New preparation method of Pranlukast

A reaction formula, the technology of phenylbutoxyl, which is applied in the field of medicine, can solve the problems of unreported starting material synthesis method, unfavorable operation and safe production, and many reaction steps in the synthesis process, and achieve novel routes, simple equipment, and advanced technology. easy effect

Inactive Publication Date: 2017-04-26
上海微巨实业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis process has many reaction steps and needs to react with hydrazine at low temperature, which is expensive and complicated to operate.
Using hydrogen sulfide gas is also not conducive to operation and safe production
Simultaneously no synthetic method of starting material was reported

Method used

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  • New preparation method of Pranlukast
  • New preparation method of Pranlukast
  • New preparation method of Pranlukast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1: the preparation (I) of 3-acetamido-4-acetoxybenzenesulfonic acid

[0059] Take 2-aminophenol-4-sulfonic acid (189g), acetic anhydride (224g), methanol 400g, concentrated sulfuric acid 10ml, reflux reaction for 4h. After the reaction, recover methanol under reduced pressure, cool to room temperature, add The saturated sodium bicarbonate solution was adjusted to pH 9-10, extracted with 400 ml of ethyl acetate, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, and the solvent was recovered under reduced pressure to obtain 264 g of light yellow solid with a yield of 97%.

Embodiment 2

[0060] Example 2: Synthesis of 3-amino-2-hydroxyacetophenone.

[0061] Take 136 g of 3-acetamido-4-acetoxybenzenesulfonic acid, dissolve it in 300 ml of nitrobenzene, add 133 g of anhydrous aluminum trichloride, heat and reflux for 5 h, and recover most of the solvent under reduced pressure after the reaction is completed. Cool to room temperature, under ice bath, slowly add the reaction solution into 30% dilute hydrochloric acid, stir at room temperature for 2 hours, slowly raise the temperature to reflux, react for 4 hours, after the reaction, cool the reaction solution to room temperature, add 20% hydrogen hydroxide to the reaction system Sodium solution adjusts pH 9-10. Add 300 ml of chloroform for extraction, wash with water until neutral, dry over anhydrous sodium sulfate, filter, and recover the filtrate under reduced pressure. The residue is recrystallized with petroleum ether: ethyl acetate = 1:3 to obtain 65.7 g of a light yellow solid, with a yield of 87%.

Embodiment 3

[0062] Example 3: Preparation of 2-acetyl-6-[4-(4-phenylbutoxy)benzamido]phenol (III)

[0063] Take 270 g of 4-(phenylbutoxy)benzoic acid, add 270 g of thionyl chloride, and keep warm at 50°C for 3 hours. After the reaction, unreacted thionyl chloride is recovered under reduced pressure. The thionyl chloride was purged with nitrogen gas. Cool to room temperature and add 270g of dichloromethane for later use. Weigh 151g of 3-amino-2-hydroxyacetophenone and dissolve it in 200g of dichloromethane, add 160g of pyridine, add dropwise the dichloromethane solution of 4-(phenylbutoxy)benzoyl chloride under ice-cooling, the dropwise addition process The medium temperature does not exceed 10°C. After the dropwise addition is completed, keep the temperature at 10°C for 2 hours. After the reaction, add dilute hydrochloric acid to the reaction system, adjust the pH to 2-3, separate the liquids, and wash the dichloromethane layer with water until it is neutral and anhydrous. It was dried ...

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Abstract

The invention provides a new preparation method of drug Pranlukast for treating asthma. The new preparation method includes the specific steps that with 2-aminophenol-4-sulfonic acid as a starting material, a key intermediate 3-amino-2-hydroxyacetophenone is prepared by means of acylation, Fries rearrangement and deprotection, then reacts with 4-(phenylbutoxy)benzoic acid, and then is subjected to condensation with ethyl 1H-tetrazole-5-acetate, and finally preparation is achieved through ring closing under the acidic condition. Compared with the prior art, the raw material used for the new preparation method is low in price and easy to obtain, industrialization of a process can be achieved easily, and the obtained final product is high in purity; and no dangerous process exists, equipment is simple, and the route is novel.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a new preparation method of pranlukast. Background technique [0002] Pranlukast (pranlukast, 1), the chemical name is N-[4-oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl]-4- (4-Phenylbutoxy)benzamide is a leukotriene receptor antagonist developed by Japan's Ono Company. It was first launched in Japan in 1995 and is mainly used clinically as an anti-asthma and anti-allergy drug. It has a good curative effect on the prevention and treatment of otitis media, dysmenorrhea and psoriasis; meanwhile, it can obviously improve the cerebral ischemia in animals, and has mild adverse reactions to the central nervous system. [0003] The synthesis of existing pranlukast has the following types: [0004] 1. Patent: WO2005077942 reports that the synthesis of pranlukast uses 3-iodo-2-hydroxyacetophenone as the starting material, condenses with ethyl tetrazole, dehydrates and cyclizes, and then reacts w...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/04
CPCC07D407/04
Inventor 刘辉
Owner 上海微巨实业有限公司
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