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Preparation method of 6-bromoimidazo [1,2-a] pyridine

A 2-a, bromoimidazole technology, which is applied in the synthesis of pharmaceutical intermediates Operinone hydrochloride intermediates, and the field of preparation of 6-bromoimidazo[1,2-a]pyridine, can solve the problems of poor product quality and reaction High temperature, complex post-processing and other problems, to achieve the effect of low cost, simple operation and shortened reaction time

Inactive Publication Date: 2012-03-28
河北九派制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But this reaction has serious defects such as long reaction time, high reaction temperature, high energy consumption, many side reactions, and complicated post-treatment, and the yield is low and the product quality is poor.

Method used

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  • Preparation method of 6-bromoimidazo [1,2-a] pyridine
  • Preparation method of 6-bromoimidazo [1,2-a] pyridine
  • Preparation method of 6-bromoimidazo [1,2-a] pyridine

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Embodiment 1

[0024] Add 400mL of water, 15.5mL of 30-36% concentrated hydrochloric acid, 120g of bromoacetaldehyde diethyl acetal to the reaction flask in sequence, and then stir at room temperature 10-30°C for 2.5 hours to obtain the hydrolyzed product bromoacetaldehyde; then in the hydrolyzate 72.8g of sodium bicarbonate and 85g of 2-amino-5-bromopyridine were added to the mixture, and after reacting at room temperature for 18 hours, the static phase was separated into an aqueous phase and an organic phase; wherein the aqueous phase was extracted with ethyl acetate, and the extract was combined with the static After phase separation, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated to dryness, and then the concentrated oil phase was recrystallized with petroleum ether to obtain 50 g of light yellow needle crystals of the present invention.

Embodiment 2

[0025] Embodiment 2: the difference between this embodiment and embodiment 1 is that

[0026] Add 400mL of water, 18.5mL of 30-36% concentrated hydrochloric acid, 120g of bromoacetaldehyde diethyl acetal to the reaction flask in sequence, and then stir at room temperature 25°C for 2.5 hours to obtain the hydrolyzed product bromoacetaldehyde; then add 82.8g of potassium bicarbonate and 95g of 2-amino-5-bromopyridine were reacted at room temperature for 18 hours and left to stand for phase separation, wherein the aqueous phase was extracted with ethyl acetate, after the extract was combined with the organic phase after standing for phase separation, Dry with anhydrous sodium sulfate, filter, concentrate to dryness, and recrystallize the concentrated oil phase with petroleum ether to obtain 55 g of light yellow needle crystals of the present invention.

Embodiment 3

[0027] Embodiment 3: the difference between this embodiment and embodiment 1 is,

[0028] Add 400mL of water, 15.5mL of 30-36% concentrated hydrochloric acid, and 120g of bromoacetaldehyde diethyl acetal to the reaction flask in sequence, and then stir at room temperature 25°C for 2.5 hours to obtain the hydrolyzed product bromoacetaldehyde; then add 72.8g of sodium bicarbonate and 85g of 2-amino-5-bromopyridine were reacted at room temperature for 18 hours and allowed to stand for phase separation, wherein the aqueous phase was extracted with ethyl acetate, after the extract was combined with the organic phase after standing for phase separation, Dry with anhydrous sodium sulfate, filter, concentrate to dryness, and then recrystallize the concentrated oil phase with isopropyl ether to obtain 50 g of light yellow needle crystals of the present invention.

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Abstract

The invention discloses a preparation method of 6-bromoimidazo [1,2-a] pyridine, which comprises the following steps of: hydrolyzing bromacetal in concentrated hydrochloric acid under the condition of agitation; adding 2-amino-5-bromopyridine into hydrolysate after hydrolysis reaction and statically placing for phase splitting after reaction; adding an aqueous phase into solvent for extraction, merging organic phases, drying, concentrating and recrystallizing to obtain light yellow needle crystals. The method which using the hydrochloric acid to hydrolyze the bromacetal to produce bromoacetaldehyde which further reacts with the 2-amino-5-bromopyridine has the characteristics of low cost, no environmental pollution and the like. Since reaction is conducted at normal temperature and heating is not required, the energy consumption is low, the reaction conditions are moderate, the reaction time is short, the side reaction is less and the yield is 20 percent higher than the yield of the traditional process. The pH is not required to be adjusted for process post treatment, the high-purity and high-content 6-bromoimidazo [1,2-a] pyridine can be obtained through direct recrystallization, compared with the prior art, the content of the 6-bromoimidazo [1,2-a] pyridine can be improved by 10 percent, the used equipment is simple, the operation is simple to conduct, the cost can be decreased by 20 percent and the method is suitable for large-scale industrialized production.

Description

technical field [0001] The invention belongs to pharmaceutical intermediates, in particular to a method for synthesizing an intermediate of Oprinone hydrochloride for treating acute heart failure, that is, a method for preparing 6-bromoimidazo[1,2-a]pyridine. Background technique [0002] Oprinone hydrochloride is a drug for treating acute heart failure, which selectively blocks the specific phosphodiesterase (PDEⅢ) of cyclic adenosine monophosphate, and has the effect of enhancing cardiac contractility and vasodilation. The drug began to be studied abroad in 1982, and clinical trials began in 1986, which proved to be effective for acute heart failure. [0003] The structural formula of Oprinone Hydrochloride is: [0004] [0005] 6-bromoimidazo[1,2-a]pyridine structural formula: [0006] [0007] The commonly used preparation method of 6-bromoimidazo[1,2-a]pyridine is: use n-butanol as solvent, reflux for more than 24 hours, 2-amino-5-bromopyridine and bromoacetalde...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
Inventor 张辑祁振海黄瑞明李培鸿张海燕张国军
Owner 河北九派制药股份有限公司
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