A kind of refining purification method of pranlukast intermediate phenbutoxybenzoic acid

A technology of phenbutoxybenzoic acid and phenbutoxybenzoic acid, which is applied in the refining of pharmaceutical intermediates and the refining of chemical drug prankast intermediates, can solve the problem that the purity of prankast cannot meet the quality standard requirements, etc. problem, to achieve the effect of low price, high quality and easy operation

Active Publication Date: 2015-12-23
CHONGQING SHENGHUAXI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] This impurity will always participate in subsequent chemical reactions until it enters the final product Pranlukast, resulting in the purity of Pranlukast failing to meet the quality standard requirements

Method used

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  • A kind of refining purification method of pranlukast intermediate phenbutoxybenzoic acid
  • A kind of refining purification method of pranlukast intermediate phenbutoxybenzoic acid
  • A kind of refining purification method of pranlukast intermediate phenbutoxybenzoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] In the three-necked flask, add 50g of crude phenylbutoxybenzoic acid (the impurity content of dicarboxylic acid is 0.8%) and 500ml of ethanol in turn, heat up to 50°C under stirring to dissolve, add 30.4g of potassium hydroxide aqueous solution (10.4g of potassium hydroxide Dissolved in 20ml of water), slowly cooled to below 20°C, and crystals were precipitated. After suction filtration, about 5 g of the filter cake was dried, and the HPLC spectrum showed that the dicarboxylic acid impurity content was 8.5%.

[0034] The mother liquor is distilled to recover ethanol, and 500ml of water is added to the concentrate to dissolve it. Cool to 5~10°C, adjust PH=1.45 with concentrated hydrochloric acid, and precipitate crystals. Suction filtration, drying the filter cake to obtain 44.2 g of the product. The HPLC content is 99.7%, and the dicarboxylic acid impurity amount is 0.09%. The refined yield is 88.4%.

Embodiment 2

[0036] In the three-necked flask, add 50g of crude phenylbutoxybenzoic acid (the impurity content of dicarboxylic acid is 0.28%) and 1000ml of methanol in sequence, heat up to 30°C under stirring to dissolve, add 19g of 25% ammonia water, cool to below 20°C to precipitate crystals . Suction filtration, about 6g of the filter cake after drying, HPLC spectrum shows wherein dicarboxylic acid impurity content is 2.4%.

[0037] Distill the mother liquor to recover methanol, add 500ml of water to the concentrate to dissolve it, adjust the pH to 3.82 with acetic acid, and precipitate crystals. After suction filtration, the filter cake was dried to obtain 43.1 g of the product, the HPLC content was 99.6%, the dicarboxylic acid impurity content was 0.05%, and the refined yield was 86.2%.

Embodiment 3

[0039] In the three-necked flask, add 50g of crude phenylbutoxybenzoic acid (the impurity content of dicarboxylic acid is 0.28%) and 500ml of n-butanol in sequence, heat up to 70°C under stirring to dissolve, add 31.5g of 20% methanolic ammonia solution, and cool to precipitate crystals. After suction filtration, the filter cake was about 4.2g after drying, and the HPLC spectrum showed that the dicarboxylic acid impurity content was 4.5%.

[0040] Distill the mother liquor to recover the solvent, add 500ml of water to the concentrate to dissolve it, adjust the pH to 1.74 with concentrated hydrochloric acid, and precipitate crystals. After suction filtration, the filter cake was dried to obtain 45.6 g of the product, the HPLC content was 99.6%, the dicarboxylic acid impurity content was 0.04%, and the refined yield was 91.2%.

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Abstract

A method for refining and purifying pranlukast intermediate phenbutoxybenzoic acid, the method comprising the following steps: (1) Salt-forming reaction: adding an appropriate amount of protic or aprotic phenbutoxybenzoic acid crude product (substrate) Add a certain amount of aqueous or alcoholic solution of inorganic base or organic base and stir to fully form a salt with phenylbutoxybenzoic acid; (2) Post-process the salt-forming solution to precipitate High-purity phenbutoxybenzoic acid crystals: filter out the impurity-dicarboxylate solids precipitated in the salt-forming solution, distill and concentrate the filtrate, add an appropriate amount of water to the concentrate to form a homogeneous aqueous solution, and then acidify to precipitate crystals. The high-purity phenbutoxybenzoic acid product is obtained by filtration, which has high purity and high yield.

Description

technical field [0001] The invention relates to a method for refining a pharmaceutical intermediate, in particular to a method for refining a chemical drug pranlukast intermediate, and belongs to the fields of medicine and chemical industry. Background technique [0002] The Chinese chemical name of Pranlukast is: 4-oxo-8-(4-(4-phenylbutoxy)benzoyl)-2-(tetrazol-5-yl)-4H-1-benzoyl Pyran; its English chemical name is: 4-oxo-8-(4-(4-phenylbutoxy)benzoylamino)-2-(tetrazl-5-y1)-4H-1-benzopyran. [0003] [0004] Pranlukast was first created by Ono Company in Japan. It was approved by the Japanese Ministry of Health and Welfare in March 1995. In June of the same year, it was first listed in Japan for the treatment of asthma. The trade name is Onon. Onon Company claims that it is the world's first leukotriene receptor Conditioner. In 1996, Pranlukast was registered in Europe and the United States. It is clinically effective not only for atopic asthma, but also for mixed, infec...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C65/24C07C51/42
CPCC07C51/43C07C51/44C07C51/487C07C65/24
Inventor 姜维平周艳婷
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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