024] Purification of phosphorus oxychloride: 100 kg of commercially available industrial grade phosphorus oxychloride is added to the distillation tower, and 10 kg of the former fraction is evaporated under normal pressure, leaving 90 kg of phosphorus oxychloride for use.

[0025] Add 400kg of DMF to the dry reaction kettle, cool to 0°C, add 84kg (5 equivalents) of purified phosphorus oxychloride dropwise, control the temperature within 10°C, keep stirring for 30min after dropping, add 4-oxo-8 -[4-(4-butoxyphenyl)benzamide]-4H-chromene-2-carboxamide 50kg, continue to keep warm for 4 hours. Add 1500 kg of ice-brine to another reaction kettle, slowly transfer the reaction solution into ice-brine, the temperature does not exceed 10°C, stir for 30 minutes, press filter, wash the filter cake to neutral, and dry to obtain N-(2-cyanide Base-4-oxo-4H-chrome...

Embodiment 3

[0026] Embodiment 3 Preparation of pranlukast intermediate N-(2-cyano-4-oxo-4H-chromen-8-yl)-4-(4-butoxyphenyl)benzamide

[0027] Purification of phosphorus oxychloride: 100 kg of commercially available industrial grade phosphorus oxychloride is added to the distillation tower, and 20 kg of the former fraction is evaporated under normal pressure, leaving 80 kg of phosphorus oxychloride for use.

[0028] Add 400kg of DMF to the dry reaction kettle, cool to 0°C, add 33.5kg (2 equivalents) of purified phosphorus oxychloride dropwise, control the temperature within 10°C, keep stirring for 30min after dropping, add 4-oxo- 50kg of 8-[4-(4-butoxyphenyl)benzamide]-4H-chromene-2-carboxamide was kept for 4 hours of heat preservation reaction. Add 1500 kg of ice-brine to another reaction kettle, slowly transfer the reaction solution into ice-brine, the temperature does not exceed 10°C, stir for 30 minutes, press filter, wash the filter cake to neutral, and dry to obtain N-(2-cyanide Bas...

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Abstract

The invention discloses a preparation method of a pranlukast intermediate N-(2-cyano-4-oxo-4H-chromene-8-yl)-4-(4-butoxyphenyl)benzamide (short for formula I), specifically a method for preparing N-(2-cyano-4-oxo-4H-chromene-8-yl)-4-(4-butoxyphenyl)benzamide by carrying out a dewatering reaction on 4-oxo-8-[4-(4-butoxyphenyl)benzamide]-4H-chromene-2-formamide (short for formula II). The preparation method of the pranlukast intermediate represented by the formula I is high in yield, good in product color, high in product purity and beneficial to industrial production.

Description

technical field [0001] The invention relates to the technical field of medical chemicals, and in particular to an industrial preparation method of a pranlukast intermediate. Background technique [0002] Asthma is a chronic respiratory disease, listed by the World Health Organization as one of the four major chronic diseases. Among the categories of asthma medicines, the market share of leukotriene receptor antagonists grew the fastest. Pranlukast (Pranlukast) was developed by Japan Ono Company, it only selectively inhibits leukotriene receptors, has almost no effect on arachidonic acid metabolizing enzymes, and has no antagonistic effect on acetylcholine, serotonin, etc.; in clinical In application, it has a good therapeutic effect on atopic asthma and other types of bronchial asthma, and has a huge market prospect. It is one of the three major leukotriene receptor antagonists (LTRAs). [0003] There are many preparation methods for pranlukast, the most classic and most s...

Claims

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Application Information

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IPC IPC(8): C07D311/24
CPCC07D311/24
Inventor 刘军向琨
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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